RU2832167C2 - Methods of treating and preventing alzheimer's disease - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention relates to biotechnology, in particular to a method for reducing clinical deterioration in a subject with Alzheimer's disease at an early stage, comprising administering a composition comprising a therapeutically effective amount of an antibody to protofibrils Ab to a subject, wherein the composition is administered in dose of 10 mg/kg of the Ab protofibril antibody in relation to the weight of the subject once every two weeks, and also wherein the subject is ApoE4-positive.

EFFECT: invention provides effective treatment of progression and/or prevention of Alzheimer's disease (AD).

25 cl, 82 dwg, 26 tbl, 5 ex

Description

[1] This application claims the benefit of priority based on U.S. Provisional Patent Application No. 62/702,659, filed July 24, 2018; U.S. Provisional Patent Application No. 62/749,614, filed October 23, 2018; U.S. Provisional Patent Application No. 62/824,162, filed March 26, 2019; U.S. Provisional Patent Application No. 62/846,902, filed May 13, 2019; and U.S. Provisional Patent Application No. 62/874,684, filed July 16, 2019, the entire contents of each of which are incorporated herein by reference.

[2] Alzheimer's disease (AD) is a progressive neurodegenerative disorder of unknown etiology and the most common form of dementia among older adults. In 2006, there were 26.6 million cases of AD worldwide (range: 11.4–59.4 million) (Brookmeyer, R.,et al., Forecasting the global burden of Alzheimer's Disease. Alzheimer's Dementia.2007; 3:186-91), with more than 5 million people in the United States reported to be living with AD (Alzheimer's Association. Alzheimer's Association report. 2010 Alzheimer's disease facts and figures.Alzheimer's Dementia.2010; 6:158-94). By 2050, the prevalence of AD is projected to increase to 106.8 million cases worldwide (range: 47.2-221.2 million), while in the United States alone the prevalence is estimated to be 11-16 million cases. (Brookmeyer, see above, and 2010 Alzheimer's disease facts and figures, see above).

[3] The disease typically involves global cognitive decline that progresses slowly, leaving patients bedridden in the final stages of the disease. Survival of patients with AD is typically only 3 to 10 years after symptom onset, although extreme values of 2 and 20 years have been reported. (Hebert, LE, et al. , Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003; 60:1119–1122.) AD is the seventh leading cause of all deaths in the United States and the fifth leading cause of death among Americans over age 65, although AD mortality is greatly underestimated because death certificates rarely list AD as the cause of death. (Alzheimer's Association. Alzheimer's Association report. 2010 Alzheimer's disease facts and figures. Alzheimer's Dement. 2010; 6:158-94)

[4] AD represents a significant economic burden in industrialized countries, with significant impacts on health care systems and government budgets, as well as on patients and their families. In the United States alone, total costs for 2010 were estimated at $172 billion, including $123 billion for Medicare and Medicaid.

[5] To the best of the present inventors' knowledge, there is currently no cure for AD and no way to slow the progression of the disease. Existing therapeutic agents for the treatment of AD include symptomatic agents such as acetylcholinesterase inhibitors (AChEIs) such as donepezil and N-methyl-D-aspartate (NMDA) receptor antagonists such as memantine. Although these agents can improve the symptoms of AD such as cognitive decline and impairment of activities of daily living and behavior, there are no reports that they alter the progression of the disease. Thus, there is an unmet need for methods to treat the progression and/or prevent AD.

[6] In some embodiments, provided herein is a method for reducing clinical worsening in a subject with early Alzheimer's disease comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the subject is an ApoE4 carrier. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[7] In some embodiments, at least one anti-Aβ protofibril antibody, such as BAN2401, prevents Aβ deposition prior to plaque formation in the brain. In some embodiments, at least one anti-Aβ protofibril antibody, such as BAN2401, reduces the number of protofibrils and existing plaques in the brain. In some embodiments, at least one anti-Aβ protofibril antibody, such as BAN2401, prevents Aβ deposition prior to plaque formation and reduces the number of protofibrils and existing plaques in the brain.

[8] In some embodiments, provided herein is a method of converting an amyloid-positive subject with early Alzheimer's disease into an amyloid-negative subject with early Alzheimer's disease, comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the subject is an ApoE4 carrier. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[9] In some embodiments, provided herein is a method for reducing amyloid levels in the brain of a subject with early Alzheimer's disease, comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the subject is an ApoE4 carrier. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[10] In some embodiments, provided herein is a method for preventing Alzheimer's disease in ApoE4-positive subjects. In some embodiments, the method comprises determining the amyloid level in the subject's brain prior to administration, and administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody if the amyloid level in the subject's brain exceeds a first predetermined level. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

[11] Figure 1 shows the delay in cognitive decline compared with placebo over 18 months, as determined by ADCOMS, for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks.

[12] Figure 2 shows the delay in cognitive decline compared with placebo over 18 months, as measured by ADCOMS, for the BAN2401 10 mg/kg once monthly dose and the BAN2401 10 mg/kg once every two weeks dose.

[13] Figure 3 shows the reduction in cognitive decline compared with placebo over 18 months, as measured by ADCOMS, for BAN2401 10 mg/kg once monthly and BAN2401 10 mg/kg once every two weeks in subjects with mild cognitive impairment moderately likely due to Alzheimer's disease dementia.

[14] Figure 4 shows the delay in cognitive decline compared with placebo over 18 months, as determined by ADCOMS, for the BAN2401 10 mg/kg once monthly dose and the BAN2401 10 mg/kg once every two weeks dose in subjects with mild Alzheimer's disease dementia.

[15] Figure 5 shows the delay in cognitive decline compared with placebo over 18 months, as determined by ADCOMS, for the BAN2401 10 mg/kg once monthly dose and the BAN2401 10 mg/kg once every two weeks dose in ApoE4-positive subjects.

[16] Figure 6 shows the delay in cognitive decline compared with placebo over 18 months, as determined by ADCOMS, for the BAN2401 10 mg/kg once monthly dose and the BAN2401 10 mg/kg once every two weeks dose in ApoE4-negative subjects.

[17] Figure 7 shows the reduction in cognitive decline compared with placebo over 18 months, as measured by ADAS-Cog, for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks.

[18] Figure 8 shows the reduction in cognitive decline compared with placebo over 18 months, as measured by ADAS-Cog, for the BAN2401 10 mg/kg once monthly dose and the BAN2401 10 mg/kg once every two weeks dose.

[19] Figure 9 shows the reduction in cognitive decline compared with placebo over 18 months, as determined by CDR-SB, for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks.

[20] Figure 10 shows the reduction in cognitive decline compared with placebo over 18 months, as measured by CDR-SB, for the BAN2401 10 mg/kg once monthly dose and the BAN2401 10 mg/kg once every two weeks dose.

[21] Figure 11 shows the reduction in brain amyloid levels determined by PET as the overall mean for the cerebral cortex compared to the whole cerebellum reference over 18 months for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks.

[22] Figure 12 shows the reduction in brain amyloid levels, as determined by imaging using brain amyloid Aβ-binding radiotracers and visualized by PET, over 18 months for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks.

[23] Figure 13 shows the conversion of amyloid-positive subjects to amyloid-negative subjects, as determined by visual reading, after 12 and 18 months of treatment for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks.

[24] Figure 14 shows the change in CSF Aβ _1-42 levels over 18 months for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks.

[25] Figure 15 shows the change in total tau protein levels in cerebrospinal fluid over 18 months for the BAN2401 10 mg/kg once monthly dose and the BAN2401 10 mg/kg once every two weeks dose.

[26] Figure 16 shows the delay in cognitive decline compared with placebo over 18 months, as determined by ADCOMS, for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks in ApoE4-positive subjects.

[27] Figure 17 shows the delay in cognitive decline compared with placebo over 18 months, as determined by ADCOMS, for BAN2401 10 mg/kg once monthly and BAN2401 10 mg/kg once every two weeks in ApoE4-positive subjects with mild cognitive impairment with intermediate probability due to Alzheimer's disease.

[28] Figure 18 shows the delay in cognitive decline compared with placebo over 18 months, as determined by ADCOMS, for the BAN2401 10 mg/kg once monthly dose and the BAN2401 10 mg/kg once every two weeks dose in ApoE4-positive subjects with mild Alzheimer's disease dementia.

[29] Figure 19 shows the delay in cognitive decline compared with placebo over 18 months, as measured by ADAS-Cog, for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks in ApoE4-positive subjects.

[30] Figure 20 shows the delay in cognitive decline compared with placebo over 18 months, as assessed by ADAS-Cog, for BAN2401 doses of 10 mg/kg once monthly and 10 mg/kg once every two weeks in ApoE4-positive subjects.

[31] Figure 21 shows the reduction in cognitive decline compared with placebo over 18 months, as measured by ADAS-Cog, for BAN2401 10 mg/kg once monthly and BAN2401 10 mg/kg once every two weeks in ApoE4-positive subjects with mild cognitive impairment with intermediate probability due to Alzheimer's disease.

[32] Figure 22 shows the delay in cognitive decline compared with placebo over 18 months, as measured by ADAS-Cog, for the BAN2401 10 mg/kg once monthly dose and the BAN2401 10 mg/kg once every two weeks dose in ApoE4-positive subjects with mild Alzheimer's disease dementia.

[33] Figure 23 shows the delay in cognitive decline compared with placebo over 18 months, as determined by CDR-SB, for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks in ApoE4-positive subjects.

[34] Figure 24 shows the delay in cognitive decline compared with placebo over 18 months, as determined by CDR-SB, for BAN2401 doses of 10 mg/kg once monthly and 10 mg/kg once every two weeks in ApoE4-positive subjects.

[35] Figure 25 shows the reduction in cognitive decline compared with placebo over 18 months, as determined by CDR-SB, for BAN2401 10 mg/kg once monthly and BAN2401 10 mg/kg once every two weeks in ApoE4-positive subjects with mild cognitive impairment with intermediate probability due to Alzheimer's disease.

[36] Figure 26 shows the delay in cognitive decline compared with placebo over 18 months, as determined by CDR-SB, for the BAN2401 10 mg/kg once monthly dose and the BAN2401 10 mg/kg once every two weeks dose in ApoE4-positive subjects with mild Alzheimer's disease dementia.

[37] Figure 27 shows the reduction in brain amyloid levels, as determined by visual amyloid PET imaging readouts, as an overall mean for the cerebral cortex compared to a reference value for the whole cerebellum over 18 months for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks in ApoE4-positive subjects.

[38] Figure 28 shows the reduction in brain amyloid levels, as determined by imaging using brain amyloid Aβ-binding radiotracers and visualized by PET, over 18 months for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks in ApoE4-positive subjects.

[39] Figure 29 shows the conversion of amyloid-positive ApoE4-positive subjects to amyloid-negative ApoE4-positive subjects after 12 and 18 months of treatment.

[40] Figure 30 shows the change in CSF Aβ _1-42 levels over 18 months for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once every month, 5 mg/kg once every two weeks, 10 mg/kg once every month, and 10 mg/kg once every two weeks in ApoE4-positive subjects.

[41] Figure 31 shows the change in total tau protein levels in cerebrospinal fluid over 18 months for the BAN2401 10 mg/kg once monthly dose and the BAN2401 10 mg/kg once every two weeks dose in ApoE4-positive subjects.

[42] Figure 32 shows the delay in cognitive decline compared with placebo over 18 months, as determined by ADCOMS, for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks in ApoE4-negative subjects.

[43] Figure 33 shows the delay in cognitive decline compared with placebo over 18 months, as determined by ADCOMS, for the BAN2401 10 mg/kg once monthly dose and the BAN2401 10 mg/kg once every two weeks dose in ApoE4-negative subjects with mild cognitive impairment with intermediate probability due to Alzheimer's disease.

[44] Figure 34 shows the delay in cognitive decline compared with placebo over 18 months, as determined by ADCOMS, for the BAN2401 10 mg/kg once monthly dose and the BAN2401 10 mg/kg once every two weeks dose in ApoE4-negative subjects with mild Alzheimer's disease dementia.

[45] Figure 35 shows the delay in cognitive decline compared with placebo over 18 months, as measured by ADAS-Cog, for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks in ApoE4-negative subjects.

[46] Figure 36 shows the delay in cognitive decline compared with placebo over 18 months, as assessed by ADAS-Cog, for BAN2401 doses of 10 mg/kg once monthly and 10 mg/kg once every two weeks in ApoE4-negative subjects.

[47] Figure 37 shows the reduction in cognitive decline compared with placebo over 18 months, as measured by ADAS-Cog, for BAN2401 10 mg/kg once monthly and BAN2401 10 mg/kg once every two weeks in ApoE4-negative subjects with mild cognitive impairment with intermediate probability due to Alzheimer's disease.

[48] Figure 38 shows the delay in cognitive decline compared with placebo over 18 months, as measured by ADAS-Cog, for BAN2401 10 mg/kg once monthly and BAN2401 10 mg/kg once every two weeks in ApoE4-negative subjects with mild Alzheimer's disease dementia.

[49] Figure 39 shows the delay in cognitive decline compared with placebo over 18 months, as determined by CDR-SB, for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks in ApoE4-negative subjects.

[50] Figure 40 shows the delay in cognitive decline compared with placebo over 18 months, as determined by CDR-SB, for BAN2401 doses of 10 mg/kg once monthly and 10 mg/kg once every two weeks in ApoE4-negative subjects.

[51] Figure 41 shows the reduction in cognitive decline compared with placebo over 18 months, as measured by CDR-SB, for BAN2401 10 mg/kg once monthly and BAN2401 10 mg/kg once every two weeks in ApoE4-negative subjects with mild cognitive impairment with intermediate probability due to Alzheimer's disease.

[52] Figure 42 shows the delay in cognitive decline compared with placebo over 18 months, as determined by CDR-SB, for the BAN2401 10 mg/kg once monthly and 10 mg/kg once every two weeks doses in ApoE4-negative subjects with mild Alzheimer's disease dementia.

[53] Figure 43 shows the reduction in brain amyloid levels, as determined by visual amyloid PET imaging readouts, as an overall mean for the cerebral cortex compared to a reference value for the whole cerebellum over 18 months for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks in ApoE4-negative subjects.

[54] Figure 44 shows the reduction in brain amyloid levels, as determined by imaging using brain amyloid Aβ-binding radiotracers and visualized by PET, over 18 months for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks in ApoE4-negative subjects.

[55] Figure 45 shows the conversion of amyloid-positive ApoE4-negative subjects to amyloid-negative ApoE4-negative subjects after 12 and 18 months of treatment.

[56] Figure 46 shows the change in CSF Aβ _1-42 levels over 18 months for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once every month, 5 mg/kg once every two weeks, 10 mg/kg once every month, and 10 mg/kg once every two weeks in ApoE4-negative subjects.

[57] Figure 47 shows the change in total tau protein levels in cerebrospinal fluid over 18 months for the 10 mg/kg once monthly dose and the 10 mg/kg once every two weeks dose in ApoE4-negative subjects.

[58] Figure 48 shows the reduction in cognitive decline compared with placebo at 18 months, as assessed by ADCOMS, ADAS-Cog, or CDR-SB, for the 10 mg/kg BAN2401 dose once every two weeks in ApoE4-positive and ApoE4-negative subjects and for all subjects regardless of genotype.

[59] Figure 49 shows the reduction in cognitive decline compared with placebo at 18 months, as assessed by ADCOMS, ADAS-Cog, or CDR-SB, for a dose of BAN2401 10 mg/kg once every two weeks in subjects with mild cognitive impairment with moderate probability due to Alzheimer's disease dementia or mild Alzheimer's disease dementia and for all subjects regardless of disease type or status.

[60] Figure 50 shows the delay in cognitive decline compared to placebo at 18 months, as measured by ADCOMS, ADAS-Cog, or CDR-SB, for a dose of BAN2401 10 mg/kg once every two weeks in subjects concomitantly administered at least one Alzheimer's disease medication other than BAN2401 and in subjects not concomitantly administered at least one Alzheimer's disease medication other than BAN2401, and for all subjects regardless of whether the subject is concomitantly administered at least one Alzheimer's disease medication other than BAN2401.

[61] Figure 51 shows brain amyloid clearance compared to placebo at 18 months, as determined by PET, for a dose of BAN2401 10 mg/kg every other week in the following subpopulations: ApoE4-positive subjects; ApoE4-negative subjects; subjects with mild cognitive impairment with a moderate probability of being due to Alzheimer's disease dementia; subjects with mild Alzheimer's disease dementia; subjects concomitantly administered at least one Alzheimer's disease treatment other than BAN2401; and subjects not concomitantly administered at least one Alzheimer's disease treatment other than BAN2401.

[62] Figure 52 shows the delay in cognitive decline compared to placebo at 18 months, as determined by ADCOMS, for the 10 mg/kg q2w dose of BAN2401 in the following subpopulations: ApoE4-positive subjects; ApoE4-negative subjects; subjects with mild cognitive impairment with moderate probability due to Alzheimer's disease dementia; subjects with mild Alzheimer's disease dementia; subjects concomitantly receiving at least one Alzheimer's disease treatment other than BAN2401; and subjects not concomitantly receiving at least one Alzheimer's disease treatment other than BAN2401.

[63] Figure 53 shows the change in CSF neurogranin levels at 18 months compared to placebo as a mean for subjects receiving either the 10 mg/kg BAN2401 dose once every two weeks or the 10 mg/kg BAN2401 dose once monthly.

[64] Figure 54 shows the change in CSF phospho-tau protein levels at 18 months compared to placebo as the mean for subjects receiving either the 10 mg/kg BAN2401 dose once every two weeks or the 10 mg/kg BAN2401 dose once per month.

[65] Figure 55 shows the change in CSF neurofilament light chain levels after 18 months compared to placebo as the mean for subjects receiving either the 10 mg/kg BAN2401 dose once every two weeks or the 10 mg/kg BAN2401 dose once monthly.

[66] Figure 56 shows the delay in cognitive decline compared with placebo at 18 months, as assessed by ADCOMS and PET, for the BAN2401 10 mg/kg once every two weeks or the BAN2401 10 mg/kg once monthly dose.

[67] Figure 57 shows the correlation between decreased brain amyloid levels and increased clinical improvement as measured by ADCOMS, ADAS-Cog, and CDR-SB.

[68] Figure 58 shows that ApoE4-positive and ApoE4-negative subjects who did not receive BAN2401 had similar rates of disease progression.

[69] Fig. 59 shows the influence of various factors on disease progression as determined by ADCOMS.

[70] Fig. 60 shows the change in BAN2401 concentration as a function of time following administration of BAN2401 10 mg/kg once monthly and BAN2401 10 mg/kg once every two weeks.

[71] Figure 61 shows that BAN2401 preferentially binds to larger Aβ protofibrils compared to monomers, dimers, and oligomers of Aβ peptides.

[72] Figure 62 shows the proportion of subjects who experienced the ARIA-E event as a function of peak plasma BAN2401 concentration.

[73] Figure 63 shows that BAN2401 administration significantly reduced PET amyloid values at all doses.

[74] Figure 64 shows a schematic outline of the study of early intervention in Alzheimer's disease and its prevention.

[75] Figure 65 shows the adjusted mean change (LSM) in CSF phospho-tau protein from baseline over 18 months compared to placebo for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks.

[76] Figure 66 shows the adjusted mean change (LSM) in CSF neurogranin levels from baseline over 18 months compared with placebo for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks.

[77] Figure 67 shows the adjusted mean change (LSM) in CSF neurofilament light chain levels from baseline over 18 months compared with placebo for BAN2401 doses of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks.

[78] Figure 68 shows the adjusted mean change (LSM) in CSF phospho-tau protein levels from baseline over 18 months compared with placebo for the 10 mg/kg BAN2401 doses combined (10 mg/kg once monthly and 10 mg/kg once every two weeks).

[79] Figure 69 shows the adjusted mean change (LSM) in CSF phospho-tau protein levels from baseline over 18 months compared with placebo for 10 mg/kg BAN2401 doses combined (10 mg/kg once monthly and 10 mg/kg once every two weeks) in ApoE4-positive subjects.

[80] Figure 70 shows the adjusted mean change (LSM) in CSF phospho-tau protein levels from baseline over 18 months compared with placebo for 10 mg/kg BAN2401 doses combined (10 mg/kg once monthly and 10 mg/kg once every two weeks) in ApoE4-negative subjects.

[81] Figure 71 shows the adjusted mean change (LSM) in CSF neurogranin levels from baseline over 18 months compared with placebo for the combined 10 mg/kg BAN2401 doses (10 mg/kg once monthly and 10 mg/kg once every two weeks).

[82] Figure 72 shows the adjusted mean change (LSM) in CSF neurogranin levels from baseline over 18 months compared with placebo for 10 mg/kg BAN2401 doses combined (10 mg/kg once monthly and 10 mg/kg once every two weeks) in ApoE4-positive subjects.

[83] Figure 73 shows the adjusted mean change (LSM) in CSF neurogranin levels from baseline over 18 months compared with placebo for BAN2401 10 mg/kg doses combined (10 mg/kg once monthly and 10 mg/kg once every two weeks) in ApoE4-negative subjects.

[84] Figure 74 shows the adjusted mean change (LSM) in CSF neurofilament light chain levels from baseline over 18 months compared with placebo for the 10 mg/kg BAN2401 doses combined (10 mg/kg once monthly and 10 mg/kg once every two weeks).

[85] Figure 75 shows the adjusted mean change (LSM) in CSF neurofilament light chain levels from baseline over 18 months compared to placebo for 10 mg/kg BAN2401 doses combined (10 mg/kg once monthly and 10 mg/kg once every two weeks) in ApoE4-positive subjects.

[86] Figure 76 shows the adjusted mean change (LSM) in CSF neurofilament light chain levels from baseline over 18 months compared with placebo for 10 mg/kg BAN2401 doses combined (10 mg/kg once monthly and 10 mg/kg once every two weeks) in ApoE4-negative subjects.

[87] Figure 77 shows the correlation between change in PET standardized uptake value (normalized to whole cerebellar mask) from baseline and ADCOMS-measured cognitive outcome at 12 and 18 months for placebo and BAN2401 doses of 2.5 mg/kg q2w, 5 mg/kg q2m, 5 mg/kg q2w, 10 mg/kg q2m, and 10 mg/kg q2w.

[88] Figure 78 shows the correlation between change in PET standardized uptake value (normalized to whole cerebellar mask) from baseline and cognitive outcome as measured by CDR-SB at 12 and 18 months for placebo and BAN2401 doses of 2.5 mg/kg q2w, 5 mg/kg q2m, 5 mg/kg q2w, 10 mg/kg q2m, and 10 mg/kg q2w.

[89] Figure 79 shows the correlation between change from baseline in PET standardized uptake value (normalized to whole cerebellar mask) and ADAS-Cog cognitive outcome at 12 and 18 months for placebo and BAN2401 doses of 2.5 mg/kg q2w, 5 mg/kg q2m, 5 mg/kg q2w, 10 mg/kg q2w, and 10 mg/kg q2w.

[90] Figure 80 shows the correlation between change in PET standardized uptake value (normalized to subcortical white matter) from baseline and ADCOMS-measured cognitive outcome at 12 and 18 months for placebo and BAN2401 doses of 2.5 mg/kg q2w, 5 mg/kg q2m, 5 mg/kg q2w, 10 mg/kg q2m, and 10 mg/kg q2w.

[91] Figure 81 shows the correlation between change in PET standardized uptake value (normalized to subcortical white matter) from baseline and cognitive outcome as measured by CDR-SB at 12 and 18 months for placebo and BAN2401 doses of 2.5 mg/kg q2w, 5 mg/kg q2m, 5 mg/kg q2w, 10 mg/kg q2m, and 10 mg/kg q2w.

[92] Figure 82 shows the correlation between change in PET standardized uptake value (normalized to subcortical white matter) from baseline and cognitive outcome as measured by ADAS-Cog at 12 and 18 months for placebo and BAN2401 doses of 2.5 mg/kg q2w, 5 mg/kg q2m, 5 mg/kg q2w, 10 mg/kg q2m, and 10 mg/kg q2w.

"Amyloid hypothesis"

[93] The "amyloid hypothesis" proposes that β-amyloid peptides (Aβ) play a central role in the pathogenesis of AD. Specifically, it is hypothesized that neurodegeneration in AD may be caused by the deposition of Aβ plaques in brain tissue due to an imbalance between Aβ production and Aβ clearance, leading to the formation of neurofibrillary tangles containing tau protein. Aβ peptides typically exist in a dynamic continuum of conformational states such that compounds tend to transform from monomeric Aβ to soluble Aβ aggregates, which include a spectrum from low molecular weight oligomers to higher molecular weight protofibrils and finally to insoluble fibrils (plaques). A number of immunotherapies have been developed with the aim of reducing the amount of insoluble Aβ fibrils deposited in the brain. However, a simple correlation between the amount and progressive accumulation of insoluble amyloid plaques and the clinical course of AD has not been established. While therapeutic strategies continue to focus on removing insoluble amyloid plaques, an additional therapeutic approach may involve reducing the amount of toxic Aβ aggregates, such as protofibrils, that may contribute to the neuronal degeneration characteristic of AD. (See, e.g. Dodort, J.-C. and May, P., "Overview on rodent models of Alzheimer's disease." Curr. Protocols Neurosci.2005; 9.22-1-9.22-6; Englund, H. et al., "Sensitive ELISA detection of amyloid-β protofibrils in biological samples." J. Neurochem. 2007; 103:334-45; and Gotz, J. et al., "Transgenic animal models of Alzheimer's disease and related disorders: histopathology, behavior and therapy." Mol. Psychiat.2004; 9:664-83)

[94] It was hypothesized that BAN2401 and other anti-Aβ protofibril antibodies could be used to slow the progression of AD in subjects early in the disease, where amyloid has already been deposited in the brain, but where the subsequent neurodegenerative cascade hypothesized to be triggered by amyloid deposition is still at a relatively early stage in its course (i.e., limited brain tissue loss has occurred and the associated clinical deficits are minimal). As disclosed herein, using BAN2401 as an exemplary anti-Aβ protofibril antibody, the present inventors have discovered a novel way to reduce amyloid levels in the brain in amyloid-positive subjects with early-stage AD. In addition, a novel method for converting amyloid-positive early AD subjects to amyloid-negative subjects is disclosed herein, comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. A method for reducing clinical worsening in amyloid-positive early AD subjects is also disclosed herein, comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. As will be discussed, unexpectedly favorable results were achieved when the subjects were ApoE4 positive.

[95] Unexpectedly and unexpectedly, the present inventors have also discovered a method for preventing and/or delaying the onset of AD in subjects with early-stage AD comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the subject is ApoE4 positive. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

Definitions

[96] The following are definitions of terms used in this application.

[97] Noun forms used in this document the only one numbers include reference to plural forms unless the context clearly indicates otherwise.

[98] The phrase " and/or ," as used herein, means "either or both" of the elements so combined, i.e., it means elements that are present together in some instances and present separately in other instances. Thus, as a non-limiting example, "A and/or B," when used in conjunction with open-ended language such as "comprising," may refer in some embodiments to only A (optionally including elements other than B); in other embodiments to only B (optionally including elements other than A); in yet other embodiments to both A and B (optionally including other elements); and so on.

[99] As used herein, the term " at least one " means one or more elements from a list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and not excluding any combination of elements from the list of elements. This definition also recognizes that elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers may optionally be present, whether or not related to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B", or equivalently, "at least one of A and/or B") may refer in one embodiment to at least one, optionally including more than one, of A without the presence of B (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, of B without the presence of A (and optionally including elements other than A); in another embodiment, to at least one, optionally including more than one, A and to at least one, optionally including more than one, B (and optionally including other elements); etc.

[100] When a number is mentioned separately or as part of a numerical range, it should be understood that the numerical value may differ up or down from the specified value with a deviation of 10% from the specified value.

[101] When a range of values is specified in this document, it is intended to cover every value and subrange within that range. For example, "2.5 mg/kg to 10 mg/kg" is intended to cover, for example, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg, 5.5 mg/kg, 6 mg/kg, 6.5 mg/kg, 7 mg/kg, 7.5 mg/kg, 8 mg/kg, 8.5 mg/kg, 9 mg/kg, 9.5 mg/kg, 10 mg/kg, 2.5 mg/kg to 3 mg/kg, 2.5 mg/kg to 4.5 mg/kg, 3 mg/kg to 4.5 mg/kg, 4.5 mg/kg to 8 mg/kg, 2.5 mg/kg to 9 mg/kg, etc.

[102] "AD in early stages" or "early stage Alzheimer's disease", as used herein, represents a continuum of AD severity from mild cognitive impairment, with an intermediate probability of being due to AD, to mild Alzheimer's disease dementia. Subjects with early AD include subjects with mild Alzheimer's disease dementia, as defined herein, and subjects with MCI, with an intermediate probability of being due to AD, as defined herein. In some embodiments, subjects with early AD have an MMSE score of 22 to 30 and a CDR total score in the range of 0.5 to 1.0.

