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WO2025019457A1 - Peptides antimicrobiens - Google Patents

Peptides antimicrobiens Download PDF

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Publication number
WO2025019457A1
WO2025019457A1 PCT/US2024/038107 US2024038107W WO2025019457A1 WO 2025019457 A1 WO2025019457 A1 WO 2025019457A1 US 2024038107 W US2024038107 W US 2024038107W WO 2025019457 A1 WO2025019457 A1 WO 2025019457A1
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subject
level
tau
treatment
sample
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Pallavi SACHDEV
Satya SAXENA
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Eisai R&D Management Co Ltd
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Eisai R&D Management Co Ltd
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2821—Alzheimer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • AD Alzheimer’s disease
  • AMPs antimicrobial peptides
  • levels of these select AMPs may be used for different aspects of treating AD, such as selecting a subject for treatment, treating AD and symptoms associated with AD, monitoring and/or adjusting the treatment, and determining maintenance dosing regimens for subjects.
  • AD Alzheimer’s disease
  • AD Alzheimer disease
  • AD Alzheimer's disease facts and figures. Alzheimer Dement.2010; 6:158-94.
  • AD represents a significant economic burden across industrialized countries with a substantial impact on healthcare systems and the public purse as well as on subjects and their families. In the United States alone, total payments for 2010 were estimated at $172 billion, including $123 billion for Medicare and Medicaid.
  • Alzheimer's disease is characterized by neuritic plaques, found primarily in the association cortex, limbic system and basal ganglia. The major constituent of these plaques is amyloid beta peptide (A ⁇ ). A ⁇ exists in various conformational states - monomers, oligomers, protofibrils, and insoluble fibrils. Details of the mechanistic relationship between onset of Alzheimer’s disease and A ⁇ production is unknown. However, some anti-A ⁇ antibodies are undergoing clinical study now as potential therapeutic agents for Alzheimer’s disease.
  • a ⁇ amyloid beta peptide
  • AD Alzheimer's disease
  • antimicrobial peptides may be used as biomarkers for diagnosing AD (Bruno et al., Antibiotics, 2022, 11:6, 726).
  • Antimicrobial peptides are small (12-50 amino acid), charged, cationic, usually amphipathic peptides that provide the first line of defense against bacteria, fungi, parasites, and viruses by oligomerizing into a “nanonet” of fibrils that trap an invading pathogen.
  • AMPs are expressed at high levels in brain and other immune-privileged organs where the activities of adaptive immunity are constrained. The majority of AMPs are synthesized as large polyprotein precursors and proteolytic processing releases small (12-50 amino acid) active peptide segments. Removal of signal peptide may be a post-translation, or a co-translational process and traditional DNA and RNA sequencing based approaches may not be suitable to study AMP peptides.
  • AD Alzheimer et al., Alzheimer’s & Dementia.2018;14: 1602-1614).
  • a ⁇ 1-42 bears convincing structural similarities with viral fusion domains and AMPs, and sequence similarities with a specific family of bacterial bacteriocins. This has opened the door for new studies identifying novel AMPs with the ability to influence neurological disorders. AMPs are also activated by inflammation.
  • the “infection hypothesis” of AD proposes that weakening of the blood-brain barrier (BBB) and the immune system in aging subjects, in combination with infections from microorganisms, leads to chronic neuroinflammation. While no specific pathogen has been identified as causing AD, coexistence of pathogens in the brain of subjects with AD and a role for A ⁇ as an antimicrobial peptide suggests that chronic neuroinflammation may contribute to the pathogenesis (Vigasova et al., Microbial Cell Factories, 2021; 20: 25). In an inflamed state, the production of A ⁇ and phosphorylated-tau is increased, which could lead to aggregation of these proteins into tangles and plaques and subsequent neurodegeneration.
  • BBB blood-brain barrier
  • antimicrobial peptides may mediate processes of aggregation and/or neurodegeneration.
  • Certain AMPs such as lactoferrin and cystatins interact with A ⁇ and are found in amyloid plaques.
  • lactoferrin, cystatin, and other AMPs show increased expression in saliva, blood, serum, and/or CSF obtained from AD patients (Bruno et al., Antibiotics, 2022, 11, 726). While this data is promising, there remains a need for further analysis of the diagnostic potential of AMPs overall, and for identification of highly-specific AMPs that may be used for diagnosis of AD.