[103] Subjects with " mild Alzheimer's disease dementia ," as used herein, are subjects who meet the NIA-AA core clinical criteria for probable Alzheimer's disease dementia according to McKhann, GM et al., "The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging - Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease." Alzheimer Dement . 2011; 7:263-9. Also included are subjects who have a CDR score of 0.5 to 1.0 and a memory cell score of 0.5 or greater at screening and baseline.

[104] Subjects with "MCI, with intermediate probability due to AD", as used herein, are subjects identified as such according to the NIA-AA core clinical criteria for mild cognitive impairment with intermediate probability due to Alzheimer's disease (see McKhann, above). For example, This refers to subjects with symptomatic Alzheimer's disease but not dementia who have evidence of brain amyloid pathology, making them less heterogeneous and more similar to subjects with mild Alzheimer's dementia in terms of cognitive and functional impairment as measured by the ADCOMS Clinical Total Score as defined herein. Also included are subjects who have a CDR score of 0.5 and a Memory Cell score of 0.5 or higher at screening and baseline. In addition, subjects who report a history of subjective memory impairment with gradual onset and slow progression during the last 1 year before screening, as confirmed by an informant, are also included.

[105] As used herein, the term " MMSE " refers to the Mini-Mental State Examination, a cognitive instrument commonly used for screening purposes but also frequently used for longitudinal measurements in clinical trials of AD, which has a 30-point scale, with higher scores indicating less severe impairment and lower scores indicating more severe impairment. In the context of this document, seven items were assessed, measuring orientation in time and space, perception, memory, attention, language, and drawing. (Folstein, MF et al., "Mini-mental state. A practical method for grading the cognitive state of patients for the clinician." J. Psychiatr. Res. 1975; 12:189-98)

[106] As used in this document, the term " ADAS-Cog " refers to the cognitive subscale of the Alzheimer's Disease Assessment Scale. The ADAS-Cog is a cognitive scale widely used in Alzheimer's disease trials that has a structured scale assessing memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing a letter in an envelope), and constructional praxis (copying geometric patterns). (Rosen, W. G. et al., "A new rating scale for Alzheimer's disease." Am. J. Psychiatry 1984; 141:1356-64.) Also assessed were spoken language, language comprehension, word-finding difficulties, ability to remember test instructions, maze completion, and number crossing. The modified version used in this document uses a score from 0 to 90, with a score of 0 indicating no violation and a score of 90 indicating the most severe violation.

[107] As used in this document, the term " CDR-SB " refers to the Clinical Dementia Rating Scale-Sum of Columns. The CDR is a clinical scale that describes 5 degrees of impairment in each of 6 categories of function, including memory, orientation, reasoning and problem solving, social functioning, household chores and hobbies, and self-care. (Berg, L. et al., "Mild senile dementia of the Alzheimer type: 2. Longitudinal assessment." Ann. Neurol. 1988; 23:477-84.) The impairment ratings obtained for each of the 6 categories of function are combined to form 1 overall CDR dementia scale score (ranging from 0 to 3). The sum of the cells score is an additional measure of change, where each category has a maximum possible score of 3 units, and the total score is the sum of the category scores, giving a total possible score of 0 to 18, with higher scores indicating more severe impairment. The total score can be used as a clinical indicator of the severity of dementia.

[108] As used in this document, the term "ADCOMS" refers to the Alzheimer's Disease Assessment Summary Score, a clinical summary score derived from the analysis of four ADAS-Cog items (delayed word recall, orientation, word recognition, and word-finding difficulties), two MMSE items (temporal orientation and drawing), and all six CDR-SB items (self-care, social functioning, household chores and hobbies, memory, orientation, and reasoning and problem solving), as discussed in the examples and in Wang, J. et al., "ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials."J. Neurol. Neurosurg. Psychiatry.2016; 87:993-999. The ADCOMS scale was designed to be particularly sensitive to disease progression in the early stages of AD, i.e. in the prodromal period and in mild AD.

[109] As used herein, the terms "ApoE4-positive subjects" and "ApoE4 carriers" refer to subjects who carry the ε4 variant of the apolipoprotein gene. The ε4 variant is one of several major alleles of the apolipoprotein gene. This gene is primarily responsible for lipid metabolism. Carriers of the ε4 apolipoprotein have been found to exhibit significantly higher rates of amyloid retention than non-carriers. (Drzezga, A. et al. , "Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease." Neurology . 2009; 72:1487-94.) In some embodiments, the subject is a heterozygous carrier of the ε4 allele of the apolipoprotein E gene. In some embodiments, the subject is a homozygous carrier of the ε4 allele of the apolipoprotein E gene.

[110] In the context of this document, whether a subject with early stage AD is "amyloid positive" or "amyloid negative", is determined based on whether the patient has a positive amyloid burden as indicated by longitudinal PET assessment of amyloid imaging agent uptake in the brain and/or CSF assessment for the presence of amyloid pathology using marker assessments such as Aβ_1-42(soluble CSF biomarker analysis). In some embodiments, qualitative visual reading of PET scan results will be used to determine amyloid-positive and amyloid-negative status by classifying subjects as having "normal" or "abnormal" uptake based on the PET imaging pattern. Interpreters will be trained and certified to recognize PET brain images with abnormal or normal uptake patterns, or amyloid detection is performed using a semi-quantitative or quantitative approach.

[111] As used herein, the term " treat " refers to the production of beneficial or desired results, including, without limitation, a therapeutically beneficial effect, which means the elimination or alleviation of the underlying condition being treated or one or more physiological symptoms associated therewith.

[112] As used herein, the term " prevent " refers to obtaining a favorable or desired result, including, but not limited to, a prophylactically beneficial effect. To achieve a prophylactically beneficial effect, the composition may be administered to a subject at risk of developing Alzheimer's disease, a subject having one or more preclinical symptoms but not clinical symptoms of Alzheimer's disease, or a subject reporting one or more physiological symptoms of Alzheimer's disease, even if a clinical diagnosis of Alzheimer's disease has not been made. As used herein, the term "prevent" may further include a therapeutically beneficial effect, which refers to the elimination or alleviation of the underlying condition being treated or one or more physiological symptoms associated therewith.

[113] Pre-AD biomarker levels that may predict the development of Alzheimer's disease include, but are not limited to, brain amyloid levels, Aβ levels,_1-42in cerebrospinal fluid, total tau protein levels in cerebrospinal fluid, neurogranin levels in cerebrospinal fluid, and neurofilament light chain levels in cerebrospinal fluid. For example, subjects treated with the BACE inhibitor elenbecestat (E2609) who had PET standardized amyloid accumulation values (SUVr values) at baseline between 1.4 and 1.9 were found to have the greatest slowing of cognitive decline during treatment. See Lynch, S. Y. et al. "Elenbecestat, a BACE inhibitor: results from a Phase 2 study in subjects with mild cognitive impairment and mild-to-moderate dementia due to Alzheimer's disease." Poster P4-389, Alzheimer's Association International Conference, July 22-26, 2018, Chicago, IL, USA. Similarly, subjects with baseline florbetapir-PET amyloid SUVr levels below 1.2 were found not to show cognitive decline sufficient to be detected, whereas subjects with SUVr levels above 1.6 appeared to correlate with a plateau effect, in which amyloid levels reached a saturated level and treatment failed to change cognitive performance. See Dhadda, S. et al., "Baseline florbetapir amyloid PET standard update value ratio (SUVr) can predict clinical progression in prodromal Alzheimer's disease (pAD)." Poster P4-291, Alzheimer's Association International Conference, July 22-26, 2018, Chicago, IL, USA.

[114] As used herein, the terms " serious adverse event " or " SAE " mean an event that (1) results in death; (2) is life-threatening; (3) requires hospitalization or prolongation of existing hospitalization; (4) results in persistent or significant disability/incapacity and/or (5) is a congenital anomaly/malformation that occurs following administration of the composition described herein.

[115] The severity of a serious adverse event may be rated according to a uniform scale used in the art. For example, the severity of a serious adverse event in a subject may be rated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events or CTCAE. A description of the various grades of adverse events according to CTCAE is provided below.

- Grade 1 : mild; asymptomatic or with mild symptoms; clinical or diagnostic observations only; intervention not indicated.

- Grade 2 : moderate; minimal, local or non-invasive intervention is indicated; limitation of age-appropriate instrumental activities in everyday life.

- Grade 3 : severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; loss of ability to work; limitation of self-care activities in everyday life.

- Grade 4 : life-threatening consequences; emergency intervention is indicated.

- Grade 5 : death associated with an adverse event.

[116] As used in this document, the term "Elenbecestat" refers to a compound which is N-[3-((4aS,5R,7aS)-2-amino-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl]-5-difluoromethylpyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof. Elenbecestat is an inhibitor of amyloid precursor protein beta-cleaving enzyme 1 (BACE1) (see, for example, US Patent Nos. 8,158,620 and 8,426,584), and it is also known as E2609.

[117] At least one antibody to Aβ protofibrils

[118] In the context of this document, at least one antibody to Aβ protofibrils is selected from monoclonal antibodies (mAbs) that preferentially bind to large soluble oligomers and/or aggregates of amyloid β (Aβ) (also referred to as protofibrils) compared to, for example, Aβ monomers.Cm., for example, Fig. 61. As used in this document, the term "predominantly associated"refers to an antibody that binds to Aβ oligomers and/or protofibrils at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, at least 125-fold, at least 150-fold, at least 175-fold, at least 200-fold, at least 225-fold, at least 250-fold, at least 275-fold, at least 300-fold, at least 325-fold, at least 350-fold, at least 375-fold, at least 400-fold, at least 425-fold, at least 450-fold, at least 475-fold times, at least 500 times, at least 550 times, at least 600 times, at least 650 times, at least 700 times, at least 750 times, at least 800 times, at least 850 times, at least 900 times, at least 950 times, at least 1000 times or at least 1050 times greater activity than its activity in binding other forms of Aβ peptides (e.g. fibrils and monomers, respectively). The binding activity of different forms of Aβ can be determined using a method well known in the art, such as ELISA and surface plasmon resonance (SPR) analysis.

[119] In some embodiments, the selectivity of at least one antibody to Aβ protofibrils is measured using an ELISA assay. In some embodiments, the preferential binding of at least one antibody to Aβ protofibrils is measured using surface plasmon resonance.

[120] In some embodiments, the preferential binding of BAN2401 is measured using an ELISA assay. In some embodiments, the selectivity of BAN2401 is measured using surface plasmon resonance.

[121] For example, BAN2401 was found to bind to Aβ protofibrils with 200-1000-fold greater potency than to Aβ monomers, and that BAN2401 binds to Aβ protofibrils with more than 40-fold greater potency than to Aβ fibrils. This is reported in International Patent Application Publication No. WO 2007/108756 A1, page 13 and Fig. 2; see also Lord, A. et al., "An amyloid-β protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer's disease." 2009; 26: 425–34; and Swanson, C. J. et al. "Pharmacology of BAN2401: A Monoclonal Antibody Selective for Aβ Protofibrils." Poster P4-286, Alzheimer's Association International Conference, July 13–18, 2013. This difference in activity was determined using a sandwich ELISA assay in which BAN2401 was coated onto the wells of a plate and increasing concentrations of the various forms of Aβ were added to the wells.Ibid.Measurement of bound forms of Aβ was performed by adding biotinylated mAb158 and HRP-labeled streptavidin and measuring color development according to the manufacturer's procedure. Similarly, BAN2401 was found to have weak affinity for the N-terminal portion of the Aβ peptide and Aβ monomers, and no binding was observed to the C-terminal fragment of Aβ.Ibid.Affinity was determined using a competitive ELISA assay where an ELISA plate was coated with human Aβ protofibrils and BAN2401 was then incubated with increasing amounts of different forms of Aβ.Ibid.The incubation mixture was added to the wells of a microtiter plate, and free antibody was allowed to bind to the immobilized protofibrils in the well, and the bound BAN2401 antibody was measured using a secondary antibody.Ibid.

[122] In some embodiments, at least one anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 5 (HCDR1), SEQ ID NO: 6 (HCDR2), and SEQ ID NO: 7 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 8 (LCDR1), SEQ ID NO: 9 (LCDR2), and SEQ ID NO: 10 (LCDR3).

[123] The assignment of amino acids to each domain generally follows the definitions in SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST (Kabat et al., ^5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242, 1991, hereinafter referred to as the "Kabat report").

[124] In some embodiments, the at least one anti-Aβ protofibril antibody comprises a human constant region. In some embodiments, the human constant region of the at least one anti-Aβ protofibril antibody comprises a heavy chain constant region selected from IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgE, and any allelic variants thereof disclosed in the report by Kabat. Any one or more of such sequences can be used in the present invention. In some embodiments, the heavy chain constant region is selected from IgG1 and allelic variants thereof. The amino acid sequence of a human IgG1 constant region is known in the art and is set forth as SEQ ID NO: 3.

[125] In some embodiments, the human constant region of the at least one anti-Aβ antibody comprises a light chain constant region selected from the κ/λ chain constant regions and any allelic variants thereof discussed in the Kabat report. Any one or more of such sequences can be used in the present invention. In some embodiments, the light chain constant region is selected from κ and allelic variants thereof. The amino acid sequence of a human κ chain constant region is known in the art and is set forth as SEQ ID NO: 4.

[126] In some embodiments, the at least one anti-Aβ protofibril antibody comprises framework regions of human heavy and light chain variable regions. In some embodiments, the at least one anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the at least one anti-Aβ protofibril antibody comprises a human IgG1 heavy chain constant region and a human Ig kappa light chain constant region. In some embodiments, the at least one anti-Aβ protofibril antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 4.

[127] In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401. BAN2401 is a humanized monoclonal IgG1 variant of mAb158, which is a murine monoclonal antibody generated to target protofibrils and disclosed in WO 2007/108756 and Journal of Alzheimer's Disease 43: 575-588 (2015). BAN2401 is at least one anti-Aβ protofibril antibody that exhibits low affinity for Aβ monomers while binding with high selectivity to compounds that are soluble Aβ aggregates. For example, BAN2401 has been reported to exhibit approximately 1000-fold and 5-fold to 10-fold greater selectivity for soluble Aβ protofibrils than for Aβ monomers or insoluble Aβ fibrils, respectively.

[128] BAN2401 comprises (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 1, and (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 2. The full-length sequence of BAN2401 is provided under SEQ ID NO: 11 and SEQ ID NO: 12 and is described in WO 2007/108756 and in Journal of Alzheimer's Disease 43:575-588 (2015).

[129] Other non-limiting examples of suitable antibodies for use as at least one anti-Aβ protofibril antibody in the present invention include the antibodies disclosed in WO 2002/003911, WO 2005/123775, WO 2007/108756, WO 2011/001366, WO 2011/104696, and WO 2016/005466.

A therapeutically effective amount of at least one antibody to Aβ protofibrils

[130] The methods of the present invention comprise administering to a subject a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils. As used herein, the term "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition sufficient to achieve a desired therapeutic effect.

[131] One of ordinary skill in the art will appreciate that a therapeutically effective amount of at least one anti-Aβ protofibril antibody administered to a subject may depend on a number of factors including the pharmacodynamic characteristics, route of administration, frequency of treatment, and the health, age, and weight of the subject being treated, and will be able to determine an appropriate amount for each subject using the information disclosed herein.

[132] In some embodiments, the therapeutically effective amount is a dose selected to improve efficacy and/or maintain efficacy and improve at least one of safety and tolerability. In some embodiments, the therapeutically effective amount is selected to reduce the intensity of at least one side effect and simultaneously improve efficacy and/or maintain efficacy.

[133] In some embodiments, the subject is administered 0.5 mg/kg to 45 mg/kg, 0.5 mg/kg to 40 mg/kg, 0.5 mg/kg to 35 mg/kg, 0.5 mg/kg to 30 mg/kg, 0.5 mg/kg to 25 mg/kg, 0.5 mg/kg to 20 mg/kg, 0.5 mg/kg to 15 mg/kg, 0.5 mg/kg to 10 mg/kg, 0.5 mg/kg to 5 mg/kg, or 0.5 mg/kg to 2.5 mg/kg of at least one anti-Aβ protofibril antibody based on the subject's body weight.

[134] In some embodiments, the subject is administered 2.5 mg/kg to 45 mg/kg, 2.5 mg/kg to 40 mg/kg, 2.5 mg/kg to 35 mg/kg, 2.5 mg/kg to 30 mg/kg, 2.5 mg/kg to 25 mg/kg, 2.5 mg/kg to 20 mg/kg, 2.5 mg/kg to 15 mg/kg, 2.5 mg/kg to 10 mg/kg, or 2.5 mg/kg to 5 mg/kg of at least one anti-Aβ protofibril antibody based on the subject's body weight.

[135] In some embodiments, the subject is administered 5 mg/kg to 45 mg/kg, 5 mg/kg to 40 mg/kg, 5 mg/kg to 35 mg/kg, 5 mg/kg to 30 mg/kg, 5 mg/kg to 25 mg/kg, 5 mg/kg to 20 mg/kg, 5 mg/kg to 15 mg/kg, or 5 mg/kg to 10 mg/kg of at least one anti-Aβ protofibril antibody based on the subject's body weight.

[136] In some embodiments, the subject is administered 7.5 mg/kg to 45 mg/kg, 7.5 mg/kg to 40 mg/kg, 7.5 mg/kg to 35 mg/kg, 7.5 mg/kg to 30 mg/kg, 7.5 mg/kg to 25 mg/kg, 7.5 mg/kg to 20 mg/kg, 7.5 mg/kg to 15 mg/kg, or 7.5 mg/kg to 10 mg/kg of at least one anti-Aβ protofibril antibody based on the subject's body weight.

[137] In some embodiments, the subject is administered 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg of at least one anti-Aβ protofibril antibody based on the subject's body weight. In some embodiments, the subject is administered up to 20 mg/kg, 19 mg/kg, 18 mg/kg, 17 mg/kg, 16 mg/kg, 15 mg/kg, 14 mg/kg, 13 mg/kg, 12 mg/kg, 11 mg/kg, 10 mg/kg, 9 mg/kg, 8 mg/kg, 7 mg/kg, 6 mg/kg, 5 mg/kg, 4 mg/kg, 3 mg/kg, 2 mg/kg, 1 mg/kg, or 0.5 mg/kg of at least one anti-Aβ protofibril antibody based on the subject's body weight.

[138] In some embodiments, the subject is administered 0.5 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 1 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 2 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 2.5 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 3 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 4 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 5 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 6 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 7 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 7.5 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 8 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 9 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 10 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 11 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 12 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 12.5 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 13 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 14 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 15 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 16, 17, 18, 19, or 20 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered 21, 22, 23, 24, or 25 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight.

[139] In some embodiments, the subject is administered 27.5 mg/kg, 30 mg/kg, 32.5 mg/kg, 35 mg/kg, 37.5 mg/kg, 40 mg/kg, 42.5 mg/kg, 45 mg/kg, 47.5 mg/kg, or 50 mg/kg of at least one anti-Aβ protofibril antibody based on the subject's body weight.

[140] As mentioned, in some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401. Accordingly, in some embodiments, the subject is administered 0.5 mg/kg to 45 mg/kg, 0.5 mg/kg to 40 mg/kg, 0.5 mg/kg to 35 mg/kg, 0.5 mg/kg to 30 mg/kg, 0.5 mg/kg to 25 mg/kg, 0.5 mg/kg to 20 mg/kg, 0.5 mg/kg to 15 mg/kg, 0.5 mg/kg to 10 mg/kg, 0.5 mg/kg to 5 mg/kg, or 0.5 mg/kg to 2.5 mg/kg of BAN2401 based on the subject's body weight.

[141] In some embodiments, the subject is administered 2.5 mg/kg to 45 mg/kg, 2.5 mg/kg to 40 mg/kg, 2.5 mg/kg to 35 mg/kg, 2.5 mg/kg to 30 mg/kg, 2.5 mg/kg to 25 mg/kg, 2.5 mg/kg to 20 mg/kg, 2.5 mg/kg to 15 mg/kg, 2.5 mg/kg to 10 mg/kg, or 2.5 mg/kg to 5 mg/kg of BAN2401 based on the subject's body weight.

[142] In some embodiments, the subject is administered 5 mg/kg to 45 mg/kg, 5 mg/kg to 40 mg/kg, 5 mg/kg to 35 mg/kg, 5 mg/kg to 30 mg/kg, 5 mg/kg to 25 mg/kg, 5 mg/kg to 20 mg/kg, 5 mg/kg to 15 mg/kg, or 5 mg/kg to 10 mg/kg of BAN2401 based on the subject's body weight.

[143] In some embodiments, the subject is administered 7.5 mg/kg to 45 mg/kg, 7.5 mg/kg to 40 mg/kg, 7.5 mg/kg to 35 mg/kg, 7.5 mg/kg to 30 mg/kg, 7.5 mg/kg to 25 mg/kg, 7.5 mg/kg to 20 mg/kg, 7.5 mg/kg to 15 mg/kg, or 7.5 mg/kg to 10 mg/kg of BAN2401 based on the subject's body weight.

[144] In some embodiments, the subject is administered 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered up to 20 mg/kg, 19 mg/kg, 18 mg/kg, 17 mg/kg, 16 mg/kg, 15 mg/kg, 14 mg/kg, 13 mg/kg, 12 mg/kg, 11 mg/kg, 10 mg/kg, 9 mg/kg, 8 mg/kg, 7 mg/kg, 6 mg/kg, 5 mg/kg, 4 mg/kg, 3 mg/kg, 2 mg/kg, 1 mg/kg, or 0.5 mg/kg of BAN2401 based on the subject's body weight.

[145] In some embodiments, the subject is administered 0.5 mg/kg BAN2401 relative to the subject's body weight. In some embodiments, the subject is administered 1 mg/kg BAN2401 relative to the subject's body weight. In some embodiments, the subject is administered 2 mg/kg BAN2401 relative to the subject's body weight. In some embodiments, the subject is administered 2.5 mg/kg BAN2401 relative to the subject's body weight. In some embodiments, the subject is administered 3 mg/kg BAN2401 relative to the subject's body weight. In some embodiments, the subject is administered 4 mg/kg BAN2401 relative to the subject's body weight. In some embodiments, the subject is administered 5 mg/kg BAN2401 relative to the subject's body weight. In some embodiments, the subject is administered 6 mg/kg BAN2401 relative to the subject's body weight. In some embodiments, the subject is administered 7 mg/kg BAN2401 relative to the subject's body weight. In some embodiments, the subject is administered 7.5 mg/kg BAN2401 relative to the subject's body weight. In some embodiments, the subject is administered 8 mg/kg BAN2401 relative to the subject's body weight. In some embodiments, the subject is administered 9 mg/kg BAN2401 relative to the subject's body weight. In some embodiments, the subject is administered 10 mg/kg BAN2401 relative to the subject's body weight. In some embodiments, the subject is administered 11 mg/kg BAN2401 relative to the subject's body weight. In some embodiments, the subject is administered 12 mg/kg BAN2401 relative to the subject's body weight. In some embodiments, the subject is administered 12.5 mg/kg BAN2401 relative to the subject's body weight. In some embodiments, the subject is administered 13 mg/kg BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 14 mg/kg BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 15 mg/kg BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 16, 17, 18, 19, or 20 mg/kg BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 21, 22, 23, 24, or 25 mg/kg BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 27.5 mg/kg, 30 mg/kg, 32.5 mg/kg, 35 mg/kg, 37.5 mg/kg, 40 mg/kg, 42.5 mg/kg, 45 mg/kg, 47.5 mg/kg, or 50 mg/kg of BAN2401 based on the subject's body weight.

[146] In some embodiments, the subject is administered 2.5 mg/kg to 10 mg/kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 5 mg/kg to 10 mg/kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 2.5 mg/kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 5 mg/kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 7.5 mg/kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 10 mg/kg of BAN2401 based on the subject's body weight.

[147] Dosage regimens for at least one anti-Aβ protofibril antibody

[148] The methods of the present invention comprise administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. One of ordinary skill in the art will appreciate that any of the therapeutically effective amounts of at least one anti-Aβ protofibril antibody disclosed above can be administered one or more times according to one or more dosage regimens. One of ordinary skill in the art will be able to determine the appropriate dosage regimen(s) for each subject depending on a number of factors including the pharmacodynamic characteristics, route of administration, dose, and the health condition, age, and weight of the subject to be treated, and with the aid of the information disclosed herein.

[149] In some embodiments, a composition comprising at least one anti-Aβ protofibril antibody is administered daily, once every two days, once every three days, once a week, once every two weeks ("every two weeks"), once every four weeks ("quadruple-week intervals"), once a month, once every six weeks, once every eight weeks, once every two months, once every ten weeks, once every twelve weeks, once every three months, once every fourteen weeks, once every sixteen weeks, once every four months, once every eighteen weeks, once every twenty weeks, once every five months, once every 22 weeks, once every 24 weeks, once every six months, once every seven months, once every eight months, once every nine months, once every ten months, once every eleven months, once every twelve months, once every thirteen months, once every fourteen months, once once every fifteen months, once every sixteen months, once every seventeen months, or once every eighteen months. In some embodiments, a composition comprising at least one anti-Aβ protofibril antibody is administered daily, once every two days, once every three days, once a week, once every two weeks ("every two weeks"), once every four weeks ("at a four-week interval"), or once a month. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every two weeks or once every four weeks. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every two weeks. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every four weeks.

[150] In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once a week. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every two weeks. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every three weeks. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every four weeks. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once a month.

[151] In some embodiments, a composition comprising a therapeutically effective amount of BAN2401 is administered once a week. In some embodiments, a composition comprising a therapeutically effective amount of BAN2401 is administered once every two weeks. In some embodiments, a composition comprising a therapeutically effective amount of BAN2401 is administered once every three weeks. In some embodiments, a composition comprising a therapeutically effective amount of BAN2401 is administered once every four weeks. In some embodiments, a composition comprising a therapeutically effective amount of BAN2401 is administered once a month.

[152] In some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight is administered to the subject once a week. In some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight is administered to the subject once every two weeks. In some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight is administered to the subject once every three weeks. In some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight is administered to the subject once every four weeks. In some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight is administered to the subject once a month.

[153] In some embodiments, a composition comprising 10 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight is administered to the subject once every two weeks. In some embodiments, a composition comprising 10 mg/kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight is administered to the subject once a month.

[154] In some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of BAN2401 based on the subject's body weight is administered to the subject once a week. In some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of BAN2401 based on the subject's body weight is administered to the subject once every two weeks. In some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of BAN2401 based on the subject's body weight is administered to the subject once every three weeks. In some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of BAN2401 based on the subject's body weight is administered to the subject once every four weeks. In some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of BAN2401 based on the subject's body weight is administered to the subject once a month.

[155] In some embodiments, a composition comprising 10 mg/kg BAN2401 based on the subject's body weight is administered to the subject once every two weeks. In some embodiments, a composition comprising 10 mg/kg BAN2401 based on the subject's body weight is administered to the subject once a month.

A composition comprising at least one antibody to Aβ protofibrils

[156] In some embodiments, the composition comprises at least one antibody to Aβ protofibrils. In some embodiments, the composition consists of at least one antibody to Aβ protofibrils. In some embodiments, the composition comprises at least one antibody to Aβ protofibrils and further comprises at least one additional component. The at least one additional component may be selected from suitable physiologically acceptable excipients for use in human and/or veterinary medicine.

[157] The compositions of the present invention may be in the form of a tablet, pill, capsule, solution, and/or any other suitable form that one of ordinary skill in the art would deem appropriate. The route of administration of the compositions of the present invention may be any suitable route, including intravenous, subcutaneous, oral, and nasal. In some embodiments, the composition is formulated as a sterile, pyrogen-free liquid for intravenous administration. In some embodiments, the composition is a saline solution.

[158] In some embodiments, at least one additional component in the composition is selected from buffers. In some embodiments, at least one additional component in the composition is selected from emulsifiers. In some embodiments, at least one additional component in the composition is selected from sodium citrate, sodium chloride, and polysorbate 80. In some embodiments, sodium citrate may be present at a concentration in the range of 1 mM to 150 mM. In some embodiments, sodium citrate may be present at a concentration of 25 mM. In some embodiments, sodium chloride may be present at a concentration in the range of 25 mM to 250 mM. In some embodiments, sodium citrate may be present at a concentration of 125 mM. In some embodiments, polysorbate 80 may be present at a concentration in the range of 0.001% (w/v) to 2% (w/v). In some embodiments, polysorbate 80 may be present at a concentration of 0.02% (w/v).

[159] In some embodiments, the composition is a liquid dosage form comprising at least one anti-Aβ protofibril antibody, such as BAN2401, and further comprising, for example, sodium citrate, sodium chloride, and polysorbate 80. In some embodiments, the composition comprises 10 mg/mL of at least one anti-Aβ protofibril antibody, such as BAN2401, 25 mM sodium citrate, 125 mM sodium chloride, and 0.2% (w/v) polysorbate 80, and has a pH of 5.7.

Therapeutic effect

Reduction of clinical deterioration

[160] Provided herein is a method for reducing clinical deterioration in a subject with early Alzheimer's disease comprising administering to said subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein. In some embodiments, the subject with early Alzheimer's disease has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease and/or has been diagnosed with mild Alzheimer's dementia. In some embodiments, the subject with early Alzheimer's disease is ApoE4 positive.

[161] Any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, dosage regimens thereof, and compositions comprising them disclosed herein can be used in a method of reducing clinical worsening in a subject with early Alzheimer's disease. For example, in some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of at least one anti-Aβ protofibril antibody, such as BAN2401, based on the subject's body weight, is administered to the subject once per week, once every two weeks, once every three weeks, once every four weeks, or once per month. In some embodiments, the clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, or at least 46% compared to placebo, as determined by ADCOMS. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[162] In some embodiments, clinical worsening is reduced by 20-35% compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by 20-30% compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by 27-35% compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by at least 20% compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by at least 35% compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by at least 20% as determined by ADCOMS. In some embodiments, clinical worsening is reduced by at least 30% as determined by ADCOMS. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[163] In some embodiments, clinical worsening is reduced by at least 45% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 35% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 46% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[164] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, or at least 52% compared to placebo, as determined by ADCOMS, where the subject has been diagnosed with mild cognitive impairment, with intermediate probability of Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[165] In some embodiments, clinical worsening is reduced by 28-33% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 20%, such as 25%, or at least 28%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 25%, such as at least 30%, or at least 33%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 25%, such as at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 52%, compared to placebo, as determined by ADCOMS, where the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 52% compared to placebo, as determined by ADCOMS, where the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[166] In some embodiments, clinical worsening in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 25% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 52% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[167] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, or at least 33% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment, with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical deterioration is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[168] In some embodiments, clinical worsening is reduced by 28-38% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 20%, such as at least 25%, at least 28%, or at least 33%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 25%, such as at least 30% or at least 33%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 33% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical deterioration is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[169] In some embodiments, clinical deterioration in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 33% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[170] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, or at least 78% compared to placebo, as determined by ADCOMS, where the subject was diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[171] In some embodiments, clinical worsening is reduced by 20-80% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 35-78% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 35% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 50%, such as at least 52% or at least 53%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 70%, such as at least 75% or at least 78%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild Alzheimer's dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[172] In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 70% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 50% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 52% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[173] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, or at least 35% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[174] In some embodiments, clinical worsening is reduced by 28-38% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having mild dementia in Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 20%, such as at least 25%, at least 28%, or at least 35%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having mild dementia in Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 25%, such as at least 30%, or at least 35%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having mild dementia in Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 35% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild dementia in Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[175] In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 35% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[176] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, or at least 150% compared to placebo, as determined by the ADAS-Cog. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[177] In some embodiments, clinical worsening is reduced by 40-150% compared to placebo, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by 45-145% compared to placebo, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by 45-55% compared to placebo, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by at least 30% compared to placebo, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by at least 35% compared to placebo, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by at least 40%, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by at least 45% as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by at least 47% as determined by ADAS-Cog. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[178] In some embodiments, clinical worsening is reduced by at least 100%, such as at least 120% or at least 140%, compared to placebo, as determined by ADAS-Cog, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 40%, such as at least 45%, compared to placebo, as determined by ADAS-Cog, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 40%, such as at least 45%, compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 47% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[179] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 56%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, or at least 58% compared to placebo, as determined by the ADAS-Cog, wherein the subject has been diagnosed with mild cognitive impairment, with an intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical deterioration is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[180] In some embodiments, clinical worsening is reduced by 50-70% compared to placebo, as determined by the ADAS-Cog, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 50%, such as at least 52%, at least 55%, or at least 58%, compared to placebo, as determined by the ADAS-Cog, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 58% compared to placebo, as determined by the ADAS-Cog, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[181] In some embodiments, clinical deterioration in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 58% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[182] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, or at least 41% compared to placebo, as determined by the ADAS-Cog, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[183] In some embodiments, clinical worsening is reduced by 30-50% compared to placebo, as determined by ADAS-Cog, wherein the subject has been diagnosed with mild dementia in Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 35%, such as at least 38%, at least 40%, or at least 41%, compared to placebo, as determined by ADAS-Cog, wherein the subject has been diagnosed with mild dementia in Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 41% compared to placebo, as determined by ADAS-Cog, wherein the subject has been diagnosed with mild dementia in Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[184] In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 41% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[185] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, or at least 40% compared to placebo, as determined by CDR-SB. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[186] In some embodiments, clinical worsening is reduced by 20-60% compared to placebo, as determined by CDR-SB. In some embodiments, clinical worsening is reduced by 25-60% compared to placebo, as determined by CDR-SB. In some embodiments, clinical worsening is reduced by 25-50% compared to placebo, as determined by CDR-SB. In some embodiments, clinical worsening is reduced by at least 20% compared to placebo, as determined by CDR-SB. In some embodiments, clinical worsening is reduced by at least 30% compared to placebo, as determined by CDR-SB. In some embodiments, clinical worsening is reduced by at least 25%, such as at least 26% or at least 28%, as determined by CDR-SB. In some embodiments, the clinical worsening is reduced by at least 30%, such as at least 35% or at least 38%, as determined by CDR-SB. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[187] In some embodiments, clinical worsening is reduced by at least 30%, such as at least 35% or at least 40%, compared to placebo, as determined by CDR-SB, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 30%, such as at least 35% or at least 45%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 20%, such as at least 25%, compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[188] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, or at least 14% compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[189] In some embodiments, clinical worsening is reduced by 10-20% compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 5%, such as at least 10%, at least 12%, or at least 14%, compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 14% compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[190] In some embodiments, clinical deterioration in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 14% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[191] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, or at least 51% compared to placebo, as determined by the CDR-SB, where the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[192] In some embodiments, clinical worsening is reduced by 40-60% compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 45%, such as at least 48%, at least 50%, or at least 51%, compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 51% compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[193] In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 51% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[194] In some embodiments, a reduction in clinical worsening is determined after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 60 months, 63 months, 66 months, and/or 72 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[195] In some embodiments, the reduction in clinical worsening is determined after 1 month of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in clinical worsening is determined after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in clinical worsening is determined after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in clinical worsening is determined after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in clinical worsening is determined after 60 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in clinical worsening is determined after 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[196] In some embodiments, the reduction in clinical worsening is determined following administration of a composition comprising a therapeutically effective amount of BAN2401.

[197] In some embodiments, a reduction in clinical worsening is determined after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 60 months, 63 months, 66 months, and/or 72 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 1 month of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 6 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 12 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 18 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 60 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 63 months of administration of a composition comprising a therapeutically effective amount of BAN2401.

[198] In some embodiments, the subject is ApoE4 positive.

[199] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, or at least 74% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[200] In some embodiments, clinical worsening is reduced by 60-80%, such as 63-74%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 60%, such as at least 63%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 65%, such as at least 67%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 70%, such as at least 74%, compared to placebo, as determined by ADCOMS, where the subject is ApoE4 positive.

[201] In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 70% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 60% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 50%, such as at least 55% or at least 60%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 63% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[202] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, at least 170%, at least 175%, at least 180%, at least 185%, at least 190%, at least 195%, at least 200%, at least 205%, at least 210%, at least 215%, at least 220%, at least 225%, at least 230%, at least 235%, at least 240%, at least 245%, at least 250%, at least 255%, at least 260%, at least 265%, at least 270%, at least 275%, at least 280%, at least 290%, at least 295%, at least 300%, at least 305%, at least 310%, at least 315%, at least 320%, at least 325%, at least 330%, or at least 331% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[203] In some embodiments, clinical worsening is reduced by 70-400%, such as 80-350%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 70%, such as at least 75%, or at least 80%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 80%, such as at least 90%, or at least 100%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 300%, such as at least 330%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[204] In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 300% compared to placebo, as determined by ADAS-Cog, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 80%, such as at least 90% or at least 100%, compared to placebo, as determined by ADAS-Cog, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 70%, such as at least 75%, at least 80%, or at least 84%, compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 84%, compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[205] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, or at least 87% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[206] In some embodiments, clinical worsening is reduced by 35-150%, such as 40-100% or 45-90%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 35%, such as at least 40% or at least 45%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 50%, such as at least 55% or at least 60%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 70%, such as at least 80% or at least 85%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[207] In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 35%, such as at least 40% or at least 45%, compared to placebo, as determined by CDR-SB, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 70%, such as at least 75% or at least 80%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 50%, such as at least 55% or at least 60%, compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 60% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[208] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, or at least 59% compared to placebo, as determined using ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical deterioration is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[209] In some embodiments, clinical worsening is reduced by 30-70%, such as 38-59%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 30%, such as at least 35% or at least 38%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 45%, such as at least 50% or at least 53%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 50%, such as at least 55% or at least 59%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[210] In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 50%, such as at least 55%, compared to placebo, as determined by ADCOMS, following 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 30%, such as at least 35%, compared to placebo, as determined by ADCOMS, following 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical deterioration in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 45%, such as at least 50% or at least 55%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[211] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, at least 170%, at least 175%, at least 180%, at least 185%, at least 190%, at least 195%, at least 200%, at least 205%, at least 210%, or at least 211% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[212] In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 100%, such as at least 110%, compared to placebo, as determined by ADCOMS, following 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 100%, such as at least 110%, compared to placebo, as determined by ADCOMS, following 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's dementia is reduced by at least 65%, such as at least 70% or at least 75%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[213] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, at least 170%, at least 175%, at least 180%, at least 185%, at least 190%, at least 195%, at least 200%, at least 205%, at least 210%, or at least 211% compared to placebo, as determined by the ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[214] In some embodiments, clinical worsening is reduced by 40-300%, such as 45-250% or 50-250%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 40%, such as at least 45% or at least 50%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 60%, such as at least 70%, at least 75%, or at least 80%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 100%, such as at least 150%, or at least 200%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[215] In some embodiments, clinical deterioration in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 100%, such as at least 150% or at least 200%, compared to placebo, as determined by ADAS-Cog, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical deterioration in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 40%, such as at least 45% or at least 50%, compared to placebo, as determined by ADAS-Cog, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical deterioration in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 50%, such as at least 60%, at least 70%, or at least 75%, compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[216] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, or at least 45% compared to placebo, as determined by CDR-SB, where the subject is ApoE4 positive and where the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[217] In some embodiments, clinical worsening is reduced by 20-90%, such as 25-80% or 30-75%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 25%, such as at least 30%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 30%, such as at least 35% or 40%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 35%, such as at least 40% or 45%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[218] In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 35%, such as at least 40% or at least 45%, compared to placebo, as determined by CDR-SB, following administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the clinical worsening in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 20%, such as at least 25% or at least 30%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the clinical worsening in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 35%, such as at least 40%, compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one antibody to Aβ protofibrils and is administered once every two weeks or once a month. In some embodiments, the at least one antibody to Aβ protofibrils is BAN2401.

[219] In some embodiments, the clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118% or at least 119% compared to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[220] In some embodiments, clinical worsening is reduced by 76-119% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 76% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 113% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 119% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[221] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139%, at least 140%, at least 141%, at least 142%, at least 143%, at least 144%, at least 145%, at least 146%, at least 147%, at least 148%, at least 149%, at least 150%, at least 151%, at least 152%, at least 153%, at least 154%, at least 155%, at least 156%, at least 157%, at least 158%, at least 159%, at least 160%, at least 161%, at least 162%, at least 163%, at least 164%, at least 165%, at least 166%, at least 167%, at least 168%, at least 169%, at least 170%, at least 171%, at least 172%, at least 173%, at least 174%, at least 175%, at least 176%, at least 177%, at least 178%, at least 179%, at least 180%, at least 190%, at least 200%, at least 210%, at least 220%, at least 230%, at least 240%, at least 250%, at least 275%, at least 300%, at least 325%, at least 350%, at least 375%, at least 400%, at least 425%, at least 450%, at least 475%, at least 500%, at least 550%, at least 600%, at least 650%, at least 700%, at least 750%, at least 800%, at least 850%, at least 900%, at least 950%, at least 1000%, at least 1001%, at least 1002%, at least 1003%, at least 1004%, at least 1005%, at least 1006%, at least 1007%, at least 1008%, at least 1009%, at least 1010%, at least 1011%, at least 1012%, at least 1013%, at least 1014%, at least 1015%, at least 1016%, at least 1017%, at least 1018%, at least 1019%, at least 1020%, at least 1021%, at least 1022%, or at least 1023% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[222] In some embodiments, clinical worsening is reduced by 58-1023% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 58% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 171% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 1023% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[223] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139%, at least 140%, at least 141%, at least 142%, at least 143%, at least 144%, at least 145%, at least 146%, at least 147%, at least 148%, at least 149%, at least 150%, at least 151%, at least 152%, at least 153%, at least 154%, at least 155%, at least 156%, at least 157%, at least 158%, at least 159%, at least 160%, at least 161%, at least 162%, at least 163%, at least 164%, at least 165%, at least 166%, at least 167%, at least 168%, at least 169%, at least 170%, at least 171%, at least 172%, at least 173% or at least 174% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[224] In some embodiments, clinical worsening is reduced by 70-200%, such as 75-180% or 82-174%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 70%, such as at least 80%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 75%, such as at least 80% or at least 85%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 150%, such as at least 160% or 170%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[225] In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 70%, such as at least 75%, at least 80%, or at least 85%, compared to placebo, as determined by CDR-SB, following administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 130%, such as at least 140%, at least 150%, at least 160%, or at least 170%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 65%, such as at least 70%, at least 75%, or at least 80%, compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[226] In some embodiments, the subject is ApoE4 negative.

[227] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, or at least 12% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[228] In some embodiments, clinical worsening is reduced by 5-15% compared to placebo as determined by ADCOMS wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 5%, such as at least 7%, compared to placebo as determined by ADCOMS wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 10%, such as at least 12%, compared to placebo as determined by ADCOMS wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[229] In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least -2% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 10% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 5%, such as at least 7%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 7% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[230] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, or at least 72% compared to placebo, as determined by the ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[231] In some embodiments, clinical worsening is reduced by 40-80% compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 35%, such as at least 40% or at least 43%, compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 40%, such as at least 45% or at least 46%, compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 65%, such as at least 70% or at least 72%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 43% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[232] In some embodiments, clinical worsening is increased by 7%, 6%, 5%, 4%, 3%, 2%, or 1% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, or at least 3% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[233] In some embodiments, clinical worsening is reduced by 3% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, or at least 26% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 negative and wherein the subject was diagnosed with mild cognitive impairment, with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical deterioration is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[234] In some embodiments, clinical worsening is reduced by 15-26% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by 15% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by 26% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[235] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, or at least 166% compared to placebo, as determined by the ADAS-Cog, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[236] In some embodiments, clinical worsening is reduced by 50-200%, such as 60-180% or 65-170%, compared to placebo, as determined by the ADAS-Cog, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 50%, such as at least 55% or at least 65%, compared to placebo, as determined by the ADAS-Cog, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 70%, such as at least 75% or at least 80%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 150%, such as at least 160%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[237] In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 150%, such as at least 160%, compared to placebo, as determined by ADAS-Cog, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 70%, such as at least 75% or at least 80%, compared to placebo, as determined by ADAS-Cog, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 50%, such as at least 60% or at least 65%, compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[238] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, or at least 5% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[239] In some embodiments, clinical worsening is reduced by at least 5% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[240] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[241] In some embodiments, clinical worsening is reduced by at least 10%, such as at least 12%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

Conversion of a subject from amyloid-positive to amyloid-negative

[242] Also provided herein is a method for converting an amyloid-positive subject into an amyloid-negative subject. In some embodiments, said method comprises administering to said subject a composition comprising at least one anti-Aβ protofibril antibody disclosed herein. In some embodiments, said subject with early Alzheimer's disease has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease and/or has been diagnosed with having mild dementia in Alzheimer's disease.

[243] Any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, dosage regimens thereof, and compositions comprising them disclosed herein can be used in a method of converting an amyloid-positive subject into an amyloid-negative subject. For example, in some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of at least one anti-Aβ protofibril antibody, such as BAN2401, based on the body weight of the subject, is administered to the subject once per week, once every two weeks, once every three weeks, once every four weeks, or once per month.

[244] In some embodiments, administering the composition results in a conversion of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, or at least 81% of subjects from amyloid-positive to amyloid-negative, as determined by visual readings of PET images of amyloid.

[245] In some embodiments, administration of the composition results in 50% to 100%, such as 60% to 90%, of the subjects being converted from amyloid positive to amyloid negative, as determined by visual readings of PET images of amyloid. In some embodiments, administration of the composition results in at least 55%, such as at least 60% or at least 65%, of the subjects being amyloid negative, as determined by visual readings of PET images of amyloid, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils. In some embodiments, administration of the composition results in at least 70%, such as at least 75% or at least 80%, of the subjects becoming amyloid negative, as determined by visual readings of PET images of amyloid, after 18 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[246] In some embodiments, administering the composition results in at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of the subjects become amyloid negative as determined by visual readings of PET images of amyloid, where the subjects are ApoE4 positive.

[247] In some embodiments, administration of the composition causes 75% to 100%, such as 80% to 100% or 85% to 100%, of the subjects to become amyloid negative, as determined by visual readings of PET images of amyloid, wherein the subjects are ApoE4 positive. In some embodiments, administration of the composition causes at least 75%, such as at least 80% or at least 85%, of the subjects to become amyloid negative, as determined by visual readings of PET images of amyloid, wherein the subjects are ApoE4 positive. In some embodiments, administration of the composition results in 100% of subjects becoming amyloid negative as determined by visual readings of amyloid PET images, wherein the subjects are ApoE4 positive.

[248] In some embodiments, at least 75%, such as at least 80% or at least 85%, of the ApoE4-positive subjects are amyloid negative, as determined by visual readings of PET images of amyloid, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, at least 75%, such as at least 80%, at least 85%, at least 90%, or at least 95%, of the ApoE4-positive subjects are amyloid negative, as determined by visual readings of PET images of amyloid, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one antibody to Aβ protofibrils and is administered once every two weeks or once a month. In some embodiments, the at least one antibody to Aβ protofibrils is BAN2401.

[249] In some embodiments, administering the composition results in at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, or at least 79% of the subjects become amyloid negative, as determined by visual readings of PET images of amyloid, wherein the subjects are ApoE4 negative.

[250] In some embodiments, administration of the composition causes 50% to 100%, such as 55% to 90%, of the subjects to become amyloid negative, as determined by visual readings of PET images of amyloid, wherein the subjects are ApoE4 negative. In some embodiments, administration of the composition causes at least 50% of the subjects to become amyloid negative, as determined by visual readings of PET images of amyloid, wherein the subjects are ApoE4 negative. In some embodiments, administration of the composition causes at least 70% of the subjects to become amyloid negative, as determined by visual readings of PET images of amyloid, wherein the subjects are ApoE4 negative.

[251] In some embodiments, clinical worsening is reduced by 35-50% compared to placebo as determined by ADCOMS wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 35%, such as at least 38%, at least 40%, or at least 41%, compared to placebo as determined by ADCOMS wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 41% compared to placebo as determined by ADCOMS wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody other than BAN2401.

[252] In some embodiments, clinical worsening in a subject not co-administered with at least one drug for treating Alzheimer's disease is reduced by at least 41% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[253] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, or at least 59% compared to placebo, as determined using ADAS-Cog, wherein the subject is not co-administered with at least one drug for the treatment of Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[254] In some embodiments, clinical worsening is reduced by 50-70% compared to placebo as determined by ADAS-Cog wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 50%, such as at least 55%, at least 57%, or at least 59%, compared to placebo as determined by ADAS-Cog wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 59% compared to placebo as determined by ADAS-Cog wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[255] In some embodiments, clinical worsening in a subject not co-administered with at least one drug for treating Alzheimer's disease is reduced by at least 59% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[256] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, or at least 45% compared to placebo, as determined by CDR-SB, wherein the subject is not co-administered with at least one drug for the treatment of Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[257] In some embodiments, clinical worsening is reduced by 50-70% compared to placebo as determined by ADAS-Cog wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 35%, such as at least 40%, at least 42%, or at least 45%, compared to placebo as determined by CDR-SB wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 45% compared to placebo as determined by CDR-SB wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[258] In some embodiments, clinical worsening in a subject not co-administered with at least one drug for treating Alzheimer's disease is reduced by at least 45% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

Concurrent administration of at least one antibody to Aβ protofibrils and at least one drug for the treatment of Alzheimer's disease, different from BAN2401

[259] In some embodiments, provided herein is a method of reducing clinical worsening in a subject with early Alzheimer's disease, comprising co-administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a therapeutically effective amount of at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, or at least 23% compared to placebo, as determined by ADCOMS. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[260] In some embodiments, clinical worsening is reduced by 15-30% compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by at least 15%, such as at least 20%, at least 21%, or at least 23%, compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by at least 23% compared to placebo as determined by ADCOMS. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[261] In some embodiments, clinical worsening in a subject co-administered with a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a therapeutically effective amount of at least one Alzheimer's disease treatment other than BAN2401 is reduced by at least 23% compared to placebo, as determined by ADCOMS, after 18 months of administration of a therapeutically effective amount of the at least one anti-Aβ protofibril antibody. In some embodiments, 10 mg/kg of the at least one anti-Aβ protofibril antibody is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401. In some embodiments, the at least one Alzheimer's disease treatment is selected from elenbecestat, donepezil, galantamine, memantine, and rivastigmine. In some embodiments, the at least one drug for treating Alzheimer's disease is a combination of donepezil and memantine.

[262] In some embodiments, donepezil may be administered at its approved dose. In some embodiments, galantamine may be administered at its approved dose. In some embodiments, memantine may be administered at its approved dose. In some embodiments, rivastigmine may be administered at its approved dose.

[263] In some embodiments, elenbecestat may be administered at a dose in the range of 5 mg/day to 100 mg/day, 10 mg/day to 75 mg/day, 5 mg/day to 50 mg/day, or 15 mg/day to 50 mg/day. In some embodiments, elenbecestat may be administered at a dose in the range of about 5 mg/day to about 100 mg/day, about 10 mg/day to about 75 mg/day, about 5 mg/day to about 50 mg/day, or about 15 mg/day to about 50 mg/day. In some embodiments, elenbecestat can be administered at a dose of 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, or 50 mg/day. In some embodiments, elenbecestat can be administered at a dose of 5 mg/day. In some embodiments, elenbecestat can be administered at a dose of 15 mg/day. In some embodiments, elenbecestat can be administered at a dose of 50 mg/day.

[264] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, or at least 41% compared to placebo, as determined by ADCOMS. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[265] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, or at least 39% compared to placebo, as determined by ADAS-Cog, wherein the subject is co-administered with at least one Alzheimer's disease treatment other than BAN2401. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[266] In some embodiments, clinical worsening is reduced by 30-50% compared to placebo as determined by ADAS-Cog wherein the subject is co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 30%, such as at least 35%, at least 37%, or at least 39%, compared to placebo as determined by ADAS-Cog wherein the subject is co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 39% compared to placebo as determined by ADAS-Cog wherein the subject is co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[267] In some embodiments, clinical worsening in a subject co-administered with at least one drug for treating Alzheimer's disease is reduced by at least 39% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401. In some embodiments, the at least one drug for treating Alzheimer's disease is selected from elenbecestat, donepezil, galantamine, memantine, and rivastigmine. In some embodiments, the at least one drug for treating Alzheimer's disease is a combination of donepezil and memantine.

[268] In some embodiments, donepezil may be administered at its approved dose. In some embodiments, galantamine may be administered at its approved dose. In some embodiments, memantine may be administered at its approved dose. In some embodiments, rivastigmine may be administered at its approved dose.

[269] In some embodiments, elenbecestat may be administered at a dose in the range of 5 mg/day to 100 mg/day, 10 mg/day to 75 mg/day, 5 mg/day to 50 mg/day, or 15 mg/day to 50 mg/day. In some embodiments, elenbecestat may be administered at a dose in the range of about 5 mg/day to about 100 mg/day, about 10 mg/day to about 75 mg/day, about 5 mg/day to about 50 mg/day, or about 15 mg/day to about 50 mg/day. In some embodiments, elenbecestat can be administered at a dose of 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, or 50 mg/day. In some embodiments, elenbecestat can be administered at a dose of 5 mg/day. In some embodiments, elenbecestat can be administered at a dose of 15 mg/day. In some embodiments, elenbecestat can be administered at a dose of 50 mg/day.

[270] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to placebo, as determined by CDR-SB, wherein the subject is co-administered with at least one Alzheimer's disease treatment other than BAN2401. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[271] In some embodiments, clinical worsening is reduced by 10-30% compared to placebo, as determined by CDR-SB, wherein the subject is co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 10%, such as at least 15%, at least 17%, or at least 20%, compared to placebo, as determined by CDR-SB, wherein the subject is co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 20% compared to placebo, as determined by CDR-SB, wherein the subject is co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[272] In some embodiments, clinical worsening in a subject co-administered with at least one drug for treating Alzheimer's disease is reduced by at least 20% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401. In some embodiments, the at least one drug for treating Alzheimer's disease is selected from elenbecestat, donepezil, galantamine, memantine, and rivastigmine. In some embodiments, the at least one drug for treating Alzheimer's disease is a combination of donepezil and memantine.

[273] In some embodiments, donepezil may be administered at its approved dose. In some embodiments, galantamine may be administered at its approved dose. In some embodiments, memantine may be administered at its approved dose. In some embodiments, rivastigmine may be administered at its approved dose.

[274] In some embodiments, elenbecestat can be administered at a dose in the range of 5 mg/day to 100 mg/day, 10 mg/day to 75 mg/day, 5 mg/day to 50 mg/day, or 15 mg/day to 50 mg/day. In some embodiments, elenbecestat can be administered at a dose in the range of about 5 mg/day to about 100 mg/day, about 10 mg/day to about 75 mg/day, about 5 mg/day to about 50 mg/day, or about 15 mg/day to about 50 mg/day. In some embodiments, elenbecestat can be administered at a dose of 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, 25 mg/day, 30 mg/day, or 50 mg/day. In some embodiments, elenbecestat can be administered at a dose of 5 mg/day. In some embodiments, elenbecestat can be administered at a dose of 15 mg/day. In some embodiments, elenbecestat can be administered at a dose of 50 mg/day.

Reducing amyloid levels in the brain

[275] Also provided herein is a method for reducing amyloid levels in the brain in a subject in need thereof, comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein.

[276] In some embodiments, the subject has early Alzheimer's disease. In some embodiments, the subject has Alzheimer's disease, Down syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, dementia with Lewy bodies, or other brain diseases or conditions associated with soluble and/or insoluble Aβ aggregates containing Aβ peptides.

[277] One of ordinary skill in the art will appreciate that, in addition to subjects with Alzheimer's disease, Aβ plaque deposits are present in the brains of subjects who have other neurodegenerative diseases and conditions, and that the methods described herein will therefore have a beneficial effect in subjects who have such neurodegenerative diseases and/or conditions. Such diseases and conditions are known to include, for example, Down syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, and dementia with Lewy bodies. (See, for example, Catafau et al., "Amyloid PET imaging: applications beyond Alzheimer's disease", Clin. Transl. Imaging3(1): 39-55 (2015); and Banerjee, G. et al., "The increasing impact of cerebral amyloid angiopathy: essential new insights for clinical practice", J. Neurol. Neurosurg. Psychiatry88: 982–994 (2017).)

[278] In some embodiments, the subject with early Alzheimer's disease has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease and/or has been diagnosed with mild dementia in Alzheimer's disease. In some embodiments, the subject with early Alzheimer's disease is ApoE4 positive.

[279] Any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, dosage regimens thereof, and compositions comprising them disclosed herein can be used in a method of reducing amyloid levels in the brain of a subject with early Alzheimer's disease. For example, in some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of at least one anti-Aβ protofibril antibody, such as BAN2401, based on the body weight of the subject, is administered to the subject once per week, once every two weeks, once every three weeks, once every four weeks, or once per month.

[280] In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[281] In some embodiments, said method results in a decrease in the amyloid level in the brain after administration compared to the amyloid level in the brain before said administration. In some embodiments, the amyloid level in the brain is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% compared to the amyloid level in the brain before said administration. In some embodiments, said reduction in amyloid levels in the brain is determined using visual readings of PET images of amyloid and is expressed as PET standardized uptake value values (SUVr values).

[282] Amyloid imaging using positron emission tomography (PET) can be used to confirm the presence of amyloid pathology in the brain of subjects with AD early in the screening phase of a study and/or to assess the effects of at least one anti-AB antibody on brain amyloid levels, either in whole-brain (e.g., averaged over 5-6 cortical regions) or in brain regions. In some embodiments, the adjusted mean change in the subject's PET SUVr from baseline is reduced by at least -0.10, at least -0.15, at least -0.20, at least -0.25, at least -0.30, at least -0.35, at least -0.40, at least -0.45, at least -0.50, at least -0.55, at least -0.60, at least -0.65, at least -0.70, at least -0.75, at least -0.80, at least -0.85, at least -0.90, or at least -0.95 compared to baseline. In some embodiments, the adjusted mean change in the subject's PET SUVr from baseline is reduced by an amount from -0.20 to -0.30.