  • One aspect of the present disclosure relates to a method of selecting a subject for a treatment with an Alzheimer’s disease (AD) therapy, comprising: a) obtaining a measurement of a level of at least one antimicrobial peptide (AMP) in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; and b) selecting the subject for treatment if the level of at least one AMP is altered compared to a control sample, e.g., compared to an AMP level in an individual who does not have Alzheimer’s disease (AD), optionally wherein the AD therapy is an anti-A ⁇ protofibril antibody (e.g., lecanemab) or an anti-tau antibody (e.g., E2814
  • An aspect of the present disclosure relates to a method of selecting a subject for a treatment with an AD therapy, comprising: a) obtaining a measurement of a level of at least one AMP in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2-microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Secretogranin-1 (SCG1), Ubiquitin-ribosomal protein eL40 fusion protein (RL40), Ubiquitin- 40S ribosomal protein S27A, Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC); b) selecting the subject for treatment if the level of at least one AMP is altered compared to a control sample, e.g., compared to an AMP-C (UBC);
  • the AMP is a peptide listed in Table 10.
  • the subject has, is suspected of having, or is at risk for developing Alzheimer’s disease (AD). In some embodiments, wherein the subject has early AD or mild to moderate AD.
  • the subject is selected for treatment if the AMP level from the subject is increased as compared to the control. In some embodiments, the subject is selected for treatment if the AMP level from the subject is decreased as compared to the control.
  • a further aspect of the present disclosure relates to a method of monitoring treatment efficacy in a subject receiving a treatment comprising a therapeutically effective dose of an AD therapy, comprising: a) obtaining a measurement of a first AMP level in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment, wherein the AMP is selected from any of those listed in Table 10; b) obtaining a measurement of a second AMP level in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first AMP level to the second AMP level, wherein a change in the second AMP level as compared to first AMP level is an indicator of treatment efficacy, optionally wherein the AD therapy is an anti- A ⁇ protofibril antibody (e.g., lecanemab) or an anti-tau antibody (e.g., E2814).
  • the AD therapy is
  • a further aspect of the present disclosure relates to a method of monitoring treatment efficacy in a subject receiving a treatment comprising a therapeutically effective dose of an AD therapy, comprising: a) obtaining a measurement of a first AMP level in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment, wherein the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2-microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Attorney Docket Number 08061.0063-00304 Secretogranin-1 (SCG1), Ubiquitin-ribosomal protein eL40 fusion protein (RL40), Ubiquitin- 40S ribosomal protein S27A, Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC); b) obtaining a measurement of a second AMP level in a second bioflui
  • the AMP is a peptide listed in Table 10.
  • a decrease in the second AMP level as compared to first AMP level indicates an effective treatment.
  • a lack of a decrease in the second AMP level as compared to first AMP level indicates a non-effective treatment.
  • a decrease in the second AMP level as compared to first AMP level indicates a non-effective treatment.
  • a lack of a decrease in the second AMP level as compared to first AMP level indicates an effective treatment.
  • An aspect of the present disclosure relates to a method of adjusting a treatment regimen in a subject receiving a treatment comprising a therapeutically effective dose of an AD therapy, comprising: a) obtaining a measurement of a level of at least one AMP in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; b) comparing the level of at least one AMP to a control sample, e.g., an AMP level concentration in an individual who does not have Alzheimer’s disease (AD); and c) adjusting the treatment regimen if the level of at least one AMP is different compared to a control sample, e.g., compared to an AMP level in an individual who does not have Alzheimer’s disease (AD), e.g., by changing the size of the dose, the frequency of administration, and/or the route of administration of the anti-A ⁇ protofibril antibody, optionally wherein the AD therapy is an anti-
  • An aspect of the present disclosure relates to a method of adjusting a treatment regimen in a subject receiving a treatment comprising a therapeutically effective dose of an AD therapy, comprising: a) obtaining a measurement of a level of at least one AMP in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2-microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Secretogranin-1 (SCG1), Ubiquitin- ribosomal protein eL40 fusion protein (RL40), Ubiquitin-40S ribosomal protein S27A, Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC); b) comparing the level of at least one Attorney Docket Number 08061.0063-00304 AMP to a control sample, e.g.