[283] In some embodiments, when comparing the overall mean value for the cerebral cortex and the reference value for the entire cerebellum, the adjusted mean change in the subject's PET SUVr value from baseline is reduced by at least -0.20, such as at least -0.25, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the adjusted mean change in the subject's PET SUVr value from baseline is reduced by at least -0.25, such as at least -0.30, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[284] In some embodiments, the reduction in brain amyloid is determined by imaging using radiotracers that bind brain amyloid Aβ and is visualized by PET. In some embodiments, the reduction in adjusted mean change from baseline is at least -50, such as at least -55 or at least -59, centiloids after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in adjusted mean change from baseline is at least -60, such as at least -65 or at least -70, centiloids after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[285] In some embodiments, said method results in a decrease in the level of Aβ _1-42 in the cerebrospinal fluid compared to the level of Aβ _1-42 in the cerebrospinal fluid prior to said administration. In some embodiments, said method results in a decrease in the Aβ _1-42 level in the cerebrospinal fluid, compared to the Aβ _1-42 level in the cerebrospinal fluid before said administration, of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, by at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%.

[286] In some embodiments, administration of the composition results in a decrease in brain amyloid levels of from -0.20 to -0.45, such as from -0.25 to -0.35, as determined by visual readings of PET images of amyloid, wherein the subject is ApoE4 positive. In some embodiments, administration of the composition results in a decrease in brain amyloid levels of at least -0.25, as determined by visual readings of PET images of amyloid, wherein the subject is ApoE4 positive. In some embodiments, administration of the composition results in a decrease in brain amyloid levels of at least 0.30, as determined by visual readings of PET images of amyloid, wherein the subject is ApoE4 positive.

[287] In some embodiments, administration of the composition results in a reduction in brain amyloid levels of at least -0.01, at least -0.02, at least -0.03, at least -0.04, at least -0.05, at least -0.06, at least -0.07, at least -0.08, at least -0.09, at least -0.10, at least -0.11, at least -0.12, at least -0.13, at least -0.14, at least -0.15, at least -0.16, at least -0.17, at least -0.18, at least -0.19, at least -0.20, at least -0.21, at least -0.22, at least -0.23, at least -0.24, at least -0.25, at least -0.26, at least -0.27, at least -0.28, or at least -0.29 compared to placebo, as determined by visual readings of amyloid PET images, where the subject is ApoE4 positive.

[288] In some embodiments, administration of the composition results in a decrease in brain amyloid levels of between -0.10 and -0.40, as determined by visual readings of PET images of amyloid, wherein the subject is ApoE4-negative. In some embodiments, administration of the composition results in a decrease in brain amyloid levels of at least -0.20, as determined by visual readings of PET images of amyloid, wherein the subject is ApoE4-negative. In some embodiments, administration of the composition results in a decrease in brain amyloid levels of at least -0.25, as determined by visual readings of PET images of amyloid, wherein the subject is ApoE4-negative.

Changes in biomarker levels

Cerebrospinal fluid neurogranin levels

[289] In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in the level of neurogranin in the cerebrospinal fluid of the subject. In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in the level of neurogranin in the cerebrospinal fluid, compared to a baseline level, of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10%.

[290] In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in the level of neurogranin in the cerebrospinal fluid after 18 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in the level of neurogranin in the cerebrospinal fluid, compared to baseline, of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% after 18 months of administration of the composition.

[291] In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in the level of neurogranin in the cerebrospinal fluid, compared to a baseline level, of at least about 25 pg/mL, at least about 30 pg/mL, at least about 35 pg/mL, at least about 40 pg/mL, at least about 45 pg/mL, at least about 50 pg/mL, at least about 55 pg/mL, at least about 60 pg/mL, or at least about 65 pg/mL. In some embodiments, administration to a subject of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in the level of neurogranin in the cerebrospinal fluid, compared to a baseline level, of at least about 65 pg/mL.

[292] In some embodiments, administration to a subject of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in the level of neurogranin in the cerebrospinal fluid, compared to a baseline level, of at least about 25 pg/mL, at least about 30 pg/mL, at least about 35 pg/mL, at least about 40 pg/mL, at least about 45 pg/mL, at least about 50 pg/mL, at least about 55 pg/mL, at least about 60 pg/mL, or at least about 65 pg/mL, after 18 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, administration to a subject of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid neurogranin levels, compared to baseline, of at least 65 pg/mL after 18 months of administration of the composition.

[293] In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[294] In some embodiments, the therapeutically effective amount of at least one anti-Aβ protofibril antibody is 10 mg/kg. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein is administered once every two weeks or once per month. In some embodiments, a composition comprising 10 mg/kg BAN2401 is administered once every two weeks. In some embodiments, a composition comprising 10 mg/kg BAN2401 is administered once per month.

Cerebrospinal fluid neurofilament light chain levels

[295] In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in the level of neurofilament light chains in the cerebrospinal fluid, compared to placebo. In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in the level of neurofilament light chains in the cerebrospinal fluid, compared to placebo, of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%.

[296] In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in the level of neurofilament light chains in the cerebrospinal fluid, compared to placebo, after 18 months of administration of the composition. In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in the level of neurofilament light chains in the cerebrospinal fluid, compared to placebo, of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%, after 18 months of administration of the composition.

[297] In some embodiments, administration to a subject of a composition comprising a therapeutically effective amount of one anti-Aβ protofibril antibody disclosed herein results in the production of a neurofilament light chain level in the cerebrospinal fluid that is greater than about 35 pg/mL, about 40 pg/mL, about 45 pg/mL, about 50 pg/mL, about 55 pg/mL, about 60 pg/mL, about 65 pg/mL, about 70 pg/mL, about 75 pg/mL higher than the baseline level. In some embodiments, administration to a subject of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in the production of a neurofilament light chain level in the cerebrospinal fluid that is no more than about 75 pg/mL higher than the baseline level.

[298] In some embodiments, administration to a subject of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in the production of a neurofilament light chain level in the cerebrospinal fluid that is greater than about 35 pg/mL, about 40 pg/mL, about 45 pg/mL, about 50 pg/mL, about 55 pg/mL, about 60 pg/mL, about 65 pg/mL, about 70 pg/mL, about 75 pg/mL higher than baseline after 18 months of administration of the composition. In some embodiments, administration to a subject of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in the production of a neurofilament light chain level in the cerebrospinal fluid that is no more than about 75 pg/mL higher than baseline after 18 months of administration of the composition.

[299] In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[300] In some embodiments, a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein is 10 mg/kg. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein is administered once every two weeks or once per month. In some embodiments, a composition comprising 10 mg/kg BAN2401 is administered once every two weeks. In some embodiments, a composition comprising 10 mg/kg BAN2401 is administered once per month.

Cerebrospinal fluid phospho-tau protein levels

[301] In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in the level of phospho-tau protein in the cerebrospinal fluid. In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in the level of phospho-tau protein in the cerebrospinal fluid, compared to a baseline level, of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, or at least 13%.

[302] In some embodiments, administration to a subject of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in the level of phospho-tau protein in the cerebrospinal fluid after 18 months of administration of the composition. In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid phospho-tau protein levels, compared to baseline, of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, or at least 13% after 18 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[303] In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in the level of phospho-tau protein in the cerebrospinal fluid, compared to a baseline level, of at least about 65 pg/mL, at least about 70 pg/mL, at least about 75 pg/mL, at least about 80 pg/mL, at least about 85 pg/mL, at least about 90 pg/mL, or at least about 95 pg/mL. In some embodiments, administration to a subject of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in cerebrospinal fluid phospho-tau protein levels, compared to baseline, of at least about 95 pg/mL.

[304] In some embodiments, administration to a subject of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in the level of phospho-tau protein in the cerebrospinal fluid, compared to a baseline level, of at least about 65 pg/mL, at least about 70 pg/mL, at least about 75 pg/mL, at least about 80 pg/mL, at least about 85 pg/mL, at least about 90 pg/mL, or at least about 95 pg/mL, after 18 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, administration to a subject of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in the level of phospho-tau protein in the cerebrospinal fluid, compared to a baseline level, of at least 95 pg/mL after 18 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[305] In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[306] In some embodiments, the therapeutically effective amount of at least one anti-Aβ protofibril antibody is 10 mg/kg. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein is administered once every two weeks or once per month. In some embodiments, a composition comprising 10 mg/kg BAN2401 is administered once every two weeks. In some embodiments, a composition comprising 10 mg/kg BAN2401 is administered once per month.

Treatments for Alzheimer's Disease

Reduction of clinical deterioration

[307] Provided herein is a method of treating a subject with early Alzheimer's disease, comprising administering to said subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein, wherein the clinical worsening in the subject is reduced by at least 35% compared to placebo, as determined by ADCOMS, after 6 months of administration of the composition, by at least 30% compared to placebo, as determined by ADCOMS, after 12 months of administration of the composition, and/or by at least 25% compared to placebo, as determined by ADCOMS, after 18 months of administration of the composition. In some embodiments, the subject with early Alzheimer's disease has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease and/or has been diagnosed with mild Alzheimer's dementia. In some embodiments, the subject with early Alzheimer's disease is ApoE4 positive.

[308] Any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, dosage regimens thereof, and compositions comprising them disclosed herein can be used in a method of reducing clinical worsening in a subject with early Alzheimer's disease. For example, in some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of at least one anti-Aβ protofibril antibody, such as BAN2401, based on the subject's body weight, is administered to the subject once per week, once every two weeks, once every three weeks, once every four weeks, or once per month. In some embodiments, clinical worsening is reduced by at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, or at least 46% compared to placebo, as determined by ADCOMS. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[309] In some embodiments, clinical worsening is reduced by 20-35% compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by 20-30% compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by 27-35% compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by at least 20% compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by at least 35% compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by at least 20% as determined by ADCOMS. In some embodiments, clinical worsening is reduced by at least 30% as determined by ADCOMS. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[310] In some embodiments, clinical worsening is reduced by at least 45% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 35% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 46% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[311] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, or at least 52% compared to placebo, as determined by ADCOMS, where the subject has been diagnosed with mild cognitive impairment, with intermediate probability of Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[312] In some embodiments, clinical worsening is reduced by 28-33% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 20%, such as 25%, or at least 28%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 25%, such as at least 30%, or at least 33%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 25%, such as at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 52%, compared to placebo, as determined by ADCOMS, where the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 52% compared to placebo, as determined by ADCOMS, where the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[313] In some embodiments, clinical worsening in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 25% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 52% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[314] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, or at least 33% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment, with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical deterioration is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[315] In some embodiments, clinical worsening is reduced by 28-38% compared to placebo, as determined by ADCOMS, where the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 20%, such as at least 25%, at least 28%, or at least 33%, compared to placebo, as determined by ADCOMS, where the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 25%, such as at least 30% or at least 33%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 33% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical deterioration is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[316] In some embodiments, clinical deterioration in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 33% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[317] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, or at least 78% compared to placebo, as determined by ADCOMS, where the subject was diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[318] In some embodiments, clinical worsening is reduced by 20-80% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 35-78% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 35% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 50%, such as at least 52% or at least 53%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 70%, such as at least 75% or at least 78%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild dementia in Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[319] In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 70% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 50% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 52% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[320] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, or at least 35% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[321] In some embodiments, clinical worsening is reduced by 28-38% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having mild dementia in Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 20%, such as at least 25%, at least 28%, or at least 35%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having mild dementia in Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 25%, such as at least 30%, or at least 35%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having mild dementia in Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 35% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild dementia in Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[322] In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 35% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[323] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, or at least 150% compared to placebo, as determined by the ADAS-Cog. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[324] In some embodiments, clinical worsening is reduced by 40-150% compared to placebo, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by 45-145% compared to placebo, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by 45-55% compared to placebo, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by at least 30% compared to placebo, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by at least 35% compared to placebo, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by at least 40%, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by at least 45% as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by at least 47% as determined by ADAS-Cog. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[325] In some embodiments, clinical worsening is reduced by at least 100%, such as at least 120% or at least 140%, compared to placebo, as determined by ADAS-Cog, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 40%, such as at least 45%, compared to placebo, as determined by ADAS-Cog, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 40%, such as at least 45%, compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 47% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[326] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 56%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, or at least 58% compared to placebo, as determined by the ADAS-Cog, wherein the subject has been diagnosed with mild cognitive impairment, with an intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical deterioration is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[327] In some embodiments, clinical worsening is reduced by 50-70% compared to placebo, as determined by the ADAS-Cog, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 50%, such as at least 52%, at least 55%, or at least 58%, compared to placebo, as determined by the ADAS-Cog, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 58% compared to placebo, as determined by the ADAS-Cog, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[328] In some embodiments, clinical deterioration in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 58% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[329] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, or at least 41% compared to placebo, as determined by the ADAS-Cog, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[330] In some embodiments, clinical worsening is reduced by 30-50% compared to placebo, as determined by ADAS-Cog, wherein the subject has been diagnosed with mild dementia in Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 35%, such as at least 38%, at least 40%, or at least 41%, compared to placebo, as determined by ADAS-Cog, wherein the subject has been diagnosed with mild dementia in Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 41% compared to placebo, as determined by ADAS-Cog, wherein the subject has been diagnosed with mild dementia in Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[331] In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 41% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[332] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, or at least 40% compared to placebo, as determined by CDR-SB. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[333] In some embodiments, clinical worsening is reduced by 20-60% compared to placebo, as determined by CDR-SB. In some embodiments, clinical worsening is reduced by 25-60% compared to placebo, as determined by CDR-SB. In some embodiments, clinical worsening is reduced by 25-50% compared to placebo, as determined by CDR-SB. In some embodiments, clinical worsening is reduced by at least 20% compared to placebo, as determined by CDR-SB. In some embodiments, clinical worsening is reduced by at least 30% compared to placebo, as determined by CDR-SB. In some embodiments, clinical worsening is reduced by at least 25%, such as at least 26% or at least 28%, as determined by CDR-SB. In some embodiments, the clinical worsening is reduced by at least 30%, such as at least 35% or at least 38%, as determined by CDR-SB. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[334] In some embodiments, clinical worsening is reduced by at least 30%, such as at least 35% or at least 40%, compared to placebo, as determined by CDR-SB, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 30%, such as at least 35% or at least 45%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 20%, such as at least 25%, compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[335] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, or at least 14% compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[336] In some embodiments, clinical worsening is reduced by 10-20% compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 5%, such as at least 10%, at least 12%, or at least 14%, compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 14% compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[337] In some embodiments, clinical deterioration in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 14% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[338] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, or at least 51% compared to placebo, as determined by the CDR-SB, where the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[339] In some embodiments, clinical worsening is reduced by 40-60% compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 45%, such as at least 48%, at least 50%, or at least 51%, compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 51% compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[340] In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 51% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[341] In some embodiments, a reduction in clinical worsening is determined after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 60 months, 63 months, 66 months, and/or 72 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[342] In some embodiments, a reduction in clinical worsening is determined after 1 month of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, a reduction in clinical worsening is determined after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, a reduction in clinical worsening is determined after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, a reduction in clinical worsening is determined after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, a reduction in clinical worsening is determined after 60 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in clinical worsening is determined after 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[343] In some embodiments, the reduction in clinical worsening is determined following administration of a composition comprising a therapeutically effective amount of BAN2401.

[344] In some embodiments, a reduction in clinical worsening is determined after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 60 months, 63 months, 66 months, and/or 72 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 1 month of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 6 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 12 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 18 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 60 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 63 months of administration of a composition comprising a therapeutically effective amount of BAN2401.

[345] In some embodiments, the subject is ApoE4 positive.

[346] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, or at least 74% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[347] In some embodiments, clinical worsening is reduced by 60-80%, such as 63-74%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 60%, such as at least 63%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 65%, such as at least 67%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 70%, such as at least 74%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive.

[348] In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 70% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 60% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 50%, such as at least 55% or at least 60%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 63% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[349] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, at least 170%, at least 175%, at least 180%, at least 185%, at least 190%, at least 195%, at least 200%, at least 205%, at least 210%, at least 215%, at least 220%, at least 225%, at least 230%, at least 235%, at least 240%, at least 245%, at least 250%, at least 255%, at least 260%, at least 265%, at least 270%, at least 275%, at least 280%, at least 290%, at least 295%, at least 300%, at least 305%, at least 310%, at least 315%, at least 320%, at least 325%, at least 330%, or at least 331% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[350] In some embodiments, clinical worsening is reduced by 70-400%, such as 80-350%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 70%, such as at least 75%, or at least 80%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 80%, such as at least 90%, or at least 100%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 300%, such as at least 330%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[351] In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 300% compared to placebo, as determined by ADAS-Cog, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 80%, such as at least 90% or at least 100%, compared to placebo, as determined by ADAS-Cog, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 70%, such as at least 75%, at least 80%, or at least 84%, compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 84%, compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[352] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, or at least 87% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[353] In some embodiments, clinical worsening is reduced by 35-150%, such as 40-100% or 45-90%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 35%, such as at least 40% or at least 45%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 50%, such as at least 55% or at least 60%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 70%, such as at least 80% or at least 85%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[354] In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 35%, such as at least 40% or at least 45%, compared to placebo, as determined by CDR-SB, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 70%, such as at least 75% or at least 80%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 50%, such as at least 55% or at least 60%, compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 60% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[355] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, or at least 59% compared to placebo, as determined using ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical deterioration is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[356] In some embodiments, clinical worsening is reduced by 30-70%, such as 38-59%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 30%, such as at least 35% or at least 38%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 45%, such as at least 50% or at least 53%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 50%, such as at least 55% or at least 59%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[357] In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 50%, such as at least 55%, compared to placebo, as determined by ADCOMS, following 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 30%, such as at least 35%, compared to placebo, as determined by ADCOMS, following 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical deterioration in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 45%, such as at least 50% or at least 55%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[358] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, at least 170%, at least 175%, at least 180%, at least 185%, at least 190%, at least 195%, at least 200%, at least 205%, at least 210%, or at least 211% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[359] In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 100%, such as at least 110%, compared to placebo, as determined by ADCOMS, following 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 100%, such as at least 110%, compared to placebo, as determined by ADCOMS, following 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's dementia is reduced by at least 65%, such as at least 70% or at least 75%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[360] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, at least 170%, at least 175%, at least 180%, at least 185%, at least 190%, at least 195%, at least 200%, at least 205%, at least 210%, or at least 211% compared to placebo, as determined by the ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[361] In some embodiments, clinical worsening is reduced by 40-300%, such as 45-250% or 50-250%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 40%, such as at least 45% or at least 50%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 60%, such as at least 70%, at least 75%, or at least 80%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 100%, such as at least 150%, or at least 200%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[362] In some embodiments, clinical deterioration in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 100%, such as at least 150% or at least 200%, compared to placebo, as determined by ADAS-Cog, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical deterioration in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 40%, such as at least 45% or at least 50%, compared to placebo, as determined by ADAS-Cog, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical deterioration in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 50%, such as at least 60%, at least 70%, or at least 75%, compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[363] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, or at least 45% compared to placebo, as determined by CDR-SB, where the subject is ApoE4 positive and where the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[364] In some embodiments, clinical worsening is reduced by 20-90%, such as 25-80% or 30-75%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 25%, such as at least 30%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 30%, such as at least 35% or 40%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 35%, such as at least 40% or 45%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[365] In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 35%, such as at least 40% or at least 45%, compared to placebo, as determined by CDR-SB, following administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the clinical worsening in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 20%, such as at least 25% or at least 30%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the clinical worsening in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 35%, such as at least 40%, compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one antibody to Aβ protofibrils and is administered once every two weeks or once a month. In some embodiments, the at least one antibody to Aβ protofibrils is BAN2401.

[366] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118% or at least 119% compared to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[367] In some embodiments, clinical worsening is reduced by 76-119% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 76% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 113% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 119% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[368] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139%, at least 140%, at least 141%, at least 142%, at least 143%, at least 144%, at least 145%, at least 146%, at least 147%, at least 148%, at least 149%, at least 150%, at least 151%, at least 152%, at least 153%, at least 154%, at least 155%, at least 156%, at least 157%, at least 158%, at least 159%, at least 160%, at least 161%, at least 162%, at least 163%, at least 164%, at least 165%, at least 166%, at least 167%, at least 168%, at least 169%, at least 170%, at least 171%, at least 172%, at least 173%, at least 174%, at least 175%, at least 176%, at least 177%, at least 178%, at least 179%, at least 180%, at least 190%, at least 200%, at least 210%, at least 220%, at least 230%, at least 240%, at least 250%, at least 275%, at least 300%, at least 325%, at least 350%, at least 375%, at least 400%, at least 425%, at least 450%, at least 475%, at least 500%, at least 550%, at least 600%, at least 650%, at least 700%, at least 750%, at least 800%, at least 850%, at least 900%, at least 950%, at least 1000%, at least 1001%, at least 1002%, at least 1003%, at least 1004%, at least 1005%, at least 1006%, at least 1007%, at least 1008%, at least 1009%, at least 1010%, at least 1011%, at least 1012%, at least 1013%, at least 1014%, at least 1015%, at least 1016%, at least 1017%, at least 1018%, at least 1019%, at least 1020%, at least 1021%, at least 1022%, or at least 1023% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[369] In some embodiments, clinical worsening is reduced by 58-1023% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 58% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 171% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 1023% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[370] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139%, at least 140%, at least 141%, at least 142%, at least 143%, at least 144%, at least 145%, at least 146%, at least 147%, at least 148%, at least 149%, at least 150%, at least 151%, at least 152%, at least 153%, at least 154%, at least 155%, at least 156%, at least 157%, at least 158%, at least 159%, at least 160%, at least 161%, at least 162%, at least 163%, at least 164%, at least 165%, at least 166%, at least 167%, at least 168%, at least 169%, at least 170%, at least 171%, at least 172%, at least 173% or at least 174% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[371] In some embodiments, clinical worsening is reduced by 70-200%, such as 75-180% or 82-174%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 70%, such as at least 80%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 75%, such as at least 80% or at least 85%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 150%, such as at least 160% or 170%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[372] In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 70%, such as at least 75%, at least 80%, or at least 85%, compared to placebo, as determined by CDR-SB, following administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 130%, such as at least 140%, at least 150%, at least 160%, or at least 170%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 65%, such as at least 70%, at least 75%, or at least 80%, compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[373] In some embodiments, the subject is ApoE4 negative.

[374] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, or at least 12% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[375] In some embodiments, clinical worsening is reduced by 5-15% compared to placebo as determined by ADCOMS wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 5%, such as at least 7%, compared to placebo as determined by ADCOMS wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 10%, such as at least 12%, compared to placebo as determined by ADCOMS wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[376] In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least -2% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 10% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 5%, such as at least 7%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 7% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[377] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, or at least 72% compared to placebo, as determined by the ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[378] In some embodiments, clinical worsening is reduced by 40-80% compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 35%, such as at least 40% or at least 43%, compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 40%, such as at least 45% or at least 46%, compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 65%, such as at least 70% or at least 72%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 43% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[379] In some embodiments, clinical worsening is increased by 7%, 6%, 5%, 4%, 3%, 2%, or 1% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, or at least 3% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[380] In some embodiments, clinical worsening is reduced by 3% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[381] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, or at least 166% compared to placebo, as determined by the ADAS-Cog, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[382] In some embodiments, clinical worsening is reduced by 50-200%, such as 60-180% or 65-170%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 50%, such as at least 55% or at least 65%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 70%, such as at least 75% or at least 80%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 150%, such as at least 160%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[383] In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 150%, such as at least 160%, compared to placebo, as determined by ADAS-Cog, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 70%, such as at least 75%, or at least 80%, compared to placebo, as determined by ADAS-Cog, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 50%, such as at least 60% or at least 65%, compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[384] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, or at least 5% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[385] In some embodiments, clinical worsening is reduced by at least 5% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[386] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[387] In some embodiments, clinical worsening is reduced by at least 10%, such as at least 12%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[388] In some embodiments, clinical worsening is reduced by 35-50% compared to placebo as determined by ADCOMS wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 35%, such as at least 38%, at least 40%, or at least 41%, compared to placebo as determined by ADCOMS wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 41% compared to placebo as determined by ADCOMS wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody other than BAN2401.

[389] In some embodiments, clinical worsening in a subject not co-administered with at least one Alzheimer's disease treatment other than BAN2401 is reduced by at least 41% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[390] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, or at least 59% compared to placebo, as determined using ADAS-Cog, wherein the subject is not co-administered with at least one drug for the treatment of Alzheimer's disease other than BAN2401. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[391] In some embodiments, clinical worsening is reduced by 50-70% compared to placebo as determined by ADAS-Cog wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 50%, such as at least 55%, at least 57%, or at least 59%, compared to placebo as determined by ADAS-Cog wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 59% compared to placebo as determined by ADAS-Cog wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[392] In some embodiments, clinical worsening in a subject not co-administered with at least one Alzheimer's disease treatment other than BAN2401 is reduced by at least 59% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[393] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, or at least 45% compared to placebo, as determined by CDR-SB, wherein the subject is not co-administered with at least one Alzheimer's disease treatment other than BAN2401. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[394] In some embodiments, clinical worsening is reduced by 50-70% compared to placebo as determined by ADAS-Cog wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 35%, such as at least 40%, at least 42%, or at least 45%, compared to placebo as determined by CDR-SB wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 45% compared to placebo as determined by CDR-SB wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[395] In some embodiments, clinical worsening in a subject not co-administered with at least one Alzheimer's disease treatment other than BAN2401 is reduced by at least 45% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

Treatment of a subject with early stage Alzheimer's disease resulting in a reduction in symptom severity compared to pre-treatment severity

[396] Provided herein is a method of treating a subject with early Alzheimer's disease, comprising administering to said subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein, wherein the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% compared to the severity of the same symptom in the same subject prior to treatment. In some embodiments, the subject with early Alzheimer's disease has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease and/or has been diagnosed with mild Alzheimer's dementia. In some embodiments, the subject with early Alzheimer's disease is ApoE4 positive.

[397] In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 1%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 10%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 20%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 30%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 40%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 50%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 60%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 70%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 80%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 90%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 95%.

[398] In some embodiments, said reduction in severity is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[399] In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is determined using ADCOMS, PET, MMSE, CDR-SB, and/or ADAS-Cog.

[400] In some embodiments, at least one symptom associated with Alzheimer's disease is selected from clinical worsening and brain amyloid levels.

[401] Any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, dosage regimens thereof, and compositions comprising them disclosed herein can be used in a method of treating a subject with early Alzheimer's disease. For example, in some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of at least one anti-Aβ protofibril antibody, such as BAN2401, based on the subject's body weight, is administered to the subject once per week, once every two weeks, once every three weeks, once every four weeks, or once per month.

[402] In some embodiments, at least one symptom associated with Alzheimer's disease is clinical worsening.

[403] In some embodiments, at least one symptom associated with Alzheimer's disease is the level of amyloid in the brain.

[404] In some embodiments, a reduction in clinical worsening is determined after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 60 months, 63 months, 66 months, and/or 72 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 1 month of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 6 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 12 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 18 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 60 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 63 months of administration of a composition comprising a therapeutically effective amount of BAN2401.

[405] In some embodiments, the subject is ApoE4 positive.

In some embodiments, the subject is ApoE4 negative.

Treatment of a subject with early Alzheimer's disease resulting in a reduction in symptom severity compared to the symptom severity in a subject treated with placebo

[406] Provided herein is a method of treating a subject with early Alzheimer's disease, comprising administering to said subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein, wherein the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% compared to the severity of the same symptom in subjects receiving a placebo. In some embodiments, the subject with early Alzheimer's disease has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease and/or has been diagnosed with mild Alzheimer's dementia. In some embodiments, the subject with early Alzheimer's disease is ApoE4 positive.

[407] In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 1%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 10%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 20%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 30%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 40%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 50%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 60%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 70%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 80%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 90%. In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 95%.

[408] In some embodiments, the aforementioned reduction in severity is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[409] In some embodiments, the severity of at least one symptom associated with Alzheimer's disease is determined using ADCOMS, PET, MMSE, CDR-SB, and/or ADAS-Cog.

[410] In some embodiments, at least one symptom associated with Alzheimer's disease is selected from clinical worsening and brain amyloid levels.

[411] Any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, dosage regimens thereof, and compositions comprising them disclosed herein can be used in a method of treating a subject with early Alzheimer's disease. For example, in some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of at least one anti-Aβ protofibril antibody, such as BAN2401, based on the subject's body weight, is administered to the subject once per week, once every two weeks, once every three weeks, once every four weeks, or once per month.

[412] In some embodiments, at least one symptom associated with Alzheimer's disease is clinical worsening.

[413] In some embodiments, at least one symptom associated with Alzheimer's disease is the level of amyloid in the brain.

[414] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, or at least 46% compared to placebo, as determined by ADCOMS. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[415] In some embodiments, clinical worsening is reduced by 20-35% compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by 20-30% compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by 27-35% compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by at least 20% compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by at least 35% compared to placebo as determined by ADCOMS. In some embodiments, clinical worsening is reduced by at least 20% as determined by ADCOMS. In some embodiments, clinical worsening is reduced by at least 30% as determined by ADCOMS. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[416] In some embodiments, clinical worsening is reduced by at least 45% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 35% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 46% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[417] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, or at least 52% compared to placebo, as determined by ADCOMS, where the subject has been diagnosed with mild cognitive impairment, with intermediate probability of Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[418] In some embodiments, clinical worsening is reduced by 28-33% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 20%, such as 25%, or at least 28%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 25%, such as at least 30%, or at least 33%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 25%, such as at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 52%, compared to placebo, as determined by ADCOMS, where the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 52% compared to placebo, as determined by ADCOMS, where the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[419] In some embodiments, clinical worsening in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 25% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 52% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[420] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, or at least 33% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment, with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical deterioration is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[421] In some embodiments, clinical deterioration is reduced by 28-38% compared to placebo, as determined by ADCOMS, where the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 20%, such as at least 25%, at least 28%, or at least 33%, compared to placebo, as determined by ADCOMS, where the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 25%, such as at least 30% or at least 33%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 33% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical deterioration is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[422] In some embodiments, clinical deterioration in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 33% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[423] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, or at least 78% compared to placebo, as determined by ADCOMS, where the subject was diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[424] In some embodiments, clinical worsening is reduced by 20-80% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 35-78% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 35% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 50%, such as at least 52% or at least 53%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 70%, such as at least 75% or at least 78%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild Alzheimer's dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[425] In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 70% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 50% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 52% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[426] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, or at least 35% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[427] In some embodiments, clinical worsening is reduced by 28-38% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 20%, such as at least 25%, at least 28%, or at least 35%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 25%, such as at least 30%, or at least 35%, compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 35% compared to placebo, as determined by ADCOMS, wherein the subject has been diagnosed with mild dementia in Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[428] In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 35% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[429] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, or at least 150% compared to placebo, as determined by the ADAS-Cog. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[430] In some embodiments, clinical worsening is reduced by 40-150% compared to placebo, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by 45-145% compared to placebo, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by 45-55% compared to placebo, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by at least 30% compared to placebo, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by at least 35% compared to placebo, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by at least 40%, as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by at least 45% as determined by ADAS-Cog. In some embodiments, clinical worsening is reduced by at least 47% as determined by ADAS-Cog. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[431] In some embodiments, clinical worsening is reduced by at least 100%, such as at least 120% or at least 140%, compared to placebo, as determined by ADAS-Cog, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 40%, such as at least 45%, compared to placebo, as determined by ADAS-Cog, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 40%, such as at least 45%, compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 47% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[432] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 56%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, or at least 58% compared to placebo, as determined by the ADAS-Cog, wherein the subject has been diagnosed with mild cognitive impairment, with an intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical deterioration is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[433] In some embodiments, clinical worsening is reduced by 50-70% compared to placebo, as determined by the ADAS-Cog, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 50%, such as at least 52%, at least 55%, or at least 58%, compared to placebo, as determined by the ADAS-Cog, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 58% compared to placebo, as determined by the ADAS-Cog, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[434] In some embodiments, clinical deterioration in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 58% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[435] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, or at least 41% compared to placebo, as determined by the ADAS-Cog, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[436] In some embodiments, clinical worsening is reduced by 30-50% compared to placebo, as determined by ADAS-Cog, wherein the subject has been diagnosed with mild dementia in Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 35%, such as at least 38%, at least 40%, or at least 41%, compared to placebo, as determined by ADAS-Cog, wherein the subject has been diagnosed with mild dementia in Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 41% compared to placebo, as determined by ADAS-Cog, wherein the subject has been diagnosed with mild dementia in Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[437] In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 41% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[438] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, or at least 40% compared to placebo, as determined by CDR-SB. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[439] In some embodiments, clinical worsening is reduced by 20-60% compared to placebo, as determined by CDR-SB. In some embodiments, clinical worsening is reduced by 25-60% compared to placebo, as determined by CDR-SB. In some embodiments, clinical worsening is reduced by 25-50% compared to placebo, as determined by CDR-SB. In some embodiments, clinical worsening is reduced by at least 20% compared to placebo, as determined by CDR-SB. In some embodiments, clinical worsening is reduced by at least 30% compared to placebo, as determined by CDR-SB. In some embodiments, clinical worsening is reduced by at least 25%, such as at least 26% or at least 28%, as determined by CDR-SB. In some embodiments, the clinical worsening is reduced by at least 30%, such as at least 35% or at least 38%, as determined by CDR-SB. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[440] In some embodiments, clinical worsening is reduced by at least 30%, such as at least 35% or at least 40%, compared to placebo, as determined by CDR-SB, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 30%, such as at least 35% or at least 45%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 20%, such as at least 25%, compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[441] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, or at least 14% compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[442] In some embodiments, clinical worsening is reduced by 10-20% compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 5%, such as at least 10%, at least 12%, or at least 14%, compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 14% compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[443] In some embodiments, clinical deterioration in a subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 14% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[444] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, or at least 51% compared to placebo, as determined by the CDR-SB, where the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[445] In some embodiments, clinical worsening is reduced by 40-60% compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 45%, such as at least 48%, at least 50%, or at least 51%, compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 51% compared to placebo, as determined by CDR-SB, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[446] In some embodiments, clinical worsening in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 51% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[447] In some embodiments, a reduction in clinical worsening is determined after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 60 months, 63 months, 66 months, and/or 72 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[448] In some embodiments, a reduction in clinical worsening is determined after 1 month of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, a reduction in clinical worsening is determined after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, a reduction in clinical worsening is determined after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, a reduction in clinical worsening is determined after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, a reduction in clinical worsening is determined after 60 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in clinical worsening is determined after 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[449] In some embodiments, the reduction in clinical worsening is determined following administration of a composition comprising a therapeutically effective amount of BAN2401.

[450] In some embodiments, a reduction in clinical worsening is determined after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 60 months, 63 months, 66 months, and/or 72 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 1 month of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 6 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 12 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 18 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 60 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical worsening is determined after 63 months of administration of a composition comprising a therapeutically effective amount of BAN2401.

[451] In some embodiments, the subject is ApoE4 positive.

[452] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, or at least 74% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[453] In some embodiments, clinical worsening is reduced by 60-80%, such as 63-74%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 60%, such as at least 63%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 65%, such as at least 67%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 70%, such as at least 74%, compared to placebo, as determined by ADCOMS, where the subject is ApoE4 positive.

[454] In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 70% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 60% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 50%, such as at least 55% or at least 60%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 63% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[455] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, at least 170%, at least 175%, at least 180%, at least 185%, at least 190%, at least 195%, at least 200%, at least 205%, at least 210%, at least 215%, at least 220%, at least 225%, at least 230%, at least 235%, at least 240%, at least 245%, at least 250%, at least 255%, at least 260%, at least 265%, at least 270%, at least 275%, at least 280%, at least 290%, at least 295%, at least 300%, at least 305%, at least 310%, at least 315%, at least 320%, at least 325%, at least 330%, or at least 331% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[456] In some embodiments, clinical worsening is reduced by 70-400%, such as 80-350%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 70%, such as at least 75%, at least 80%, or at least 84%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening in an ApoE4 positive subject is reduced by at least 84% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 80%, such as at least 90% or at least 100%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 300%, such as at least 330%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[457] In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 300% compared to placebo, as determined by ADAS-Cog, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 80%, such as at least 90% or at least 100%, compared to placebo, as determined by ADAS-Cog, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 70%, such as at least 75%, at least 80%, or at least 84%, compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 84%, compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[458] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, or at least 87% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[459] In some embodiments, clinical worsening is reduced by 35-150%, such as 40-100% or 45-90%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 35%, such as at least 40% or at least 45%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 50%, such as at least 55% or at least 60%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, clinical worsening is reduced by at least 70%, such as at least 80% or at least 85%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[460] In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 35%, such as at least 40% or at least 45%, compared to placebo, as determined by CDR-SB, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 70%, such as at least 75% or at least 80%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 50%, such as at least 55% or at least 60%, compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject is reduced by at least 60% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[461] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, or at least 59% compared to placebo, as determined using ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical deterioration is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[462] In some embodiments, clinical worsening is reduced by 30-70%, such as 38-59%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 30%, such as at least 35% or at least 38%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 45%, such as at least 50% or at least 53%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 50%, such as at least 55% or at least 59%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[463] In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 50%, such as at least 55%, compared to placebo, as determined by ADCOMS, following 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 30%, such as at least 35%, compared to placebo, as determined by ADCOMS, following 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical deterioration in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 45%, such as at least 50% or at least 55%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[464] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, at least 170%, at least 175%, at least 180%, at least 185%, at least 190%, at least 195%, at least 200%, at least 205%, at least 210%, or at least 211% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[465] In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 100%, such as at least 110%, compared to placebo, as determined by ADCOMS, following 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 100%, such as at least 110%, compared to placebo, as determined by ADCOMS, following 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's dementia is reduced by at least 65%, such as at least 70% or at least 75%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[466] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, at least 170%, at least 175%, at least 180%, at least 185%, at least 190%, at least 195%, at least 200%, at least 205%, at least 210%, or at least 211% compared to placebo, as determined by the ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[467] In some embodiments, clinical worsening is reduced by 40-300%, such as 45-250% or 50-250%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 40%, such as at least 45% or at least 50%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 60%, such as at least 70%, at least 75%, or at least 80%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 100%, such as at least 150%, or at least 200%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[468] In some embodiments, clinical deterioration in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 100%, such as at least 150% or at least 200%, compared to placebo, as determined by ADAS-Cog, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical deterioration in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 40%, such as at least 45% or at least 50%, compared to placebo, as determined by ADAS-Cog, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical deterioration in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 50%, such as at least 60%, at least 70%, or at least 75%, compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[469] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, or at least 45% compared to placebo, as determined by CDR-SB, where the subject is ApoE4 positive and where the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[470] In some embodiments, clinical worsening is reduced by 20-90%, such as 25-80% or 30-75%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 25%, such as at least 30%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 30%, such as at least 35% or 40%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 35%, such as at least 40% or 45%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[471] In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 35%, such as at least 40% or at least 45%, compared to placebo, as determined by CDR-SB, following administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the clinical worsening in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 20%, such as at least 25% or at least 30%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the clinical worsening in an ApoE4-positive subject diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease is reduced by at least 35%, such as at least 40%, compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one antibody to Aβ protofibrils and is administered once every two weeks or once a month. In some embodiments, the at least one antibody to Aβ protofibrils is BAN2401.

[472] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118% or at least 119% compared to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[473] In some embodiments, clinical worsening is reduced by 76-119% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 76% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 113% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 119% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[474] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139%, at least 140%, at least 141%, at least 142%, at least 143%, at least 144%, at least 145%, at least 146%, at least 147%, at least 148%, at least 149%, at least 150%, at least 151%, at least 152%, at least 153%, at least 154%, at least 155%, at least 156%, at least 157%, at least 158%, at least 159%, at least 160%, at least 161%, at least 162%, at least 163%, at least 164%, at least 165%, at least 166%, at least 167%, at least 168%, at least 169%, at least 170%, at least 171%, at least 172%, at least 173%, at least 174%, at least 175%, at least 176%, at least 177%, at least 178%, at least 179%, at least 180%, at least 190%, at least 200%, at least 210%, at least 220%, at least 230%, at least 240%, at least 250%, at least 275%, at least 300%, at least 325%, at least 350%, at least 375%, at least 400%, at least 425%, at least 450%, at least 475%, at least 500%, at least 550%, at least 600%, at least 650%, at least 700%, at least 750%, at least 800%, at least 850%, at least 900%, at least 950%, at least 1000%, at least 1001%, at least 1002%, at least 1003%, at least 1004%, at least 1005%, at least 1006%, at least 1007%, at least 1008%, at least 1009%, at least 1010%, at least 1011%, at least 1012%, at least 1013%, at least 1014%, at least 1015%, at least 1016%, at least 1017%, at least 1018%, at least 1019%, at least 1020%, at least 1021%, at least 1022%, or at least 1023% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[475] In some embodiments, clinical worsening is reduced by 58-1023% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 58% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 171% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by 1023% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[476] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139%, at least 140%, at least 141%, at least 142%, at least 143%, at least 144%, at least 145%, at least 146%, at least 147%, at least 148%, at least 149%, at least 150%, at least 151%, at least 152%, at least 153%, at least 154%, at least 155%, at least 156%, at least 157%, at least 158%, at least 159%, at least 160%, at least 161%, at least 162%, at least 163%, at least 164%, at least 165%, at least 166%, at least 167%, at least 168%, at least 169%, at least 170%, at least 171%, at least 172%, at least 173% or at least 174% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[477] In some embodiments, clinical worsening is reduced by 70-200%, such as 75-180% or 82-174%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 70%, such as at least 80%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 75%, such as at least 80% or at least 85%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 150%, such as at least 160% or 170%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4-positive and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[478] In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 70%, such as at least 75%, at least 80%, or at least 85%, compared to placebo, as determined by CDR-SB, following administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 130%, such as at least 140%, at least 150%, at least 160%, or at least 170%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 65%, such as at least 70%, at least 75%, or at least 80%, compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[479] In some embodiments, the subject is ApoE4 negative.

[480] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, or at least 12% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[481] In some embodiments, clinical worsening is reduced by 5-15% compared to placebo as determined by ADCOMS wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 5%, such as at least 7%, compared to placebo as determined by ADCOMS wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 10%, such as at least 12%, compared to placebo as determined by ADCOMS wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[482] In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least -2% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 10% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 5%, such as at least 7%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 7% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[483] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, or at least 72% compared to placebo, as determined by the ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[484] In some embodiments, clinical worsening is reduced by 40-80% compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 35%, such as at least 40% or at least 43%, compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 40%, such as at least 45% or at least 46%, compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 65%, such as at least 70% or at least 72%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 43% compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[485] In some embodiments, clinical worsening is increased by 7%, 6%, 5%, 4%, 3%, 2%, or 1% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative. In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, or at least 3% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[486] In some embodiments, clinical worsening is reduced by 3% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, or at least 26% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 negative and wherein the subject was diagnosed with mild cognitive impairment, with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical deterioration is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[487] In some embodiments, clinical worsening is reduced by 15-26% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by 15% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by 26% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[488] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, or at least 166% compared to placebo, as determined by the ADAS-Cog, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[489] In some embodiments, clinical worsening is reduced by 50-200%, such as 60-180% or 65-170%, compared to placebo, as determined by the ADAS-Cog, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical worsening is reduced by at least 50%, such as at least 55% or at least 65%, compared to placebo, as determined by the ADAS-Cog, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 70%, such as at least 75% or at least 80%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, clinical deterioration is reduced by at least 150%, such as at least 160%, compared to placebo, as determined by ADAS-Cog, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[490] In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 150%, such as at least 160%, compared to placebo, as determined by ADAS-Cog, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 70%, such as at least 75% or at least 80%, compared to placebo, as determined by ADAS-Cog, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical worsening in an ApoE4-negative subject is reduced by at least 50%, such as at least 60% or at least 65%, compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[491] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, or at least 5% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[492] In some embodiments, clinical worsening is reduced by at least 5% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with mild cognitive impairment with intermediate probability due to Alzheimer's disease. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[493] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with having mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

In some embodiments, clinical worsening is reduced by at least 10%, such as at least 12%, compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[494] In some embodiments, clinical worsening is reduced by 35-50% compared to placebo as determined by ADCOMS wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 35%, such as at least 38%, at least 40%, or at least 41%, compared to placebo as determined by ADCOMS wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 41% compared to placebo as determined by ADCOMS wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody other than BAN2401.

[495] In some embodiments, clinical worsening in a subject not co-administered with at least one drug for treating Alzheimer's disease is reduced by at least 41% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[496] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, or at least 59% compared to placebo, as determined using ADAS-Cog, wherein the subject is not co-administered with at least one drug for the treatment of Alzheimer's disease other than BAN2401. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[497] In some embodiments, clinical worsening is reduced by 50-70% compared to placebo as determined by ADAS-Cog wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 50%, such as at least 55%, at least 57%, or at least 59%, compared to placebo as determined by ADAS-Cog wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, clinical worsening is reduced by at least 59% compared to placebo as determined by ADAS-Cog wherein the subject is not co-administered with at least one drug for treating Alzheimer's disease other than BAN2401. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[498] In some embodiments, clinical worsening in a subject not co-administered with at least one Alzheimer's disease treatment other than BAN2401 is reduced by at least 59% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[499] In some embodiments, clinical worsening is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, or at least 45% compared to placebo, as determined by CDR-SB, wherein the subject is not co-administered with at least one Alzheimer's disease treatment other than BAN2401. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[500] In some embodiments, clinical worsening is reduced by 50-70% compared to placebo as determined by ADAS-Cog wherein the subject is not co-administered with at least one Alzheimer's disease treatment other than BAN2401. In some embodiments, clinical worsening is reduced by at least 35%, such as at least 40%, at least 42%, or at least 45%, compared to placebo as determined by CDR-SB wherein the subject is not co-administered with at least one Alzheimer's disease treatment other than BAN2401. In some embodiments, clinical worsening is reduced by at least 45% compared to placebo as determined by CDR-SB wherein the subject is not co-administered with at least one Alzheimer's disease treatment other than BAN2401. In some embodiments, said reduction in clinical worsening is determined after 1 month, 6 months, 12 months, 18 months, 60 months and/or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[501] In some embodiments, clinical worsening in a subject not co-administered with at least one Alzheimer's disease treatment other than BAN2401 is reduced by at least 45% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once per month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

Prevention and/or delay of the onset of Alzheimer's disease

[502] Also provided herein is a method for preventing and/or delaying the onset of Alzheimer's disease in ApoE4-positive subjects. In some embodiments, the method comprises determining the level of amyloid in the brain of the subject and then, if the level of amyloid in the brain of the subject exceeds a first predetermined level, administering a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[503] In some embodiments, the method further comprises measuring the amyloid level in the subject's brain after administration.

[504] In some embodiments, the method further comprises determining the level of Aβ _1-42 in the cerebrospinal fluid and/or the level of total tau protein in the cerebrospinal fluid.

[505] In some embodiments, the method further comprises determining the level of neurogranin in the cerebrospinal fluid.

[506] In some embodiments, the method further comprises determining the level of neurofilament light chains in the cerebrospinal fluid.

[507] In some embodiments, the method further comprises administering the composition if the amyloid level in the brain after administration exceeds a second predetermined level.

[508] In some embodiments, the method further comprises monitoring the amyloid level in the subject's brain after administration until the amyloid level in the subject's brain is below a first predetermined level.

[509] In some embodiments, the method further comprises administering the composition if the level of Aβ _1-42 in the cerebrospinal fluid and/or the level of total tau protein in the cerebrospinal fluid after administration exceeds a predetermined level.

[510] In some embodiments, the method further comprises administering the composition if the level of neurogranin in the cerebrospinal fluid after administration exceeds a predetermined level.

[511] In some embodiments, the method further comprises administering the composition if the level of neurofilament light chains after administration exceeds a predetermined level.

[512] In some embodiments, the method further comprises administering at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent is selected from BACE inhibitors, gamma-secretase inhibitors, gamma-secretase modulators, inhibitors of the formation of Aβ peptides other than said at least one anti-Aβ protofibril antibody, agents that reduce levels of Aβ peptides other than said at least one anti-Aβ protofibril antibody, and combinations thereof. In some embodiments, the at least one additional therapeutic agent is a BACE inhibitor. In some embodiments, the BACE inhibitor is selected from CNP520, BI-1181181, LY2886721, LY3202626, PF-06751979, RG7129, atabecestat, elenbecestat, lanabecestat, and verubecestat. In some embodiments, the BACE inhibitor is elenbecestat.

[513] Any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, dosage regimens thereof, and compositions comprising them disclosed herein can be used in a method of reducing amyloid levels in the brain of a subject with early Alzheimer's disease. For example, in some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of at least one anti-Aβ protofibril antibody, such as BAN2401, based on the body weight of the subject, is administered to the subject once per week, once every two weeks, once every three weeks, once every four weeks, or once per month.

[514] In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[515] In some embodiments, administering a composition comprising at least one anti-Aβ protofibril antibody results in at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, by at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of subjects become amyloid negative as determined by visual readings of PET images of amyloid.

[516] In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody results in 75% to 100%, such as 80% to 100% or 85% to 100%, of the subjects becoming amyloid negative, as determined by visual readings of PET images of amyloid. In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody results in at least 75%, such as at least 80% or at least 85%, of the subjects becoming amyloid negative, as determined by visual readings of PET images of amyloid. In some embodiments, administration of a composition comprising at least one antibody to Aβ protofibrils results in 100% of subjects becoming amyloid negative, as determined by visual readings of PET images of amyloid.

[517] In some embodiments, at least 75%, such as at least 80% or at least 85%, of the subjects are amyloid negative, as determined by visual readings of PET images of amyloid, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, at least 75%, such as at least 80%, at least 85%, at least 90%, or at least 95%, of the subjects are amyloid negative, as determined by visual readings of PET images of amyloid, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one antibody to Aβ protofibrils and is administered once every two weeks or once a month. In some embodiments, the at least one antibody to Aβ protofibrils is BAN2401.

[518] In some embodiments, the method results in a decrease in the amyloid level in the brain after administration compared to the amyloid level in the brain before administration. In some embodiments, the amyloid level in the brain is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% compared to the amyloid level in the brain before said administration. In some embodiments, said reduction in amyloid levels in the brain is determined using visual readings of PET images of amyloid and is expressed as PET standardized uptake value values (SUVr values).

[519] In some embodiments, the adjusted mean change in the PET SUVr value in a subject compared to the brain amyloid level prior to administration of the composition comprising at least one anti-Aβ protofibril antibody is reduced by at least -0.10, at least -0.15, at least -0.20, at least -0.25, at least -0.30, at least -0.35, at least -0.40, at least -0.45, at least -0.50, at least -0.55, at least -0.60, at least -0.65, at least -0.70, at least -0.75, at least -0.80, at least -0.85, at least -0.90, or at least -0.95. In some embodiments, the adjusted mean change in the subject's PET SUVr relative to the brain amyloid level prior to administration of the composition comprising at least one anti-Aβ protofibril antibody is reduced by a value between -0.20 and -0.30.

[520] In some embodiments, when comparing the overall mean value for the cerebral cortex and the reference value for the whole cerebellum, the adjusted mean change in the PET SUVr value of the subject relative to the amyloid level in the brain prior to administration of the composition comprising at least one anti-Aβ protofibril antibody is reduced by at least -0.20, such as at least -0.25, after 12 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the adjusted mean change in the PET SUVr value of the subject relative to the PET SUVr value of the subject prior to administration is reduced by at least -0.25, such as at least -0.30, after 18 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[521] In some embodiments, the reduction in brain amyloid levels is determined by imaging using radiotracers that bind brain amyloid Aβ and is visualized using PET. In some embodiments, the reduction in adjusted mean change relative to the level in the subject prior to administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is at least -50, such as at least -55, or at least -59, centiloids after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in adjusted mean change relative to the level in the subject before administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is at least -60, such as at least -65 or at least -70, centiloids after 18 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[522] In some embodiments, the method results in a decrease in the level of Aβ _1-42 in the cerebrospinal fluid compared to the level of Aβ _1-42 in the cerebrospinal fluid prior to administration. In some embodiments, the method results in a decrease in the Aβ _1-42 level in the cerebrospinal fluid, compared to the Aβ _1-42 level in the cerebrospinal fluid before administration, of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, by at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%.

[523] In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody results in a decrease in the amyloid level in the brain compared to the amyloid level in the brain prior to administration of the composition comprising at least one anti-Aβ protofibril antibody of from -0.20 to -0.45, such as from -0.25 to -0.35, as determined by visual readings of PET images of amyloid. In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody results in a decrease in the amyloid level in the brain compared to the amyloid level in the brain prior to administration of the composition comprising at least one anti-Aβ protofibril antibody of at least -0.25, as determined by visual readings of PET images of amyloid. In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody results in a decrease in brain amyloid levels, compared to brain amyloid levels prior to administration of the composition comprising at least one anti-Aβ protofibril antibody, of at least 0.30, as determined by visual readings of PET images of amyloid.

[524] Also provided herein is another method for preventing and/or delaying the onset of Alzheimer's disease in ApoE4-positive subjects. In some embodiments, the method comprises determining the level of amyloid in the brain of the subject and then, if the level of amyloid in the brain of the subject exceeds a first predetermined level, administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent selected from BACE inhibitors, gamma-secretase inhibitors, gamma-secretase modulators, inhibitors of the formation of Aβ peptides other than said at least one anti-Aβ protofibril antibody, and agents that reduce the levels of Aβ peptides other than said at least one anti-Aβ protofibril antibody.

[525] In some embodiments, the method further comprises measuring the amyloid level in the subject's brain after administration.

[526] In some embodiments, the method further comprises determining the level of Aβ _1-42 in the cerebrospinal fluid and/or the level of total tau protein in the cerebrospinal fluid.

[527] In some embodiments, the method further comprises determining the level of neurogranin in the cerebrospinal fluid.

[528] In some embodiments, the method further comprises determining the level of neurofilament light chains in the cerebrospinal fluid.

[529] In some embodiments, said method further comprises administering a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils and a composition comprising a therapeutically effective amount of at least one therapeutic agent selected from BACE inhibitors, gamma-secretase inhibitors, gamma-secretase modulators, inhibitors of the formation of Aβ peptides other than said at least one antibody to Aβ protofibrils, and agents that reduce levels of Aβ peptides other than said at least one antibody to Aβ protofibrils if the amyloid level in the brain exceeds a second predetermined level following administration.

[530] In some embodiments, the method further comprises administering the composition if the level of Aβ _1-42 in the cerebrospinal fluid and/or the level of total tau protein in the cerebrospinal fluid after administration exceeds a predetermined level.

[531] In some embodiments, the method further comprises administering the composition if the level of neurogranin in the cerebrospinal fluid after administration exceeds a predetermined level.

[532] In some embodiments, the method further comprises administering the composition if the level of neurofilament light chains in the cerebrospinal fluid after administration exceeds a predetermined level.

[533] In some embodiments, the method further comprises monitoring the amyloid level in the subject's brain after administration until the amyloid level in the subject's brain is below a first predetermined level.

[534] In some embodiments, the method further comprises administering at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent is selected from BACE inhibitors, gamma-secretase inhibitors, gamma-secretase modulators, inhibitors of the formation of Aβ peptides other than said at least one anti-Aβ protofibril antibody, agents that reduce levels of Aβ peptides other than said at least one anti-Aβ protofibril antibody, and combinations thereof.

[535] In some embodiments, the at least one additional therapeutic agent is a BACE inhibitor. In some embodiments, the BACE inhibitor is elenbecestat.

[536] Any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, dosage regimens thereof, and compositions comprising them disclosed herein can be used in a method of reducing amyloid levels in the brain of a subject with early Alzheimer's disease. For example, in some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of at least one anti-Aβ protofibril antibody, such as BAN2401, based on the body weight of the subject, is administered to the subject once per week, once every two weeks, once every three weeks, once every four weeks, or once per month.

[537] In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[538] In some embodiments, the at least one therapeutic agent is a BACE inhibitor. In some embodiments, the BACE inhibitor is elenbecestat.

[539] In some embodiments, administering a composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent results in at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, by at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of subjects become amyloid negative, as determined by visual readings of PET images of amyloid.

[540] In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent results in 75% to 100%, such as 80% to 100% or 85% to 100%, of the subjects becoming amyloid negative, as determined by visual readings of PET images of amyloid. In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent results in at least 75%, such as at least 80% or at least 85%, of the subjects becoming amyloid negative, as determined by visual readings of PET images of amyloid. In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent results in 100% of subjects becoming amyloid negative, as determined by visual readings of PET images of amyloid.

[541] In some embodiments, at least 75%, such as at least 80% or at least 85%, of the subjects are amyloid negative, as determined by visual readings of PET images of amyloid, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent. In some embodiments, at least 75%, such as at least 80%, at least 85%, at least 90%, or at least 95%, of the subjects are amyloid negative, as determined by visual readings of PET images of amyloid, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent. In some embodiments, the composition comprises 10 mg/kg of at least one antibody to Aβ protofibrils and is administered once every two weeks or once a month. In some embodiments, the at least one antibody to Aβ protofibrils is BAN2401.

[542] In some embodiments, the method results in a decrease in the amyloid level in the brain after administration compared to the amyloid level in the brain before administration. In some embodiments, the amyloid level in the brain is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% compared to the amyloid level in the brain before said administration. In some embodiments, said reduction in amyloid levels in the brain is determined using visual readings of PET images of amyloid and is expressed as PET standardized uptake value values (SUVr values).