  • the AMP is a peptide listed in Table 10.
  • the treatment regimen is adjusted if the AMP level is higher than a control. In some embodiments, the treatment regimen is adjusted if the AMP level is lower than a control.
  • An aspect of the present disclosure relates to a method of detecting a decrease in a brain A ⁇ level in a subject receiving a treatment comprising a therapeutically effective dose of an AD therapy, comprising: a) obtaining a measurement of a first AMP level in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment, wherein the AMP is selected from any of those listed in Table 10; b) obtaining a measurement of a second AMP level in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second AMP levels, wherein an altered AMP level in the second sample relative to the first sample indicates a decrease of a brain A ⁇ level in the subject; optionally wherein the AD therapy is an anti-A ⁇ protofibril antibody (e.g., lecanemab).
  • a first biofluid sample e.g., a
  • An aspect of the present disclosure relates to a method of detecting a decrease in a brain A ⁇ level in a subject receiving a treatment comprising a therapeutically effective dose of an AD therapy, comprising: a) obtaining a measurement of a first AMP level in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment, wherein the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2-microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Secretogranin-1 (SCG1), Ubiquitin-ribosomal protein eL40 fusion protein (RL40), Ubiquitin- 40S ribosomal protein S27A, Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC); b) obtaining a measurement of a second AMP level in a second biofluid sample, e.
  • the AMP is a peptide listed in Table 10.
  • a decreased AMP level in the second sample relative to the first sample indicates a decrease of a brain A ⁇ level in the subject.
  • an increased AMP level in the second sample relative to the first sample indicates a decrease of a brain A ⁇ level in the subject.
  • An aspect of the present disclosure relates to a method of detecting a decrease in a brain tau level (e.g., a reduction in tau tangles) in a subject receiving a treatment comprising a therapeutically effective dose of an AD therapy, comprising: a) obtaining a measurement of a first AMP level in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment, wherein the AMP is selected from any of those listed in Table 10; b) obtaining a measurement of a second AMP level in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second AMP levels, wherein an altered AMP level in the second sample relative to the first sample indicates a decrease of a brain tau level in the subject; optionally wherein the AD therapy is an anti-A ⁇ protofibril antibody (e.g., lecanemab) or an anti-
  • An aspect of the present disclosure relates to a method of detecting a decrease in a brain tau level (e.g., a reduction in tau tangles) in a subject receiving a treatment comprising a therapeutically effective dose of an AD therapy, comprising: a) obtaining a measurement of a first AMP level in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment, wherein the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2-microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Secretogranin-1 (SCG1), Ubiquitin-ribosomal protein eL40 fusion protein (RL40), Ubiquitin-40S ribosomal protein S27A, Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC); b) obtaining a measurement of a second AMP
  • the AMP is a peptide listed in Table 10.
  • a decreased AMP level in the second sample relative to the first sample indicates a decrease of a brain tau level in the subject.
  • an Attorney Docket Number 08061.0063-00304 increased AMP level in the second sample relative to the first sample indicates a decrease of a brain tau level in the subject.
  • a decrease of a brain tau level is a decrease in tau tangles.
  • An aspect of the present disclosure relates to a method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a first AMP level in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-tau protofibril antibody if the a first AMP level is elevated compared to a control sample, e.g., compared to an AMP level in an individual who does not have Alzheimer’s disease (AD); and c) obtaining a measurement of a second AMP level, wherein a change in the second AMP level as compared to the first AMP level indicates a reduction in tau tangles, optionally wherein the anti-tau antibody comprises three heavy chain complementarity determining regions (HCDR1, HC
  • An aspect of the present disclosure relates to a method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a first AMP level in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2-microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Secretogranin-1 (SCG1), Ubiquitin-ribosomal protein eL40 fusion protein (RL40), Ubiquitin-40S ribosomal protein S27A, Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC); b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-tau protofibril antibody if the first AMP level
  • An aspect of the present disclosure relates to a method of treating a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a level of at least one AMP in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; and b) administering to the subject a treatment comprising a therapeutically effective dose of an AD therapy if the level of at least one AMP is altered compared to a control sample, e.g., compared to an AMP level in an individual who does not have Alzheimer’s disease (AD), optionally wherein the AD therapy is an anti-A ⁇ protofibril antibody (e.g., lecanemab) or an anti-tau antibody (e.g., E2814).