[543] In some embodiments, the adjusted mean change in the PET SUVr value of the subject compared to the brain amyloid level prior to administration of the composition comprising at least one anti-Aβ protofibril antibody and the composition comprising a therapeutically effective amount of at least one therapeutic agent is reduced by at least -0.10, at least -0.15, at least -0.20, at least -0.25, at least -0.30, at least -0.35, at least -0.40, at least -0.45, at least -0.50, at least -0.55, at least -0.60, at least -0.65, at least -0.70, at least -0.75, at least -0.80, at least -0.85, at least -0.90, or at least -0.95. In some embodiments, the adjusted mean change in the subject's PET SUVr relative to the brain amyloid level prior to administration of the composition comprising at least one anti-Aβ protofibril antibody and the composition comprising a therapeutically effective amount of at least one therapeutic agent is reduced by a value of -0.20 to -0.30.

[544] In some embodiments, when comparing the overall mean score for the cerebral cortex and the reference score for the whole cerebellum, the adjusted mean change in the subject's PET SUVr value relative to the brain amyloid level prior to administration of the composition comprising at least one anti-Aβ protofibril antibody and the composition comprising a therapeutically effective amount of at least one therapeutic agent is reduced by at least -0.20, such as by at least -0.25, following 12 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody and the composition comprising a therapeutically effective amount of at least one therapeutic agent. In some embodiments, the adjusted mean change in the subject's PET SUVr value compared to the subject's PET SUVr value prior to administration is reduced by at least -0.25, such as at least -0.30, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent.

[545] In some embodiments, the reduction in brain amyloid levels is determined by imaging using radiotracers that bind brain amyloid Aβ and is visualized using PET. In some embodiments, the reduction in adjusted mean change from the level in the subject before administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent is at least -50, such as at least -55, or at least -59, centiloids after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent. In some embodiments, the reduction in adjusted mean change relative to the level in the subject before administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is at least -60, such as at least -65, or at least -70, centiloids after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent.

[546] In some embodiments, the method results in a decrease in the level of Aβ _1-42 in the cerebrospinal fluid compared to the level of Aβ _1-42 in the cerebrospinal fluid prior to administration. In some embodiments, the method results in a decrease in the Aβ _1-42 level in the cerebrospinal fluid, compared to the Aβ _1-42 level in the cerebrospinal fluid before administration, of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, by at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%.

[547] In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent results in a decrease in the amyloid level in the brain, compared to the amyloid level in the brain prior to administration of the composition comprising at least one anti-Aβ protofibril antibody and the composition comprising a therapeutically effective amount of at least one therapeutic agent, of from -0.20 to -0.45, such as from -0.25 to -0.35, as determined by visual readings of PET images of amyloid. In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent results in a decrease in brain amyloid levels, compared to brain amyloid levels prior to administration of the composition comprising at least one anti-Aβ protofibril antibody, of at least -0.25, as determined by visual readings of PET images of amyloid. In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent results in a decrease in brain amyloid levels, compared to brain amyloid levels prior to administration of the composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent, of at least 0.30, as determined by visual readings of PET images of amyloid.

Prevention and/or delay of the onset of Alzheimer's disease

[548] Also provided herein is a method of preventing and/or delaying the onset of Alzheimer's disease in a subject. In some embodiments, the subject is ApoE4 positive. In some embodiments, the subject is ApoE4 negative. In some embodiments, the method comprises determining the level of amyloid in the subject's brain and then, if the level of amyloid in the subject's brain exceeds a first predetermined level, administering a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[549] In some embodiments, the method further comprises measuring the amyloid level in the subject's brain after administration.

[550] In some embodiments, the method further comprises determining the level of Aβ _1-42 in the cerebrospinal fluid and/or the level of total tau protein in the cerebrospinal fluid.

[551] In some embodiments, the method further comprises determining the level of neurogranin in the cerebrospinal fluid.

[552] In some embodiments, the method further comprises determining the level of neurofilament light chains in the cerebrospinal fluid.

[553] In some embodiments, the method further comprises administering the composition if the amyloid level in the brain after administration exceeds a second predetermined level.

[554] In some embodiments, the method further comprises monitoring the amyloid level in the subject's brain after administration until the amyloid level in the subject's brain is below a first predetermined level.

[555] In some embodiments, the method further comprises administering the composition if the level of Aβ _1-42 in the cerebrospinal fluid and/or the level of total tau protein in the cerebrospinal fluid after administration exceeds a predetermined level.

[556] In some embodiments, the method further comprises administering the composition if the level of neurogranin in the cerebrospinal fluid after administration exceeds a predetermined level.

[557] In some embodiments, the method further comprises administering the composition if the level of neurofilament light chains after administration exceeds a predetermined level.

[558] In some embodiments, the method further comprises administering at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent is selected from BACE inhibitors, gamma-secretase inhibitors, gamma-secretase modulators, inhibitors of the formation of Aβ peptides other than said at least one anti-Aβ protofibril antibody, agents that reduce levels of Aβ peptides other than said at least one anti-Aβ protofibril antibody, and combinations thereof. In some embodiments, the at least one additional therapeutic agent is a BACE inhibitor. In some embodiments, the BACE inhibitor is selected from CNP520, BI-1181181, LY2886721, LY3202626, PF-06751979, RG7129, atabecestat, elenbecestat, lanabecestat, and verubecestat. In some embodiments, the BACE inhibitor is elenbecestat.

[559] Any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, dosage regimens thereof, and compositions comprising them disclosed herein can be used in a method of reducing amyloid levels in the brain of a subject with early Alzheimer's disease. For example, in some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of at least one anti-Aβ protofibril antibody, such as BAN2401, based on the body weight of the subject, is administered to the subject once per week, once every two weeks, once every three weeks, once every four weeks, or once per month.

[560] In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[561] In some embodiments, administering a composition comprising at least one anti-Aβ protofibril antibody results in at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, by at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of subjects become amyloid negative as determined by visual readings of PET images of amyloid.

[562] In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody results in 75% to 100%, such as 80% to 100% or 85% to 100%, of the subjects becoming amyloid negative, as determined by visual readings of PET images of amyloid. In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody results in at least 75%, such as at least 80% or at least 85%, of the subjects becoming amyloid negative, as determined by visual readings of PET images of amyloid. In some embodiments, administration of a composition comprising at least one antibody to Aβ protofibrils results in 100% of subjects becoming amyloid negative, as determined by visual readings of PET images of amyloid.

[563] In some embodiments, at least 75%, such as at least 80% or at least 85%, of the subjects are amyloid negative, as determined by visual readings of PET images of amyloid, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, at least 75%, such as at least 80%, at least 85%, at least 90%, or at least 95%, of the subjects are amyloid negative, as determined by visual readings of PET images of amyloid, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg/kg of at least one antibody to Aβ protofibrils and is administered once every two weeks or once a month. In some embodiments, the at least one antibody to Aβ protofibrils is BAN2401.

[564] In some embodiments, the method results in a decrease in the amyloid level in the brain after administration compared to the amyloid level in the brain before administration. In some embodiments, the amyloid level in the brain is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% compared to the amyloid level in the brain before said administration. In some embodiments, said reduction in amyloid levels in the brain is determined using visual readings of PET images of amyloid and is expressed as PET standardized uptake value values (SUVr values).

[565] In some embodiments, the adjusted mean change in the PET SUVr value in a subject compared to the brain amyloid level prior to administration of the composition comprising at least one anti-Aβ protofibril antibody is reduced by at least -0.10, at least -0.15, at least -0.20, at least -0.25, at least -0.30, at least -0.35, at least -0.40, at least -0.45, at least -0.50, at least -0.55, at least -0.60, at least -0.65, at least -0.70, at least -0.75, at least -0.80, at least -0.85, at least -0.90, or at least -0.95. In some embodiments, the adjusted mean change in the subject's PET SUVr relative to the brain amyloid level prior to administration of the composition comprising at least one anti-Aβ protofibril antibody is reduced by a value between -0.20 and -0.30.

[566] In some embodiments, when comparing the overall mean for the cerebral cortex and the reference value for the whole cerebellum, the adjusted mean change in the PET SUVr value of the subject relative to the amyloid level in the brain prior to administration of the composition comprising at least one anti-Aβ protofibril antibody is reduced by at least -0.20, such as at least -0.25, after 12 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the adjusted mean change in the PET SUVr value of the subject relative to the PET SUVr value of the subject prior to administration is reduced by at least -0.25, such as at least -0.30, after 18 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[567] In some embodiments, the reduction in brain amyloid levels is determined by imaging using radiotracers that bind brain amyloid Aβ and is visualized using PET. In some embodiments, the reduction in adjusted mean change relative to the level in the subject prior to administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is at least -50, such as at least -55, or at least -59, centiloids after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in adjusted mean change relative to the level in the subject before administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is at least -60, such as at least -65 or at least -70, centiloids after 18 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[568] In some embodiments, the method results in a decrease in the level of Aβ _1-42 in the cerebrospinal fluid compared to the level of Aβ _1-42 in the cerebrospinal fluid prior to administration. In some embodiments, the method results in a decrease in the Aβ _1-42 level in the cerebrospinal fluid, compared to the Aβ _1-42 level in the cerebrospinal fluid before administration, of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, by at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%.

[569] In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody results in a decrease in the amyloid level in the brain compared to the amyloid level in the brain prior to administration of the composition comprising at least one anti-Aβ protofibril antibody of from -0.20 to -0.45, such as from -0.25 to -0.35, as determined by visual readings of PET images of amyloid. In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody results in a decrease in the amyloid level in the brain compared to the amyloid level in the brain prior to administration of the composition comprising at least one anti-Aβ protofibril antibody of at least -0.25, as determined by visual readings of PET images of amyloid. In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody results in a decrease in brain amyloid levels, compared to brain amyloid levels prior to administration of the composition comprising at least one anti-Aβ protofibril antibody, of at least 0.30, as determined by visual readings of PET images of amyloid.

[570] Also provided herein is another method for preventing and/or delaying the onset of Alzheimer's disease in a subject. In some embodiments, the subject is ApoE4 positive. In some embodiments, the subject is ApoE4 negative. In some embodiments, the method comprises determining the level of amyloid in the subject's brain and then, if the level of amyloid in the subject's brain exceeds a first predetermined level, administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent selected from BACE inhibitors, gamma-secretase inhibitors, gamma-secretase modulators, inhibitors of the formation of Aβ peptides other than said at least one anti-Aβ protofibril antibody, and agents that reduce the levels of Aβ peptides other than said at least one anti-Aβ protofibril antibody.

[571] In some embodiments, the method further comprises measuring the amyloid level in the subject's brain after administration.

[572] In some embodiments, the method further comprises determining the level of Aβ _1-42 in the cerebrospinal fluid and/or the level of total tau protein in the cerebrospinal fluid.

[573] In some embodiments, the method further comprises determining the level of neurogranin in the cerebrospinal fluid.

[574] In some embodiments, the method further comprises determining the level of neurofilament light chains in the cerebrospinal fluid.

[575] In some embodiments, said method further comprises administering a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils and a composition comprising a therapeutically effective amount of at least one therapeutic agent selected from BACE inhibitors, gamma-secretase inhibitors, gamma-secretase modulators, inhibitors of the formation of Aβ peptides other than said at least one antibody to Aβ protofibrils, and agents that reduce levels of Aβ peptides other than said at least one antibody to Aβ protofibrils if the amyloid level in the brain exceeds a second predetermined level following administration.

[576] In some embodiments, the method further comprises administering the composition if the level of Aβ _1-42 in the cerebrospinal fluid and/or the level of total tau protein in the cerebrospinal fluid after administration exceeds a predetermined level.

[577] In some embodiments, the method further comprises administering the composition if the level of neurogranin in the cerebrospinal fluid after administration exceeds a predetermined level.

[578] In some embodiments, the method further comprises administering the composition if the level of neurofilament light chains in the cerebrospinal fluid after administration exceeds a predetermined level.

[579] In some embodiments, the method further comprises monitoring the amyloid level in the subject's brain after administration until the amyloid level in the subject's brain is below a first predetermined level.

[580] In some embodiments, the method further comprises administering at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent is selected from BACE inhibitors, gamma-secretase inhibitors, gamma-secretase modulators, inhibitors of the formation of Aβ peptides other than said at least one anti-Aβ protofibril antibody, agents that reduce levels of Aβ peptides other than said at least one anti-Aβ protofibril antibody, and combinations thereof.

[581] In some embodiments, the at least one additional therapeutic agent is a BACE inhibitor. In some embodiments, the BACE inhibitor is elenbecestat.

[582] Any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, dosage regimens thereof, and compositions comprising them disclosed herein can be used in a method of reducing amyloid levels in the brain of a subject with early Alzheimer's disease. For example, in some embodiments, a composition comprising 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, or 10 mg/kg of at least one anti-Aβ protofibril antibody, such as BAN2401, based on the body weight of the subject, is administered to the subject once per week, once every two weeks, once every three weeks, once every four weeks, or once per month.

[583] In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[584] In some embodiments, the at least one therapeutic agent is a BACE inhibitor. In some embodiments, the BACE inhibitor is elenbecestat.

[585] In some embodiments, administering a composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent results in at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, by at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of subjects become amyloid negative, as determined by visual readings of PET images of amyloid.

[586] In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent results in 75% to 100%, such as 80% to 100% or 85% to 100%, of the subjects becoming amyloid negative, as determined by visual readings of PET images of amyloid. In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent results in at least 75%, such as at least 80% or at least 85%, of the subjects becoming amyloid negative, as determined by visual readings of PET images of amyloid. In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent results in 100% of subjects becoming amyloid negative, as determined by visual readings of PET images of amyloid.

[587] In some embodiments, at least 75%, such as at least 80% or at least 85%, of the subjects are amyloid negative, as determined by visual readings of PET images of amyloid, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent. In some embodiments, at least 75%, such as at least 80%, at least 85%, at least 90%, or at least 95%, of the subjects are amyloid negative, as determined by visual readings of PET images of amyloid, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent. In some embodiments, the composition comprises 10 mg/kg of at least one antibody to Aβ protofibrils and is administered once every two weeks or once a month. In some embodiments, the at least one antibody to Aβ protofibrils is BAN2401.

[588] In some embodiments, the method results in a decrease in the amyloid level in the brain after administration compared to the amyloid level in the brain before administration. In some embodiments, the amyloid level in the brain is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, by at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% compared to the amyloid level in the brain before said administration. In some embodiments, said reduction in amyloid levels in the brain is determined using visual readings of PET images of amyloid and is expressed as PET standardized uptake value values (SUVr values).

[589] In some embodiments, the adjusted mean change in the PET SUVr value in a subject compared to the brain amyloid level prior to administration of a composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent is reduced by at least -0.10, at least -0.15, at least -0.20, at least -0.25, at least -0.30, at least -0.35, at least -0.40, at least -0.45, at least -0.50, at least -0.55, at least -0.60, at least -0.65, at least -0.70, at least -0.75, at least -0.80, at least -0.85, at least -0.90, or at least -0.95. In some embodiments, the adjusted mean change in the subject's PET SUVr relative to the brain amyloid level prior to administration of the composition comprising at least one anti-Aβ protofibril antibody and the composition comprising a therapeutically effective amount of at least one therapeutic agent is reduced by a value of -0.20 to -0.30.

[590] In some embodiments, when comparing the overall mean score for the cerebral cortex and the reference score for the whole cerebellum, the adjusted mean change in the subject's PET SUVr value relative to the brain amyloid level prior to administration of the composition comprising at least one anti-Aβ protofibril antibody and the composition comprising a therapeutically effective amount of at least one therapeutic agent is reduced by at least -0.20, such as by at least -0.25, following 12 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody and the composition comprising a therapeutically effective amount of at least one therapeutic agent. In some embodiments, the adjusted mean change in the subject's PET SUVr value compared to the subject's PET SUVr value prior to administration is reduced by at least -0.25, such as at least -0.30, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent.

[591] In some embodiments, the reduction in brain amyloid levels is determined by imaging using radiotracers that bind brain amyloid Aβ and is visualized using PET. In some embodiments, the reduction in adjusted mean change from the level in the subject before administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent is at least -50, such as at least -55, or at least -59, centiloids after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent. In some embodiments, the reduction in adjusted mean change relative to the level in the subject before administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is at least -60, such as at least -65, or at least -70, centiloids after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent.

[592] In some embodiments, the method results in a decrease in the level of Aβ _1-42 in the cerebrospinal fluid compared to the level of Aβ _1-42 in the cerebrospinal fluid prior to administration. In some embodiments, the method results in a decrease in the Aβ _1-42 level in the cerebrospinal fluid, compared to the Aβ _1-42 level in the cerebrospinal fluid before administration, of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, by at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%.

[593] In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent results in a decrease in the amyloid level in the brain, compared to the amyloid level in the brain prior to administration of the composition comprising at least one anti-Aβ protofibril antibody and the composition comprising a therapeutically effective amount of at least one therapeutic agent, of from -0.20 to -0.45, such as from -0.25 to -0.35, as determined by visual readings of PET images of amyloid. In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent results in a decrease in brain amyloid levels, compared to brain amyloid levels prior to administration of the composition comprising at least one anti-Aβ protofibril antibody, of at least -0.25, as determined by visual readings of PET images of amyloid. In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent results in a decrease in brain amyloid levels, compared to brain amyloid levels prior to administration of the composition comprising at least one anti-Aβ protofibril antibody and a composition comprising a therapeutically effective amount of at least one therapeutic agent, of at least 0.30, as determined by visual readings of PET images of amyloid.

Adverse events

[594] In some embodiments, the methods provided herein do not result in one or more serious adverse events. In some embodiments, the methods provided herein result in one or more serious adverse events that are less than Grade 5 in severity, less than Grade 4 in severity, less than Grade 3 in severity, less than Grade 2 in severity, and/or less than Grade 1 in severity. In some embodiments, the subject does not report one or more adverse events because they are less than Grade 1 in severity.

[595] In some embodiments, the methods described herein result in less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, less than 10%, less than 11%, less than 12%, less than 13%, less than 14%, less than 15%, less than 16%, less than 17%, less than 18%, less than 19%, or less than 20% of subjects experiencing a serious adverse event.

[596] In some embodiments, the methods described herein result in less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10% of subjects experiencing vasogenic edema.

[597] In some embodiments, the methods described herein result in less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, less than 10%, less than 12%, less than 13%, less than 14%, or less than 15% of ApoE4-positive subjects experiencing vasogenic edema.

[598] In some embodiments, the methods described herein result in less than 15% of ApoE4-positive subjects experiencing vasogenic edema.

[599] In some embodiments, the methods described herein result in less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10% of ApoE4-negative subjects experiencing vasogenic edema.

[600] In some embodiments, the methods described herein result in less than 10% of ApoE4-negative subjects experiencing vasogenic edema.

[601] The contents of articles and patent documents referenced in this document are incorporated herein by reference in their entirety.

EXAMPLES

Example 1: Treatment of subjects with early stage Alzheimer's disease

[602] Both male and female subjects aged 50 to 90 years inclusive with mild cognitive impairment with intermediate probability due to Alzheimer's disease and/or mild Alzheimer's dementia were screened for treatment eligibility. 854 subjects were randomized to treatment.

[603] The study consisted of a pre-randomization phase and a randomization phase.

Pre-randomization phase

[604] The phase lasted for up to 60 days and consisted of a screening period and a baseline period. During the screening period, subjects were assessed based on study eligibility criteria. If a subject was deemed eligible for participation in the study, the subject proceeded to the baseline period.

[605] During the baseline period, a number of analyses were performed, including clinical tests (e.g., blood tests (e.g., to determine ApoE4 status), etc.), magnetic resonance imaging (MRI) safety analyses, amyloid PET assessments (e.g., visual readings of amyloid PET images), and cerebrospinal fluid examination (for biomarker analysis) if the subject consented. Additional clinical testing of subjects included the MMSE, CDR, ADAS-Cog, and FAQ.

Randomization phase

[606] The randomization phase consisted of an 18-month treatment period and a 3-month follow-up period. Subjects were randomized to one of the following regimens:

- placebo;

- a composition containing 2.5 mg/kg BAN2401, once every 2 weeks;

- a composition containing 5 mg/kg BAN2401, once every 2 weeks;

- a composition containing 10 mg/kg BAN2401, once every 2 weeks;

- a composition containing 5 mg/kg BAN2401, once a month; or

- a composition containing 10 mg/kg BAN2401, once a month.

[607] All subjects were administered an intravenous infusion over approximately 60 minutes once every 2 weeks. BAN2401 was administered in isotonic saline as 60-minute IV infusions using an infusion set containing a 0.22 μm end-in-line filter. All subjects received infusions once every two weeks, and subjects who received a monthly dose of BAN2401 received a placebo infusion alternating with BAN2401.

[608] All subjects were assessed for cognitive function, safety, pharmacokinetic parameters, MRI-based safety, volumetric MRI data, and CSF analysis if the subject consented to such analysis. Additional clinical assessments included MMSE, CDR, ADAS-Cog, and FAQ.

[609] Treatment was terminated after 18 months at the request of the subject, at the request of the treating physician and/or the Independent Safety Monitoring Committee and/or if one or more adverse events occurred requiring discontinuation of treatment.

[610] After completion of treatment, subjects were assessed as during the baseline and randomization phases.

Compilation

[611] BAN2401 was supplied as a sterile clear injection solution containing 10 mg/mL in a single-use 10 mL vial (total 100 mg/vial). The drug was formulated in 25 mM sodium citrate, 125 mM sodium chloride, 0.02% (w/v) polysorbate 80, and the pH was determined to be 5.7.

Study endpoints

[612] The primary objectives of the study included (1) assessing the efficacy of BAN2401 compared with placebo by establishing the _ED90 (as defined in the protocol) for BAN2401 based on the Alzheimer's Disease Comprehensive Assessment (ADCOMS) score after 12 months of treatment in subjects with early Alzheimer's disease (EAD), defined as mild cognitive impairment (MCI) with intermediate probability due to Alzheimer's disease or mild Alzheimer's dementia; and (2) assessing the safety and tolerability of 3 doses and 2 dosing schedules of BAN2401 in subjects with early Alzheimer's disease.

[613] Key secondary objectives included:

to evaluate the effects of BAN2401 compared with placebo on the pathophysiological features of cerebral amyloidosis after 18 months of treatment in subjects with early Alzheimer's disease as measured by PET;

to evaluate the efficacy of BAN2401 compared with placebo based on ADCOMS after 18 months of treatment in subjects with early Alzheimer's disease;

to evaluate the efficacy of BAN2401 compared with placebo based on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score after 18 months of treatment in subjects with early Alzheimer's disease;

to evaluate the efficacy of BAN2401 compared with placebo based on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) in subjects with EAD at 18 months;

to assess the effects of BAN2401 compared with placebo at 18 months on clinical status separately in subjects with MCI and mild dementia in AD based on the following assessments: ADCOMS, CDR-SB and ADAS-Cog;

to evaluate the effects of BAN2401 compared with placebo on cerebrospinal fluid biomarker levels (Aβ _1-42 , total tau, and phospho-tau) after 18 months of treatment in subjects with early Alzheimer's disease and

To evaluate the effects of BAN2401 compared with placebo on total hippocampal volume using volumetric magnetic resonance imaging (vMRI) after 18 months of treatment in subjects with early Alzheimer's disease.

Table 1. Inclusion in the treatment regimen

Duration of exposure (months) Placebo
(N=245) 2.5 mg/kg
once every two weeks
(N=52) 5 mg/kg
once a month
(N=51) 5 mg/kg
once every two weeks
(N=92) 10 mg/kg
once a month
(N=253) 10 mg/kg
once every two weeks
(N=161) Total
(N=609) n 245 52 51 92 253 161 609 Average value 15.55 15.01 16.44 15.21 13.95 12.03 13.93 Number of subject-months 3810,0 780.5 838.6 1399.4 3529.6 1936.2 8484.2

Table 2. General demographic data and characteristics at baseline

Characteristic BAN2401
(N=587) Placebo
(N=238) Age in years (mean ± S.D.) 71.4±7.91 71.1±8.89 Men (n (%)) 315 (53.7) 101 (42.4) Clinical stage (n (%)) MCI 375 (63.9) 154 (64.7) Light AD 212 (36.1) 84 (35.3) ApoE4 (n (%)) Carriers 420 (71.6) 169 (71.0) Non-carriers 167 (28.4) 69 (29.0) Current treatment with acetycholinesterase inhibitors/memantine at baseline No 268 (45.7) 110 (46.2) Yes 319 (54.3) 128 (53.8) Overall CDR score (n (%)) 0.5 504 (85.9) 200 (84.0) 1 83 (14.1) 38 (16.0) ADCOMS
(mean ± SD) 0.378±0.158 0.370±0.166 ADAS-Cog ^#
(mean ± SD) 22.2±7.4 22.6±7.7 CDR-SB
(mean ± SD) 2.95±1.37 2.89±1.45 MMSE
(mean ± SD) 25.6±2.4 26.0±2.3 SUVr ^* according to PET
(mean ± SD) 1.41±0.16 1.40±0.16

^# N=586 in the BAN2401 group, N=237 in the placebo group;

*PET substudy; N=214 in the BAN2401 group, N=98 in the placebo group.

Table 3. Baseline demographic data in subjects with mild cognitive impairment moderately likely due to Alzheimer's disease

Characteristic BAN2401
(N=375) Placebo
(N=154) Age in years (mean ± S.D.) 71.3±7.47 71.3±8.69 Men (n (%)) 203 (54.1) 70 (45.5) ApoE4 (n (%)) Carriers 272 (72.5) 110 (71.4) Non-carriers 103 (27.5) 44 (28.6) Current treatment with acetycholinesterase inhibitors/memantine at baseline No 203 (54.1) 85 (55.2) Yes 172 (45.9) 69 (44.8) Overall CDR score (n (%)) 0.5 373 (99.5) 153 (99.4) 1 2 (0.5) 1 (0.6)

Table 4. Baseline demographic data in subjects with mild Alzheimer's disease dementia

Characteristic BAN2401
(N=212) Placebo
(N=84) Age in years (mean ± S.D.) 71.5±8.64 70.7±9.29 Men (n (%)) 112 (52.8) 31 (36.9) ApoE4 (n (%)) Carriers 148 (69.8) 59 (70.2) Non-carriers 64 (30.2) 25 (29.8) Current treatment with acetycholinesterase inhibitors/memantine at baseline No 65 (30.7) 25 (29.8) Yes 147 (69.3) 59 (70.2) Overall CDR score (n (%)) 0.5 131 (61.8) 47 (56.0) 1 81 (38.2) 37 (44.0)

End points

[614] The primary endpoint used ADCOMS to measure clinical outcome measures using 12-month longitudinal study data using Bayesian analysis.

[615] Secondary endpoints (12 and 18 months) included change from baseline in PET SUVr (amyloid load); conversion of amyloid-positive to amyloid-negative subjects (visual reading); change from baseline in ADCOMS score; change from baseline in ADAS-Cog score; change from baseline in CDR-SB score; change from baseline in CSF parameters (Aβ _1-42 , total tau, etc.).

Results

Results in relation to cognitive function

[616] In the overall subject population, there was a dose-dependent, clinically meaningful, and statistically significant slower deterioration in cognitive and functional clinical outcome measures at 18 months on the ADCOMS with a 30% reduction in deterioration at the highest dose and on the ADAS-Cog with a 47% reduction in deterioration at the highest dose; and a dose-dependent, clinically meaningful slower deterioration at 18 months on the CDR-SB with a 26% reduction in deterioration at the highest dose.

[617] Tables 5 and 6 present the change from baseline after 12 months of BAN2401 administration as determined by ADCOMS.

Table 5. Change from Baseline for BAN2401 Doses of 2.5 mg/kg Q2W, 5 mg/kg QM, 5 mg/kg Q2W, 10 mg/kg QM, and 10 mg/kg Q2W, Determined by ADCOMS at 12 Months

Placebo 2.5 mg/kg once every two weeks 5 mg/kg once a month 5 mg/kg once every two weeks 10 mg/kg once a month 10 mg/kg once every two weeks N 187 38 42 67 165 93 Observed mean CFB (SD) 0.102 (0.155) 0.149 (0.201) 0.106 (0.169) 0.098 (0.141) 0.079 (0.163) 0.076 (0.144) Observed difference -- 0.047 0.004 -0.004 -0.023 -0.026 Mean value calculated by LS method (SE) 0.131 (0.013) 0.158 (0.027) 0.149 (0.027) 0.139(0.021) 0.102 (0.014) 0.085 (0.017) Difference between LSM -- 0.028 0,019 0.008 -0.029 -0.046 % reduction in deterioration -- 21.4 14.5 6.1 -22.1 -35.1 P-value -- 0.336 0.514 0.731 0.101 0.027

Table 6. Change from baseline for 10 mg/kg doses combined (once every two weeks and once monthly) determined by ADCOMS at 12 months

Placebo The groups receiving 10 mg/kg, in total, N 187 258 Observed mean CFB (SD) 0.102 (0.155) 0.078 (0.156) Observed difference -- -0.024 Mean value calculated by LS method (SE) 0.128 (0.013) 0.093 (0.012) Difference between LSM -- -0.035 % reduction in deterioration -- -27.3 P-value -- 0,019

[618] Similarly, Tables 7 and 8 present the change from baseline after 18 months of administration of different doses of BAN2401, as determined using ADCOMS. See also fig. 56.