  • AD therapy is an anti-A ⁇ protofibril antibody (e.g., lecanemab) or an anti-tau antibody (
  • An aspect of the present disclosure relates to a method of treating a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a level of at least one AMP in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2-microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Secretogranin-1 (SCG1), Ubiquitin-ribosomal protein eL40 fusion protein (RL40), Ubiquitin-40S ribosomal protein S27A, Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC); and b) administering to the subject a treatment comprising a therapeutically effective dose of an AD therapy if the level of at least one AMP is altered compared to a control
  • the AMP is a peptide listed in Table 10.
  • the AD therapy is administered if the AMP level is increased compared to the control sample. In some embodiments, the AD therapy is administered if the AMP level is decreased compared to the control sample.
  • the method of treating a subject comprises, after steps a) obtaining a measurement of a level of at least one AMP in a biofluid sample, e.g., a CSF or blood sample, from the subject; and b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-tau antibody if the level of at least one AMP is elevated compared to a control sample, applying further steps of c) obtaining a further measurement of the level of at least one AMP (e.g., a further AMP level) in a second biofluid sample, e.g., a CSF or blood sample, from the subject; d) determining that the Attorney Docket Number 08061.0063-00304 further AMP level has changed relative to the level of at least one AMP obtained prior to administration of the AD therapy; and e) administering a further therapeutically effective dose of the AD therapy to the subject, optionally wherein the AD therapy is an anti-A ⁇ protofibril antibody
  • the further therapeutically effective dose is administered according to a maintenance dosing regimen.
  • the treatment comprises administration of a therapeutically effective dose of the AD therapy according to an initiation dosing regimen, optionally after which the subject is switched to a maintenance dosing regimen.
  • the subject is switched from an initiation dosing regimen to a maintenance dosing regimen when a further measurement of AMP level in a further biofluid sample, e.g., a CSF or blood sample, from the subject differs from a threshold, e.g., a level seen in a control sample from an individual who does not have AD.
  • the subject is switched when the AMP level is below the threshold.
  • the subject is switched when the AMP level is above the threshold.
  • the AMP level is quantified by LC/MS.
  • the biofluid sample is CSF.
  • the subject shows a change and/or difference in a measurement of one or more additional biomarkers associated with AD pathology prior to treatment.
  • the change and/or difference in the measurement is selected from: a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), c) decreased cerebrospinal fluid levels of ratio of A ⁇ 1-42/1-40 and/or increased total tau, phosphorylated tau (e.g., p- tau181, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non- phosphorylated tau (e.g., tau181/np-tau181, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243
  • the subject shows a change and/or difference in a measurement of one or more additional biomarkers associated with AD pathology during and/or after treatment.
  • the change and/or difference in the measurement is selected from: a) decreased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) decreased tau in the brain, e.g., as measured by positron emission tomography (PET), c) increased cerebrospinal fluid levels of ratio of A ⁇ 1-42/1-40 and/or decreased total tau, phosphorylated tau (e.g., p- tau181, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non- phosphorylated tau (e.g., tau181/np
  • amyloid PET e.g., a centiloid measure of
  • the treatment a) delays clinical decline as determined by ADCOMS; b) delays clinical decline as determined by ADAS MCI-ADL; c) delays clinical decline as determined by modified iADRS; d) delays clinical decline as measured by a CDR- SB; or e) delays clinical decline as measured by an ADAS-Cog.
  • the subject has a genetic mutation for a dominantly inherited Alzheimer’s disease, e.g., wherein the subject a genetic mutation in at least one of three genes — PSEN1, PSEN2, or APP. In some embodiments, the subject has a mutation in APP.
  • the subject has a family history of Alzheimer’s disease, e.g., a history of a family member being diagnosed with Alzheimer’s disease before the age of 60.
  • the subject is ApoE4-positive.
  • the subject is 65 to 80 years old.
  • the subject is 55 to 64 years old and has at least one risk factor chosen from: (i) a first degree relative diagnosed with dementia onset before age 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid according to PET or cerebrospinal fluid (CSF) testing prior to said administration.
  • the subject is amyloid positive.