Table 7. Change from Baseline for BAN2401 Doses of 2.5 mg/kg Q2W, 5 mg/kg QM, 5 mg/kg Q2W, 10 mg/kg QM, and 10 mg/kg Q2W, Determined by ADCOMS at 18 Months

Placebo 2.5 mg/kg once every two weeks 5 mg/kg once a month 5 mg/kg once every two weeks 10 mg/kg once a month 10 mg/kg once every two weeks N* 160 33 35 61 146 79 Observed mean CFB (SD) 0.164 (0.197) 0.167 (0.234) 0.121 (0.194) 0.166 (0.205) 0.138 (0.215) 0.122 (0.180) Observed difference -- 0.003 -0.043 0.002 -0.026 -0.042 Mean value calculated by LS method (SE) 0.193 (0.017) 0.173 (0.035) 0.192 (0.035) 0.199(0.026) 0.166 (0.018) 0.136 (0.022) Difference between LSM -- -0.020 -0.001 0.006 -0.028 -0.057 % reduction in deterioration -- -10.4 -0.5 3.1 -14.5 -29.5 P-value -- 0.592 0.971 0.855 0.228 0.034

Table 8. Change from baseline for 10 mg/kg doses combined (once every two weeks and once monthly) determined by ADCOMS at 18 months

Placebo The groups receiving 10 mg/kg, in total, N* 160 225 Observed mean CFB (SD) 0.164 (0.197) 0.132 (0.204) Observed difference -- -0.032 Mean value calculated by LS method (SE) 0.190 (0.017) 0.152 (0.014) Difference between LSM -- -0.039 % reduction in deterioration -- -20.5 P-value -- 0.053

[619] Tables 9 and 10 present the change from baseline after 12 months of administration of the various doses of BAN2401, as determined by the CDR-SB. As shown in Figs. 9 and 10, the 10 mg/kg once monthly and 10 mg/kg once every two weeks doses resulted in a slower decline in cognitive function compared to placebo, as determined by the CDR-SB, after 12 and 18 months of treatment with a composition containing a therapeutically effective amount of BAN2401. A similar trend was observed using ADAS-Cog as the statistical analysis method. See Fig. 7 and 8.

Table 9. Change from Baseline for BAN2401 Doses of 2.5 mg/kg Q2W, 5 mg/kg QM, 5 mg/kg Q2W, 10 mg/kg QM, and 10 mg/kg Q2W, Determined by CDR-SB, at 12 Months

Placebo 2.5 mg/kg once every two weeks 5 mg/kg once a month 5 mg/kg once every two weeks 10 mg/kg once a month 10 mg/kg once every two weeks N* 188 38 42 70 166 94 Observed mean CFB (SD) 0.73 (1.402) 1.18 (1.906) 0.99 (1.371) 0.75 (1.451) 0.59 (1.526) 0.46 (1.382) Observed difference -- 0.45 0.26 0.02 -0.14 -0.27 Mean value calculated by LS method (SE) 0.911
(0.124) 1,038 (0,257) 1.277 (0.253) 0.945(0.194) 0.705 (0.133) 0.568 (0.163) Difference between LSM -- 0.127 0.366 0.034 -0.207 -0.344 % reduction in deterioration -- 13.9 40.2 3.7 -22.7 -37.8 P-value -- 0.644 0.179 0.878 0,210 0,077

Table 10. Change from baseline for 10 mg/kg doses combined (once every two weeks and once monthly) determined by ADCOMS at 12 months

Placebo The groups receiving 10 mg/kg, in total, N* 188 260 Observed mean CFB (SD) 0.73 (1.402) 0.54 (1.476) Observed difference -0.19 Mean value calculated by LS method (SE) 0.894 (0.123) 0.642 (0.108) Difference between LSM -0.253 % reduction in deterioration -28.3 P-value 0.079

[620] Tables 11 and 12 present the change from baseline after 18 months of administration of different doses of BAN2401, as determined using CDR-SB.

Table 11. Change from Baseline for BAN2401 Doses of 2.5 mg/kg Q2W, 5 mg/kg QM, 5 mg/kg Q2W, 10 mg/kg QM, and 10 mg/kg Q2W, Determined by CDR-SB, at 18 Months

Placebo 2.5 mg/kg once every two weeks 5 mg/kg once a month 5 mg/kg once every two weeks 10 mg/kg once a month 10 mg/kg once every two weeks N* 161 34 36 67 149 84 Observed mean CFB (SD) 1.27 (1.778) 1.37 (2.174) 1.23 (1.776) 1.26 (2.014) 1.10 (2.033) 1.04 (1.978) Observed difference -- 0.10 -0.04 -0.01 -0.17 -0.23 Mean value calculated by LS method (SE) 1,499 (0,160) 1,227 (0,338) 1.713 (0.334) 1,463(0,250) 1,248 (0,169) 1.102 (0.213) Difference between LSM -- -0.271 0.214 -0.036 -0.250 -0.396 % reduction in deterioration -- -18.1 14.3 -2.4 -16.7 -26.4 P-value -- 0.459 0.555 0.901 0.255 0.125

Table 12. Change from baseline for 10 mg/kg doses combined (once every two weeks and once monthly) determined using CDR-SB at 18 months

Placebo The groups receiving 10 mg/kg, in total, N* 161 233 Observed mean CFB (SD) 1.27 (1.778) 1.08 (2.010) Observed difference -- -0.19 Mean value calculated by LS method (SE) 1,473 (0,158) 1,171 (0,136) Difference between LSM -- -0.302 % reduction in deterioration -- -20.5 P-value -- 0.119

Results in ApoE4-positive subjects

[621] As reported below, when subjects were ApoE4 positive, unexpectedly favorable results were achieved compared to subjects who were ApoE4 negative. This is unexpected at least in light of previously published results from studies conducted with other anti-Aβ antibodies.

[622] For example, in a phase Ib trial using aducanumab, another anti-Aβ antibody outside the scope of the present invention, it was reported that the reduction in total amyloid SUVR score by PET in patients treated with aducanumab was similar in ApoE4 carriers and non-carriers (Sevigny, J. et al., “The antibody aducanumab reduces Aβ plaques in Alzheimer's disease,”Nature 537:50-56, 50-51 (Sept. 1, 2016), citation of the extended data in Fig. 2b). However, the results according to the extended data in Fig. 2b reflect better treatment outcomes in non-ApoE4 carriers compared to ApoE4 carriers.

[623] In a phase II trial using bapineuzumab, an anti-Aβ antibody outside the scope of the present invention, in the treatment of mild to moderate Alzheimer's disease, results suggested potential differences in some clinical measures depending on ApoE4 carrier status, with potential treatment differences favoring non-carrier subjects. (See Salloway et al., "A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease", Neurology73:2061–2070, 2067 (December 15, 2009).) Accordingly, two different phase III clinical trials using bapineuzumab were conducted, one in ApoE4-positive carriers and one in ApoE4-negative subjects with mild to moderate Alzheimer's disease. Despite the phase II indications, the phase III results not only failed to differentiate between the two ApoE4 genotypes, but also failed to demonstrate a beneficial effect of bapineuzumab on clinical outcomes. (Salloway et al., "Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease,"N. Engl. J. Med.370:322–33 (2014).) Similarly, two phase III clinical trials using solanezumab, another anti-Aβ antibody outside the scope of the present invention, also failed to demonstrate a beneficial effect on the primary clinical outcomes in patients with mild to moderate Alzheimer's disease. (Salloway et al.,N. Engl. J. Med.370:322-33, 332 (2014); Doody, R.S. et al., "Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease", N. Engl. J. Med.370:311-21 (2014).)

[624] Based on results such as those discussed below, the statistically significant results reported herein in ApoE4-positive subjects compared to ApoE4-negative subjects were not only unexpected but also unpredictable.

Unpredictable and unexpected results in ApoE4-positive subjects

[625] Generally, ApoE4-positive subjects responded better to treatment with BAN2401 than ApoE4-negative subjects. In some embodiments, these differences were clinically significant and statistically significant.

[626] Figures 5 and 16 show dose-dependent delays in cognitive decline, as measured by ADCOMS, in ApoE4-positive subjects administered various doses of BAN2401 starting at 6 months compared to subjects administered placebo. See See also Fig. 48. Figs. 6 and 30 show a more moderate decline in cognitive function after administration to ApoE4-negative subjects. See also Fig. 48. The difference in response between ApoE4-positive subjects and ApoE4-negative subjects was observed regardless of whether cognitive decline was measured by ADCOMS (ApoE4-positive: Figs. 5 and 16; ApoE4-negative: Figs. 6 and 30), ADAS-Cog (ApoE4-positive: Figs. 19 and 20; ApoE4-negative: Figs. 35 and 36), or CDR-SB (ApoE4-positive: Figs. 23 and 24; ApoE4-negative: Figs. 39 and 40).

[627] For example, ApoE4-negative subjects experienced a 7% reduction in clinical worsening as measured by ADCOMS after 18 months of administration of 10 mg/kg BAN2401 once every two weeks, whereas ApoE4-positive subjects experienced a 63% reduction in clinical worsening as measured by ADCOMS after 18 months of administration of 10 mg/kg BAN2401 once every two weeks.

[628] For example, ApoE4-negative subjects experienced a 43% reduction in clinical worsening as measured by ADCOMS after 18 months of 10 mg/kg BAN2401 administered once every two weeks, whereas ApoE4-positive subjects experienced an 84% reduction in clinical worsening as measured by ADAS-Cog after 18 months of 10 mg/kg BAN2401 administered once every two weeks.

[629] For example, ApoE4-negative subjects experienced a -7% reduction in clinical worsening, as measured by CDR-SB, after 18 months of administration of 10 mg/kg BAN2401 once every two weeks, whereas ApoE4-positive subjects experienced a 60% reduction in clinical worsening, as measured by CDR-SB, after 18 months of administration of 10 mg/kg BAN2401 once every two weeks.

Subjects with mild cognitive impairment with intermediate probability due to Alzheimer's disease and subjects with mild dementia in Alzheimer's disease

[630] The responsiveness of subjects with mild cognitive impairment with intermediate probability due to Alzheimer's disease and subjects with mild dementia in Alzheimer's disease was also compared. Overall, subjects with mild cognitive impairment with intermediate probability due to Alzheimer's disease and subjects with mild dementia in Alzheimer's disease responded well to treatment with compositions containing BAN2401. (See, e.g., Fig. 3, 4 and 49.)

[631] However, ApoE4-positive subjects with mild Alzheimer's disease dementia responded better to treatment with BAN2401 than subjects with mild cognitive impairment due to Alzheimer's disease dementia as determined by ADCOMS (cf. Fig. 17 and 18), using ADAS-Cog (compare Fig. 21 and 22) and using CDR-SB (compare Fig. 25 and 26). ApoE4-positive subjects with mild Alzheimer's disease dementia responded better to treatment with a composition containing BAN2401 than ApoE4-positive subjects with mild cognitive impairment with intermediate probability due to Alzheimer's disease.

[632] Among ApoE4-negative subjects, subjects with mild cognitive impairment with intermediate probability due to Alzheimer's disease and subjects with mild dementia in Alzheimer's disease responded to treatment. (See Figs. 33 and 34 (ADCOMS); Figs. 37 and 38 (ADAS-Cog); and Figs. 41 and 42 (CDR-SB).)

Results regarding brain amyloid levels

[633] Tables 13 and 14 present the change in brain amyloid levels from baseline in all subjects after 12 months of administration of different doses of BAN2401, as determined by PET (standardized uptake value (SUVR)), where the reference area is the whole cerebellum mask.

Table 13. Change from baseline in brain amyloid for BAN2401 doses of 2.5 mg/kg q2w, 5 mg/kg q2m, 5 mg/kg q2w, 10 mg/kg q2m, and 10 mg/kg q2w, as determined by PET standardized uptake value, at 12 months

Placebo 2.5 mg/kg once every two weeks 5 mg/kg once a month 5 mg/kg once every two weeks 10 mg/kg once a month 10 mg/kg once every two weeks N* 96 27 28 25 89 43 Baseline SUVR mean (SD) 1.40 (0.16) 1.41 (0.11) 1.42 (0.17) 1.40 (0.12) 1.42 (0.18) 1.36 (0.18) Observed mean % CFB value (SD) -0.07 (6.05) -4.11 (5.76) -5.05 (6.91) -11.02 (6.11) -11.96 (7.27) -17.09 (14.67) The observed difference between % CFB -- -4.04 -4.98 -10.95 -11.89 -17.02 Average % CFB value calculated by LS method (SE) -0.26 (0.84) -4.16 (1.48) -4.75 (1.49) -11.35 (1.55) -11.78 (0.92) -17.41 (1.20) Difference between LSM % CFB -- -3.90 -4.49 -11.09 -11.52 -17.15 P-value -- 0,018 0,007 <0.001 <0.001 <0.001

Table 14. Change from baseline in brain amyloid levels for 10 mg/kg doses combined (once every two weeks and once monthly) as determined by PET standardized uptake value at 12 months

Placebo 10 mg/kg in total N* 96 132 Baseline SUVR mean (SD) 1.40 (0.158) 1.40 (0.178) Observed mean % CFB value (SD) -0.07 (6.046) -13.64 (10.525) The observed difference between % CFB -13.57 Average % CFB value calculated by LS method (SE) -0.64
(0.90) -13.84
(0.76) Difference between LSM % CFB -13.20 P-value <0.001

[634] Tables 15 and 16 present the change from baseline in brain amyloid levels after 12 months of administration of different doses of BAN2401, as determined by PET (PET amyloid visual readouts; standardized uptake value (SUVR)), where the reference area is the whole cerebellum mask. The change from baseline, as determined by ADCOMS and CDR-SB, was positively correlated in a statistically significant manner with amyloid clearance as determined by PET (SUVR), where the reference area is the whole cerebellum mask. See Fig. 77 and 78. Change from baseline as determined by ADCOMS, CDR-SB, and ADAS-Cog was positively correlated in a statistically significant manner with amyloid clearance as determined by PET (SUVR), where the reference region is the subcortical white matter. See Fig. 80-82.

Table 15. Change from baseline in brain amyloid for BAN2401 doses of 2.5 mg/kg q2w, 5 mg/kg q2w, 5 mg/kg q2w, 10 mg/kg q2w, and 10 mg/kg q2w, as determined by PET standardized uptake value, at 18 months

Placebo 2.5 mg/kg once every two weeks 5 mg/kg once a month 5 mg/kg once every two weeks 10 mg/kg once a month 10 mg/kg once every two weeks N* 88 23 23 24 83 37 Baseline SUVR mean (SD) 1.40 (0.16) 1.41 (0.11) 1.42 (0.17) 1.40 (0.12) 1.42 (0.18) 1.36 (0.18) Observed mean % CFB value (SD) 0.78 (7.03) -5.83 (5.15) -8.99 (6.95) -13.51 (7.85) -15.12 (7.81) -19.29 (14.91) The observed difference between % CFB -- -6.61 -9.77 -14.29 -15.90 -20.07 Average % CFB value calculated by LS method (SE) 0.77 (0.87) -6.51 (1.56) -8.93 (1.57) -13.88 (1.59) -15.15 (0.95) -20.37 (1.26) Difference between LSM % CFB -- -7.28 -9.70 -14.65 -15.92 -21.14 P-value -- <0.001 <0.001 <0.001 <0.001 <0.001

Table 16. Change from baseline in brain amyloid for 10 mg/kg doses combined (once every two weeks and once monthly) as measured by PET standardized accumulation value at 18 months

Placebo 10 mg/kg in total N* 88 120 Baseline SUVR mean (SD) 1.40 (0.158) 1.40 (0.178) Observed mean % CFB value (SD) 0.78 (7.03) -16.42 (10.65) The observed difference between % CFB -- -15.64 Average % CFB value calculated by LS method (SE) 0.39
(0.91) -17.07
(0.77) Difference between LSM % CFB -- -17.46 P-value -- <0.001

[635] Figures 11 and 12 show dose-dependent reductions in brain amyloid levels following administration of 2.5 mg/kg BAN2401 once every two weeks, 5 mg/kg BAN2401 once monthly, 5 mg/kg BAN2401 once every two weeks, 10 mg/kg BAN2401 once monthly, or 10 mg/kg BAN2401 once every two weeks at 12 and 18 months. See also fig. 51.

[636] As can be seen, statistically significant reductions in brain amyloid levels were observed in subjects with early Alzheimer's disease following administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. For example, administration of 10 mg/kg BAN2401 once every two weeks for 18 months resulted in a reduction of -70 (p<0.0001). (See, for example, Figure 12 (centiloids).)

[637] Similarly, administration of varying doses of BAN2401 to ApoE4-positive subjects (Figures 27 (-0.32 reduction for 10 mg/kg q2w at 18 months) and 28 (-76 reduction for 10 mg/kg q2w at 18 months)) and ApoE4-negative subjects (Figures 43 (-0.29 reduction for 10 mg/kg q2w at 18 months) and 44 (-68 reduction for 10 mg/kg q2w at 18 months)) resulted in reductions in brain amyloid levels in these subjects. Reductions in brain amyloid levels were also found to correlate with slowed cognitive decline. See Fig. 57.

Results regarding the conversion of amyloid-positive subjects into amyloid-negative ones

[638] Tables 17 and 18 show the subjects who became amyloid negative after administration of various doses of BAN2401. Figure 13 shows the proportion of positive subjects by PET after administration of 2.5 mg/kg BAN2401 once every two weeks, 5 mg/kg BAN2401 once every month, 5 mg/kg BAN2401 once every two weeks, 10 mg/kg BAN2401 once every month, or 10 mg/kg BAN2401 once every two weeks at 12 and 18 months, determined by visual reading of PET data using florbetapir as a tracer.

[639] As can be seen, a significant proportion of amyloid-positive subjects with early Alzheimer's disease were converted to amyloid-negative following administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. For example, after 18 months of administration of 10 mg/kg BAN2401 once every two weeks, 81% (p<0.0001) of amyloid-positive subjects were converted to amyloid-negative. (See, for example, Table 17 and Fig. 13.)

[640] A significant proportion of ApoE4-positive (Figure 28) and ApoE4-negative (Figure 42) amyloid-positive subjects with early Alzheimer's disease converted to amyloid-negative following administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. However, a greater proportion of ApoE4-positive subjects converted to amyloid-negative than ApoE4-negative subjects. For example, after 18 months of once-monthly administration of 10 mg/kg BAN2401, 79% (p < 0.0001) of ApoE4-negative amyloid-positive subjects converted to amyloid-negative (see, eg, Fig. 31), with 100% (p < 0.0001) of ApoE4-positive amyloid-positive subjects converted to amyloid-negative. (See, for example, Fig. 47.)

Table 17. Proportion of subjects who became amyloid negative during the study among the BAN2401 dose groups of 2.5 mg/kg once every two weeks, 5 mg/kg once monthly, 5 mg/kg once every two weeks, 10 mg/kg once monthly, and 10 mg/kg once every two weeks

Placebo 2.5 mg/kg once every two weeks 5 mg/kg once a month 5 mg/kg once every two weeks 10 mg/kg once a month 10 mg/kg once every two weeks Analysis after 12 months n/m * 11/96 5/27 10/28 12/25 37/89 28/43 % of negative subjects 11.5 18.5 35.7 48.0 41.6 65.1 90% CI for proportions (%) -- (7.6, 35.1) (20.8, 53.0) (30.5, 65.9) (32.7, 50.8) (51.5, 77.1) p-value -- 0,1504 0.0039 0,0001 <0.0001 <0.0001 Analysis after 18 months n/m * 19/88 9/23 11/23 14/24 64/83 30/37 % of negative subjects 21.6 39.1 47.8 58.3 77.1 81.1 90% CI for proportions (%) -- (22.2, 58.3) (29.6, 66.5) (39.7, 75.4) (68.3, 84.5) (67.4, 90.8) p-value -- 0.0497 0.0105 0,0007 <0.0001 <0.0001

Table 18. Proportion of subjects who became amyloid negative at 10 mg/kg doses combined (once every two weeks and once monthly)

Placebo The groups receiving 10 mg/kg, in total, Analysis after 12 months n/m * 11/96 65/132 % of negative subjects 11.5 49.2 90% CI for proportions (%) -- (41.8, 56.7) p-value -- <0.0001 Analysis after 18 months n/m * 19/88 94/120 % of negative subjects 21.6 78.3 90% CI for proportions (%) -- (71.2, 84.4) p-value -- <0.0001

[641] As discussed above in this paper, biomarkers were also measured. For example, CSF Aβ _1-42 levels and CSF total tau levels were measured. Additional biomarkers measured included CSF neurogranin and neurofilament light chain levels.

[642] Dose-dependent statistically significant effects were observed on CSF Aβ _1-42 levels and a statistically significant reduction in CSF total tau protein levels in a longitudinal analysis.

[643] Overall (Figure 14) and in each subgroup (Figure 30 - ApoE4-positive subjects; Figure 46 - ApoE4-negative subjects), administration of the composition containing BAN2401 resulted in an increase in CSF Aβ _1-42 levels. Without being limited by theory, it is believed that this is due to a normalization of CSF Aβ _1-42 levels, reflecting less sequestration of soluble Aβ _1-42 in the CSF to form Aβ plaques due to plaque removal. These results demonstrate that BAN2401 interacts with its target.

[644] Similarly, a decrease in total tau protein levels in the CSF was observed in all patient groups. (See Fig. 15, 31, 47, 54, 65 and 68-70.)

[645] Following administration of BAN2401, decreased levels of neurogranin in cerebrospinal fluid and lower amounts of neurofilament light chains were observed compared with placebo. (See (Figs. 53, 55, 66, 67, and 71-76.) Administration of 10 mg/kg BAN2401 once every two weeks or once monthly resulted in a 10% decrease in neurogranin levels (compared to baseline) (see Fig. 53) and 50% lower production of neurofilament light chains compared with placebo (see Fig. 55).

Safety Results

[646] Table 19 provides a summary of treatment-related adverse events.

Table 19. Treatment-emergent adverse events (“TEAEs”)

Category Placebo
(N=245),
n (%) Treatment regimen 2.5 mg/kg
once every two weeks (N=52),
n (%) 5 mg/kg once a month
(N=51),
n (%) 5 mg/kg once every two weeks
(N=92),
n (%) 10 mg/kg once a month
(N=253),
n (%) 10 mg/kg once every two weeks
(N=161),
n (%) Any TEAE 216 (88.2) 46 (88.5) 48 (94.1) 81 (88.0) 238 (94.1) 139 (86.3) Treatment-related TEAE 65 (26.5) 23 (44.2) 25 (49.0) 31 (33.7) 135 (53.4) 76 (47.2) Serious adverse event 43 (17.6) 10 (19.2) 4 (7.8) 16 (17.4) 31 (12.3) 25 (15.5) ARIA-E 2 (0.8) 1 (1.9) 1 (2.0) 3 (3.3) 25 (9.9) 16 (9.9) Death cases 2 (0.8) 2 (3.8) 0 1 (1,1) 2 (0.8) 0 AE leading to discontinuation of study treatment 15 (6.1) 7 (13.5) 4 (7.8) 10 (10.9) 47 (18.6) 24 (14.9)

[647] Table 20 provides a summary of the most common treatment-related adverse events.

[648] Table 21 provides a summary of the incidence of vasogenic edema (ARIA-E).

Table 21. Summary of ARIA-E incidence rates

Category Placebo
(N=245),
n (%) Treatment regimen 2.5 mg/kg
once every two weeks (N=52),
n (%) 5 mg/kg once a month
(N=51),
n (%) 5 mg/kg once every two weeks
(N=92),
n (%) 10 mg/kg once a month
(N=253),
n (%) 10 mg/kg once every two weeks
(N=161),
n (%) ARIA-E 2 (0.8) 1 (1.9) 1 (2.0) 3 (3.3) 25 (9.9) 16 (9.9) ApoE4+ 2/173 (1.2%) 1/38
(2.6%) 1/40
(2.5%) 3/84
(3.6%) 23/225 (10.2%) 7/48 (14.6%) ApoE4- 0/72 0/14 0/11 0/8 2/28
(7.1%) 9/113
(8%)

Results in ApoE4-positive subjects

[649] As discussed above, when subjects were ApoE4 positive, unexpectedly favorable results were achieved compared to subjects who were ApoE4 negative. This is unexpected at least in light of previously published results from studies conducted with other anti-Aβ antibodies.

[650] For example, a phase Ib trial using aducanumab, another anti-Aβ antibody, reported a reduction in total amyloid SUVr score by PET in patients treated with aducanumab was similar in ApoE4 carriers and non-carriers (Sevigny, J. et al., "The antibody aducanumab reduces Aβ plaques in Alzheimer's disease",Nature 537:50-56, 50-51 (Sept. 1, 2016), (citation of extended data in Fig. 2b.) However, the results according to extended data in Fig. 2b reflect better treatment outcomes in non-ApoE4 carriers compared to ApoE4 carriers.

[651] In a phase II trial using bapineuzumab, an anti-Aβ antibody outside the scope of the present invention, in the treatment of mild to moderate Alzheimer's disease, results suggested potential differences in some clinical measures depending on ApoE4 carrier status, with potential treatment differences favoring non-carrier subjects. (See Salloway et al., "A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease", Neurology73:2061–2070, 2067 (December 15, 2009).) Accordingly, two different phase III clinical trials using bapineuzumab were conducted, one in ApoE4-positive carriers and one in ApoE4-negative subjects with mild to moderate Alzheimer's disease. Despite the phase II indications, the phase III results not only failed to differentiate between the two ApoE4 genotypes, but also failed to demonstrate a beneficial effect of bapineuzumab on clinical outcomes. (Salloway et al., "Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease,"N. Engl. J. Med.370:322–33 (2014).) Similarly, two phase III clinical trials using solanezumab, another anti-Aβ antibody outside the scope of the present invention, also failed to demonstrate a beneficial effect on the primary clinical outcomes in patients with mild to moderate Alzheimer's disease. (Salloway et al.,N. Engl. J. Med.370:322-33, 332 (2014); Doody R.S. et al., "Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease", N. Engl. J. Med.370:311-21 (2014).)

[652] Based on results such as those discussed above, the statistically significant results reported herein in ApoE4-positive subjects compared to ApoE4-negative subjects were not only unexpected but also unpredictable.

Pharmacokinetic profile

[653] Analysis of the pharmacokinetic profile of subjects showed that administration of the composition containing BAN2401 resulted in a linear dose-dependent effect. See, for example, Fig. 60.

[654] The mean steady-state plasma concentrations for each dose are shown in Table 22. The slowing of the rate of disease progression as measured by ADCOMS, ADAS-Cog, and CDR-SB was found to be positively correlated with the mean steady-state plasma concentrations of BAN2401. See, for example, Figs. 1, 7, and 9 (dose magnitude positively correlates with slowing of disease progression) and Table 22 (dose magnitude positively correlates with mean steady-state plasma concentration).

Table 22. Average plasma concentration at steady state

Dose of BAN2401 C _{ss, av} (mcg/ml) 2.5 mg/kg once every two weeks 28.7 5 mg/kg once a month 28.7 5 mg/kg once every two weeks 57.3 10 mg/kg once a month 57.3 10 mg/kg once every two weeks 114.7

[655] Table 23 shows population pharmacokinetic parameters following administration of BAN2401.

Table 23. Population pharmacokinetic parameters for BAN2401

Parameter Point estimate % RSE 95% CI Clearance: CL Basal CL (l/h) 0,0191 2.84 0.0180-0.0202 Floor effect on CL (ratio) 0.786 3.97 0.725-0.847 Effect of body mass on CL (power factor) 0.384 18.5 0.245-0.523 Effect of albumin on CL (exponent) -0.267 22.5 -0.385 - -0.149 Central distribution volume: V1 Basal V1 (l) 3.18 1.21 3.10-3.26 Body mass effect on V1 (power factor) 0.621 7.94 0.524-0.718 Floor effect on V1 (ratio) 0.904 1.85 0.871-0.937 Interchamber clearance: Q Basal Q (l/h) 0,0350 8.00 0.0295-0.0405 Peripheral volume of distribution: V2 Basal V2 (l) 2.24 8.12 1.88-2.60 Japanese Race Effect on V2 (Ratio) 0.423 31.2 0.164-0.682 Inter-individual variability (% CV) CL 41.0 6.49 - Covariance CL_V1 0.104 59.9 - V1 13.6 8.76 - Q NE - - V2 97.1 8.36 - Residual variability Proportionality Study 1 (% CV) 13.9 3.51 - Proportionality Study 2 (% CV) 18.8 3.94 - Proportionality Study 3 (% CV) 27.5 0.938 - Abbreviations: NE = not estimated; %RSE = percent relative standard error of the estimate = SE/parameter estimate * 100; CL = clearance; V1 = central volume of distribution; Q = interchamber clearance; V2 = peripheral volume of distribution; L = liter; h = hour; CI = confidence interval; %CV = square root of variance * 100.

[656] It was also found that the proportion of ApoE4-positive subjects who experienced the ARIA-E phenomenon was positively correlated with the maximum plasma concentration of BAN2401 at all doses studied. See Fig. 62. In contrast, the proportion of ApoE4-negative subjects who experienced the ARIA-E event and who were administered BAN2401 at a dose resulting in a peak plasma concentration of approximately 230 mcg/mL or less was approximately comparable to the proportion of ApoE4-negative subjects who were administered placebo.See ibid.

Concomitant administration of at least one medicinal product for the treatment of Alzheimer's disease other than BAN2401

[657] Subjects, regardless of whether they were receiving at least one other Alzheimer's disease drug other than BAN2401, were administered BAN2401 as described herein above. Surprisingly, it was found that subjects who wereNotwere co-administered with at least one Alzheimer's disease drug other than BAN2401, demonstrated greater slowing of cognitive decline from baseline than subjects co-administered with BAN2401 and at least one Alzheimer's disease drug other than BAN2401. These results were consistent across all analyses: ADCOMS (23% slowing of cognitive decline in subjects co-administered with at least one Alzheimer's disease drug other than BAN2401, compared with 41% without co-administration); ADAS-Cog (39% slowing of cognitive decline in subjects with concurrent administration of at least one Alzheimer's disease medication other than BAN2401, compared with 59% without concurrent administration) and CDR-SB (20% slowing of cognitive decline in subjects with concurrent administration of at least one Alzheimer's disease medication other than BAN2401, compared with 45% without concurrent administration). See Fig. 50.

Risk factors for disease progression

[658] A subject's ApoE4 status was not found to be a statistically significant risk factor in determining disease progression. However, other factors, such as clinical stage of the disease, concomitant administration of at least one other Alzheimer's disease drug other than BAN2401, and ADCOMS score at baseline, were found to be statistically significant risk factors. See Fig. 58 and 59.

Example of potential use A: Prevention of Alzheimer's disease in ApoE4-positive subjects

[659] Subjects of either sex are screened for ApoE4 carrier status. Subjects may be selected for screening based on age, such as 50 years or older, risk of developing Alzheimer's disease, and/or other criteria.

[660] If the screening determines that the subject is ApoE4 positive, the amyloid level in the subject's brain is measured, such as by visual readings of PET images of amyloid, as discussed above, or by another technique known to one of ordinary skill in the art. The level of Aβ _1-42 in the cerebrospinal fluid and/or the level of total tau protein in the subject's cerebrospinal fluid may also be measured.

[661] If the amyloid level in the subject's brain exceeds a predetermined level, such as a PET SUVr value exceeds 1.1, such as exceeds 1.2, exceeds 1.3, exceeds 1.4, exceeds 1.5, or exceeds 1.6, then the subject is administered a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, if the amyloid level in the subject's brain exceeds a predetermined level, such as a PET SUVr value exceeds 1.3, such as exceeds 1.4, exceeds 1.5, exceeds 1.6, exceeds 1.7, exceeds 1.8, or exceeds 1.9, then the subject is administered a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. The composition may be administered in an amount and in accordance with the schedule and route of administration of dosages described herein, such as those disclosed in Example 1.

[662] If the subject's brain amyloid level is below the above-determined predetermined level, the subject may be monitored and/or have his or her brain amyloid levels determined at a later date, such as after six months.

[663] Following administration to a subject of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils, the amyloid level in the subject's brain is measured again. If the amyloid level in the subject's brain is above a predetermined level, the composition is administered again. If the amyloid level in the subject's brain is below a predetermined level, the subject may be monitored and/or have amyloid levels in the subject's brain determined at a later date, such as over a six-month period.

[664] In a later determination, if the amyloid level in the subject's brain exceeds a predetermined level, then the subject is administered a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[665] If, during monitoring of the subject, the amyloid level in the subject's brain rises above a predetermined level, as determined by, for example, PET or cerebrospinal fluid measurements, then administration of the composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils is resumed. The amyloid level in the brain is again measured after administration of the composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[666] After administration of the composition, the subject is optionally administered at least one maintenance therapy, such as a BACE inhibitor. In some embodiments, the BACE inhibitor may be elenbecestat.

[667] In addition to measuring and recording brain amyloid levels, cerebrospinal fluid Aβ _1-42 levels, and/or cerebrospinal fluid total tau levels, other measures of the subject's health status are measured and/or monitored, such as MMSE, ADAS-Cog, CDR, and FAQ scores.

Example of potential use B: treatment of subjects with early stage Alzheimer's disease

[668] Both male and female subjects between the ages of 50 and 90 years, inclusive, with mild cognitive impairment with intermediate probability due to Alzheimer's disease and/or mild dementia in Alzheimer's disease are screened for treatment eligibility. A total of 990 subjects are randomized into two treatment groups as described below, in the following ratio: 1 subject receives placebo for every 2 subjects receive BAN2401.

[669] The study consists of a pre-randomization phase and a randomization phase.

Pre-randomization phase

[670] The phase lasts for up to 60 days and consists of a screening period and a baseline determination period. During the screening period, subjects are assessed based on study eligibility criteria. If a subject is deemed eligible for participation in the study, the subject then proceeds to the baseline determination period.

[671] During the baseline period, a number of tests are performed, including clinical tests (e.g., blood tests (e.g., to determine ApoE4 status), etc.), magnetic resonance imaging (MRI) safety tests, amyloid PET assessments (e.g., visual readings of amyloid PET images), and cerebrospinal fluid testing (for biomarker analysis) if the subject has consented. Additional clinical testing of subjects includes the MMSE, CDR, ADAS-Cog, and FAQ.

Randomization phase

[672] The randomization phase consists of an 18-month treatment period and a 3-month follow-up period. Subjects are randomized to receive placebo or a formulation containing 10 mg/kg BAN2401 every 2 weeks.

[673] All subjects were administered an intravenous infusion over approximately 60 minutes once every 2 weeks. BAN2401 was administered in isotonic saline as a 60-minute IV infusion.

[674] All subjects will be assessed for cognitive function, safety, pharmacokinetic parameters, MRI safety, PET imaging, volumetric MRI, and CSF analysis if the subject has consented to such analysis. Additional clinical assessments include MMSE, CDR, ADAS-Cog, FAQ, and amyloid measurements. These measurements will be performed at regular intervals, such as during baseline and at 3 months, 6 months, 9 months, 12 months, 15 months, and/or 18 months after initiation of treatment.

[675] Treatment is terminated after 18 months at the request of the subject, at the request of the treating physician and/or the Independent Safety Monitoring Committee and/or if one or more adverse events occur that require discontinuation of treatment.

[676] Following completion of treatment, subjects are assessed as during the baseline and randomization phases. Subjects not participating in the extension phase (described below) have a 3-month follow-up visit at which parameters similar to those measured during the randomization phase are measured/assessed.

Extension phase

[677] A subject who completes the randomisation phase has the option to participate in an extension phase. During this phase, the subject will remain on the same treatment as during the randomisation phase. Similarly, during the extension phase, symptoms will also be monitored and other parameters will be measured as described for the randomisation phase. The extension phase will continue until terminated at the request of the subject, at the request of the treating physician and/or the Independent Safety Data Monitoring Committee, if one or more adverse events occur that require discontinuation of treatment, depending on the commercial availability of BAN2401, and/or if the study results do not demonstrate a favourable risk/benefit balance. Following administration of the last dose of study medicinal product, a 3-month follow-up visit will be conducted during which parameters similar to those measured during the randomisation phase will be measured/assessed.

Compilation

[678] BAN2401 is supplied as a sterile, clear injection solution containing 10 mg/mL in a 10 mL single-use vial (total 100 mg/vial). The drug was formulated in 25 mM sodium citrate, 125 mM sodium chloride, 0.02% (w/v) polysorbate 80, and the pH was determined to be 5.7. BAN2401 is administered using an infusion set containing a 0.22 μm end-cap filter.

Study endpoints

[679] The primary endpoint of the study is the change from baseline in the Alzheimer's Disease Comprehensive Assessment (ADCOMS) score at 18 months. Key secondary endpoints include the change from baseline in the PET amyloid SUVr total score at 18 months for brain amyloid levels and the change from baseline in the ADAS-Cog score at 18 months.

[680] Secondary endpoints include change from baseline in CDR-SB score at 18 months and time to worsening of CDR-SB score at 18 months.

[681] Biomarker-based endpoints include change from baseline in total amyloid SUVr score by PET at 6 and 12 months for brain amyloid levels; change from baseline in neurogranin, neurofilament light chain, Aβ _1-42 , and total tau protein levels in cerebrospinal fluid at 12 and 18 months; and change from baseline in morphometric metrics measured by MRI (including hippocampal volume) at 6, 12, and 18 months by vMRI.

[682]Entities that meet the criteria for participation in OLE in example C.Subjects, Eligible for treatment in Use Case C below are subjects with early AD (subjects with MCI due to AD and mild dementia in AD) who were treated in an international, multicenter, double-blind, placebo-controlled, 18-month, parallel-group study evaluating the clinical safety and efficacy and the dose-response effect of BAN2401 after 12 and 18 months of treatment using the Alzheimer's Disease Comprehensive Assessment (ADCOMS) score in early AD. This study used a Bayesian design with adaptive randomization according to response to placebo or 5 active BAN2401 treatment groups in subjects with early AD for the analysis of ADCOMS scores at 12 months. Slower deterioration in subjects with early AD was observed at both 12 and 18 months with BAN2401 10 mg/kg once every two weeks as measured by ADCOMS (30% reduction in deterioration), ADAS-Cog (47% reduction), MMSE (19% reduction), and CDR-SB (26% reduction). Differences in these clinical measures were observed as early as 6 months. Clinical outcomes were accompanied by sustained and dose-dependent reductions in brain amyloid at all doses as measured by quantitative amyloid PET. See, for example, fig. 63.

Example of potential use C: Open-label extension study of BAN2401: Treatment of subjects with early Alzheimer's disease

[683] Subjects who meet the study eligibility criteria, as discussed above, will be treated with BAN2401 at 10 mg/kg once every two weeks in an open-label extension study (OLE) for up to 24 months. The OLE will evaluate the long-term safety and tolerability of BAN2401, and will also evaluate the effects of BAN2401 on brain amyloid levels in subjects who participated in the previous study, as summarized below.

[684] Approximately 200-250 subjects meeting the study eligibility criteria as discussed above, both male and female, regardless of ApoE status, may be eligible for the OLE study based on the inclusion and exclusion criteria presented below.

[685] OLE inclusion criteria include:

prior treatment in a previous study for at least 79 weeks or for less than 79 weeks due to:

ARIA-E phenomenon testing;

experiencing ARIA-H phenomena (eg, superficial siderosis, microbleeding, and/or symptomatic microbleeding);

taking a medicinal product that was prohibited during previous treatment with BAN2401 but which is no longer prohibited; and/or

any cause not related to the prohibited medicinal product, including any adverse event not related to treatment with BAN2401 and not considered severe or life-threatening;

the presence of a caregiver/informant who can provide detailed information about the subject related to his/her treatment;

the opportunity to provide informed consent and

the opportunity to make visits to the clinic.

[686] OLE exclusion criteria include:

prior treatment in a previous study that was discontinued after less than 79 weeks for reasons other than:

ARIA-E case trials;

testing for ARIA-H (eg, superficial siderosis, microbleeding and/or symptomatic microbleeding);

taking a medicinal product that was prohibited during previous treatment with BAN2401 but which is no longer prohibited; and/or

being ApoE4 positive and receiving treatment with BAN2401 at a dose of 10 mg/kg once every two weeks; and/or

experiencing an adverse event that was judged to be unrelated to the study drug (placebo or BAN2401) and was not severe or life-threatening;

breastfeeding women or women of childbearing potential who may be pregnant or at risk of becoming pregnant; and/or

development of a condition following treatment in a previous study that may interfere with or pose a safety risk to the administration of BAN2401.

[687] Prior to administration of BAN2401 in this OLE, participating subjects will be assessed to determine baseline characteristics such as cognitive function, safety parameters, pharmacokinetic parameters, MRI-based safety, PET imaging, and volumetric MRI data. Additional clinical assessments may include MMSE, CDR, ADAS-Cog, FAQ, and amyloid level measurements.

[688] Treatment in the OLE in this potential use example involves administering to eligible subjects a dose of BAN2401 10 mg/kg once every two weeks for up to 24 months.

[689] BAN2401 is supplied as any formulation suitable for human administration, such as a sterile clear injection solution containing 10 mg/mL BAN2401 in a 10 mL single-use vial (100 mg/vial total) containing 25 mM sodium citrate, 125 mM sodium chloride, 0.02% (w/v) polysorbate 80 and having a pH of 5.7. BAN2401 may be administered using an infusion set containing a 0.22 μm end-cap filter.

[690] During treatment in the OLE at various time intervals (3 months, 6 months, 9 months, 12 months, 18 months, and/or 24 months) and at the completion of treatment in the OLE, subjects are assessed using one or more assessment methods, such as baseline assessment methods and/or clinical assessment methods. Suitable assessments may include assessments of cognitive function, safety parameters, pharmacokinetic parameters, MRI-based safety, PET imaging, volumetric MRI, MMSE, CDR, ADAS-Cog, FAQ, and amyloid measurements.

[691] During treatment under the OLE, the subject continues to receive BAN2401 without interruption even if the subject develops asymptomatic ARIA-H consisting of a cerebral microbleed, multiple asymptomatic cerebral microbleeds, asymptomatic superficial siderosis, a single asymptomatic microbleed, and/or asymptomatic or radiographically mild to moderate ARIA-E. If the subject develops symptomatic ARIA-H and/or asymptomatic ARIA-E or moderate to severe radiographically ARIA-E, BAN2401 administration is suspended until ARIA-H or ARIA-E has stabilized or resolved radiographically and clinical signs have resolved, after which BAN2401 administration may be resumed at the same dose and according to the same schedule. If treatment needs to be resumed more than twice within an OLE, the subject is excluded from the study.

OLE Study Outcomes and Endpoints

[692] The OLE is evaluating the long-term safety and tolerability of treatment of subjects with early Alzheimer's disease with BAN2401 at a dose of 10 mg/kg once every two weeks. The evaluation includes determining the incidence and severity of ARIA-H, ARIA-E, and non-ARIA-H/ARIA-E adverse events.

[693] The brain amyloid level (e.g., as determined by PET imaging) is determined before and/or at the end of the previous study, before and optionally during and after treatment in the OLE in the present example of potential use with BAN2401 to assess the removal and/or maintenance of amyloid-free brain due to treatment with BAN2401. The brain amyloid level (e.g., as determined by longitudinal PET imaging) is assessed after 3 months, 6 months, 12 months, 18 months, and/or 24 months of treatment in the OLE in the present example of potential use with BAN2401, such as in terms of the change in brain amyloid level from baseline following the previous study, as discussed above. The proportion of amyloid-positive subjects, such as determined by visual readings of PET images of amyloid, is also assessed over a period of time in the OLE.

[694] Assessment of subjects' cognitive function in this OLE study, as measured by, for example, ADCOMS, CDR-SB, ADAS-Cog, and MMSE, may provide insight into the long-term cognitive effects of treatment with BAN2401. Assessments may provide insight into long-term disease progression and the durability of any slowing in the rate of cognitive decline observed in the previous study.

[695] Because parameters such as pharmacokinetic characteristics, hippocampal volume, and other biomarkers will be measured, this OLE study may provide insight into the long-term effects of treatment with BAN2401.

[696] Information regarding the management of ARIA-E and ARIA-H events may be obtained from this OLE study because, unlike the previous protocol, the OLE protocol in the present use case calls for subjects to continue treatment with BAN2401 even if they experience ARIA-E and/or ARIA-H events, unless their severity warrants discontinuing treatment.

[697] Additional insight into the durability of amyloid reduction after a “drug holiday” (e.g., how long the reduction persists after stopping treatment with BAN2401), the dynamics of amyloid increase and/or deposition, and/or the dynamics of amyloid clearance (how quickly amyloid is cleared by treatment with BAN2401) may also be gained from the OLE study in this potential use case.

Initial results

[698] Enrollment in the OLE study is ongoing. Baseline amyloid PET data are available for 56 subjects enrolled in the OLE study, which includes data from 39 subjects who were treated with BAN2401 in the previous study with a median off-treatment period of 21 months (range 9-52 months off-treatment period). It was determined that 85% (33/39) of subjects who were previously amyloid-positive and who were treated with BAN2401 (10 mg/kg once monthly or once every two weeks for 18 months) remained amyloid-negative after a off-treatment period of 9 months to 52 months. All subjects enrolled in the OLE study who were amyloid-negative in the previous study at 18 months were also amyloid-negative at baseline measurement in the OLE study, regardless of treatment group in the previous study. Thus, these initial results unexpectedly demonstrate that BAN2401-mediated return of subjects to amyloid-negative status, as determined by PET, was maintained from the end of the previous study to baseline measurement in the OLE study, despite subjects not receiving treatment for a period of 9 to 52 months.

[699] In some embodiments, the methods disclosed herein result in a reduction in amyloid levels. In some embodiments, the reduction in amyloid levels is determined by PET. In some embodiments, the reduction in amyloid levels, as determined by PET, is maintained for a period of 9 months to 52 months after administration of BAN2401.

[700] In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 1 month after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 2 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 3 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 4 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 5 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 6 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 7 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 8 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 9 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 10 months after administration of BAN2401.

[701] In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 15 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 20 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 25 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 30 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 35 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 40 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 45 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for at least 50 months after administration of BAN2401.

[702] In some embodiments, the reduction in amyloid as determined by PET is maintained for 9 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 10 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 11 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 12 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 13 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 14 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 15 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for 16 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for 17 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for 18 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for 19 months after administration of BAN2401.

[703] In some embodiments, the reduction in amyloid as determined by PET is maintained for 20 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 21 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 22 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 23 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 24 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 25 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 26 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for 27 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for 28 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for 29 months after administration of BAN2401.

[704] In some embodiments, the reduction in amyloid as determined by PET is maintained for 30 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 31 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 32 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 33 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 34 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 35 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 36 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for 37 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for 38 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for 39 months after administration of BAN2401.

[705] In some embodiments, the reduction in amyloid as determined by PET is maintained for 40 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 41 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 42 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 43 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 44 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 45 months after administration of BAN2401. In some embodiments, the reduction in amyloid as determined by PET is maintained for 46 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for 47 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for 48 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for 49 months after administration of BAN2401.

[706] In some embodiments, the reduction in amyloid levels as determined by PET is maintained for 50 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for 51 months after administration of BAN2401. In some embodiments, the reduction in amyloid levels as determined by PET is maintained for 52 months after administration of BAN2401.

Example of possible use of D: prevention of Alzheimer's disease

[707] Subjects may be selected for screening based on age, such as age 50 years or older, risk of developing Alzheimer's disease, and/or other criteria. The subject's ApoE4 carrier status is determined, but this does not affect the subject's eligibility for participation in the study.

[708] The level of amyloid in the brain of a subject is measured, for example, using visual readings of PET images of amyloid, as discussed above, or other techniques known to those of ordinary skill in the art. The level of Aβ _1-42 in the cerebrospinal fluid and/or the level of total tau protein in the cerebrospinal fluid of a subject can also be measured.

[709] If the amyloid level in the subject's brain exceeds a predetermined level, such as a PET SUVr value exceeds 1.1, such as exceeds 1.2, exceeds 1.3, exceeds 1.4, exceeds 1.5, or exceeds 1.6, then the subject is administered a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, if the amyloid level in the subject's brain exceeds a predetermined level, such as a PET SUVr value exceeds 1.3, such as exceeds 1.4, exceeds 1.5, exceeds 1.6, exceeds 1.7, exceeds 1.8, or exceeds 1.9, then the subject is administered a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. The composition may be administered in an amount and in accordance with the schedule and route of administration of dosages described herein, such as those disclosed in Example 1.

[710] If the subject's brain amyloid level is below the above-mentioned predetermined level, the subject may be monitored and/or have his or her brain amyloid levels determined at a later date, such as after six months.

[711] Following administration to a subject of a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils, the amyloid level in the subject's brain is measured again. If the amyloid level in the subject's brain is above a predetermined level, administration of the composition is repeated. If the amyloid level in the subject's brain is below a predetermined level, the subject may be monitored and/or have amyloid levels in the brain determined at a later date, such as over a period of six months.

[712] In a later determination, if the amyloid level in the subject's brain exceeds a predetermined level, then the subject is administered a composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[713] If, during monitoring of the subject, the amyloid level in the subject's brain rises above a predetermined level, as determined by, for example, PET or cerebrospinal fluid measurements, then administration of the composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils is resumed. The amyloid level in the brain is measured again after administration of the composition comprising a therapeutically effective amount of at least one antibody to Aβ protofibrils.

[714] After administration of the composition, the subject is optionally administered at least one maintenance therapy, such as a BACE inhibitor. In some embodiments, the BACE inhibitor may be elenbecestat.

[715] In addition to measuring and recording the brain amyloid level, the cerebrospinal fluid Aβ _1-42 level, and/or the cerebrospinal fluid total tau protein level, other health status indicators of the subject are measured and/or monitored, such as MMSE, ADAS-Cog, CDR, and FAQ scores. See, for example, Fig. 64.

SEQUENCE LIST

Table 24. Amino acid sequences of variable regions of mAb

mAb IgG chain SEQ ID NO Amino acid sequence BAN2401 Heavy chain 1 EVQLVESGGGLVQPGGSLRLSCSASGTFSSFGMHWVRQAPGKGLEWVAYISSGSSTIYYGDTVKGRFTISRDNAKNSLFLQMSSLRAEDTAVYYCAREGGYYYGRSYYTMDYWGQGTTVTVSS BAN2401 Light chain 2 DVVMTQSPLSLPVTPGAPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLRISRVEAEDVGIYYCFQGSHVPPTFGPGTKLEIK

Table 25. Amino acid sequences of mAb constant regions

mAb IgG chain Class SEQ ID NO Amino acid sequence BAN2401 Heavy chain IgG1 3 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK BAN2401 Light chain Kappa chain 4 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Table 26. Amino acid sequences of mAb CDRs

mAb IgG chain SEQ ID NO Amino acid sequence BAN2401 HCDR1 5 SFGMH HCDR2 6 YISSGSSTIYYGDTVKG HCDR3 7 EGGYYYGRSYYTMDY BAN2401 LCDR1 8 RSSQSIVHSNGNTYLE LCDR2 9 KVSNRFS LCDR3 10 FQGSHVPPT

SEQ ID NO: 11

heavy chain: evqlvesggglvqpggslrlscsasgftfssfgmhwvrqapgkglewvayissgsstiyygdtvkgrftisrdnaknslflqmsslraed tavyycareggyyygrsyytmdywgqgttvtvssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfp avlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkrvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcv vvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepq vytlppsreemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhn hytqkslslspgk

SEQ ID NO:12

light chain: dvvmtqsplslpvtpgapasiscrssqsivhsngntylewylqkpgqspklliykvsnrfsgvpdrfsgsgsgtdftlrisrveaedvgiy ycfqgshvpptfgpgtkleikrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysls stltlskadyekhkvyacevthqglsspvtksfnrgec

--->

SEQUENCE LIST

<110> EISAI R&D MANAGEMENT CO., LTD.

<120> METHODS OF TREATMENT AND PREVENTION OF ALZHEIMER'S DISEASE

<130> 08061.0039-00304

<140> PCT/US2019/043067

<141> 23.07.2019

<150> 62/874,684

<151> 2019-07-16

<150> 62/846,902

<151> 2019-05-13

<150> 62/824,162

<151> 2019-03-26

<150> 62/749,614

<151> 2018-10-23

<150> 62/702,659

<151> 2018-07-24

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Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Gly Tyr Tyr Tyr Gly Arg Ser Tyr Tyr Thr Met Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys

115 120 125

Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly

130 135 140

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

145 150 155 160

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

165 170 175

Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val

180 185 190

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

195 200 205

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

210 215 220

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

225 230 235 240

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

245 250 255

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

260 265 270

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

275 280 285

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

290 295 300

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

305 310 315 320

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

325 330 335

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

340 345 350

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

355 360 365

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

370 375 380

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

385 390 395 400

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

405 410 415

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

420 425 430

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

435 440 445

Ser Leu Ser Pro Gly Lys

450

<210> 12

<211> 219

<212> PROTEIN

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

synthetic polypeptide"

<400> 12

Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly

1.5 10 15

Ala Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser His Val Pro Pro Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys

100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

115 120 125

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

130 135 140

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

145 150 155 160

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<---

Claims (28)

1. A method for reducing clinical deterioration in a subject with early Alzheimer's disease, comprising administering a composition comprising a therapeutically effective amount of an anti-protofibril antibody Ab to the subject, wherein the composition is administered at a dose of 10 mg/kg of the anti-protofibril antibody Ab relative to the subject's weight once every two weeks for a period of time sufficient to reduce clinical deterioration in the subject by at least 21% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of the composition, where the subject is ApoE4 positive, and wherein the anti-protofibril antibody Ab comprises three heavy chain complementarity determining regions comprising the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6 and SEQ ID NO: 7; and three light chain complementarity determining regions comprising the amino acid sequences of SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10. 2. The method according to claim 1, wherein the antibody to protofibrils Ab comprises a heavy chain variable region comprising the amino acid sequence under SEQ ID NO: 1, and a light chain variable region comprising the amino acid sequence under SEQ ID NO: 2. 3. The method according to claim 1 or 2, wherein the subject with early stage Alzheimer's disease has been diagnosed with mild cognitive impairment, with intermediate probability due to Alzheimer's disease, and/or has been diagnosed with mild dementia in Alzheimer's disease. 4. The method according to any one of claims 1-3, wherein the anti-protofibril antibody Ab comprises a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12. 5. The method of any one of claims 1-4, wherein clinical worsening is reduced by at least 45% compared to placebo, as determined by ADCOMS, after 6 months of administration of the composition. 6. The method of any one of claims 1-5, wherein clinical worsening is reduced by at least 35% compared to placebo, as determined by ADCOMS, after 12 months of administration of the composition. 7. The method of any one of claims 1-6, wherein clinical worsening is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 18 months of administration of the composition. 8. The method of any one of claims 1-7, wherein clinical worsening is reduced by at least 47% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of the composition. 9. The method of any one of claims 1-8, wherein clinical worsening is reduced by at least 25% compared to placebo, as determined by the CDR-SB, after 18 months of administration of the composition. 10. The method of any one of claims 1-9, wherein clinical worsening is reduced by at least 26% compared to placebo, as determined by the CDR-SB, after 18 months of administration of the composition. 11. The method of claim 7, wherein the subject with early Alzheimer's disease has been diagnosed with mild cognitive impairment, with intermediate probability due to Alzheimer's disease, and wherein clinical deterioration is reduced by at least 33% compared to placebo, as determined by ADCOMS, after 18 months of administration of the composition. 12. The method of claim 7, wherein the subject with early Alzheimer's disease has been diagnosed with mild Alzheimer's dementia, and wherein clinical worsening is reduced by at least 35% compared to placebo, as determined by ADCOMS, after 18 months of administration of the composition. 13. The method of any one of claims 1-12, wherein clinical worsening is reduced by at least 63% compared to placebo, as determined by ADCOMS, after 18 months of administration of the composition. 14. The method of any one of claims 1-13, wherein clinical worsening is reduced by at least 84% compared to placebo, as determined by ADAS-Cog, after 18 months of administration of the composition. 15. The method of any one of claims 1-14, wherein clinical worsening is reduced by at least 60% compared to placebo, as determined by the CDR-SB, after 18 months of administration of the composition. 16. The method according to any one of claims 1-15, wherein the level of Ab _1-42 , total tau protein, phospho-tau protein or neurogranin is measured, and an additional dose of the antibody to protofibril Ab is administered if the level of Ab _1-42 in the cerebrospinal fluid increases above or the level of total tau protein, phospho-tau protein or neurogranin decreases below the pre-treatment level. 17. The method according to any one of claims 1-16, wherein the administration results in a slowing of the increase in the level of neurofilament light chains in the cerebrospinal fluid. 18. The method according to any one of claims 1-17, wherein the subject is administered an anti-protofibril antibody Ab comprising a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12, and at least one drug for the treatment of Alzheimer's disease is administered in parallel, other than the anti-protofibril antibody Ab comprising a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12. 19. The method according to any one of claims 1-17, wherein the subject is administered an anti-protofibril Ab antibody comprising the heavy chain of SEQ ID NO: 11 or the light chain of SEQ ID NO: 12, and is not simultaneously administered at least one drug for the treatment of Alzheimer's disease other than the anti-protofibril Ab antibody comprising the heavy chain of SEQ ID NO: 11 or the light chain of SEQ ID NO: 12. 20. The method according to any one of claims 1-19, which comprises confirming the presence of beta-amyloid pathology prior to administration. 21. The method according to any one of claims 1-20, wherein the administration is carried out by intravenous infusion. 22. The method according to claim 21, wherein the intravenous infusion lasts for approximately 60 minutes. 23. The method according to any one of claims 1-22, wherein the composition comprises sodium chloride. 24. The method according to any one of claims 1-23, wherein before administration, obtaining the composition comprises dissolving the antibody to protofibrils Ab. 25. The method of any one of claims 1-24, wherein the subject is heterozygous for ApoE4.

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