  • the subject is amyloid positive based on a PET assessment, a CSF assessment of A ⁇ (1-42), a CSF assessment of total tau, a CSF assessment of phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., tau181/np-tau181, tau205/np-tau205, p- tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, MRI, retinal amyloid accumulation, and/or a blood biomarker assessment (e.g.
  • a plasma A ⁇ 1-42/1-40 ratio total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., tau181/np-tau181, tau205/np-tau205, p- tau217/np-tau217 and/or tau231/np-tau231) and/or MTBR-tau243.
  • the subject has Alzheimer’s disease. In some embodiments, the subject has early Alzheimer’s disease.
  • the subject has been diagnosed with a) mild cognitive impairment due to Alzheimer’s disease – intermediate likelihood and/or has been diagnosed as having mild Alzheimer’s disease dementia; b) mild cognitive impairment due to Alzheimer’s disease – intermediate likelihood by National Institute of Aging – Alzheimer’s Association (NIA-AA) core clinical criteria; c) mild cognitive impairment due to Alzheimer’s disease – intermediate likelihood by a CDR global score of 0.5 and a Memory Box score of 0.5 or greater before treatment; d) mild cognitive impairment due to Alzheimer’s disease – intermediate likelihood by a history of subjective memory decline with gradual onset and slow progression over the last 1 year before treatment, e.g., as corroborated by an informant; e) mild Alzheimer’s disease dementia by the NIA-AA core clinical criteria for probable Alzheimer’s disease dementia; or f) mild Alzheimer’s disease dementia by a CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or greater before treatment.
  • NIA-AA National Institute of Aging – Alzheimer’s Association
  • the subject is suspected of having AD. In some embodiments, the subject is a subject at risk for developing AD. In some embodiments, the subject at risk for developing AD has pre-Alzheimer’s disease (pre-AD). In some embodiments, the subject does not have cognitive impairment.
  • pre-AD pre-Alzheimer’s disease
  • the anti-A ⁇ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).
  • HCDR1, HCDR2, and HCDR3 comprising amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3)
  • LCDR1, LCDR2, and LCDR3 three light chain complementarity determining regions
  • LCDR1, LCDR2, and LCDR3 comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR
  • the anti-tau antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), and SEQ ID NO: 17 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).
  • the anti-tau antibody is E2814.
  • the antimicrobial peptide comprises any one of SEQ ID NOs: 27-50. Enumerated Embodiments 1.
  • a method of treating Alzheimer’s disease (AD) in a subject having or suspected of having AD comprising: determining an altered level of at least one antimicrobial peptide (AMP) in a biofluid, e.g., a cerebrospinal fluid (CSF), from the subject as compared to a control, e.g., CSF from an individual who has not been diagnosed with AD, wherein the AMP is selected from any of those listed in Table 10, and administering to the subject a therapeutically effective dose of an AD therapy, e.g., an anti- amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody.
  • an AD therapy e.g., an anti- amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody.
  • a method of treating Alzheimer’s disease (AD) in a subject having or suspected of having AD comprising: determining an altered level of at least one antimicrobial peptide (AMP) in a biofluid, e.g., a cerebrospinal fluid (CSF), from the subject as compared to a control, e.g., CSF from an individual who has not been diagnosed with AD, wherein the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2-microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Secretogranin-1 (SCG1), Ubiquitin-ribosomal protein eL40 fusion protein (RL40), Ubiquitin-ribosomal protein eS31 fusion protein (RS27A), Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC), and administering to the subject a therapeutically effective dose of an AD therapy, e.g
  • control is the level of AMP in a biofluid (e.g., CSF) from an individual who does not have Alzheimer’s disease.
  • anti-A ⁇ protofibril antibody is lecanemab.
  • a method of treating Alzheimer’s disease (AD) in a subject having or suspected of having AD comprising: determining a first level of at least one antimicrobial peptide (AMP) in a biofluid, e.g., a cerebrospinal fluid (CSF), from the subject, wherein the first level of the AMP is altered in CSF from the subject as compared to a control, e.g., CSF from an individual who has not been diagnosed with AD, wherein the AMP is selected from any of those listed in Table 10; administering to the subject a first therapeutically effective dose of an AD therapy, e.g., an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody; determining a second level of the AMP in CSF from the subject; and administering a second therapeutically effective dose of the AD therapy if there is a change from the first level of the AMP to the second level of the AMP.
  • AMP antimicrobial peptide
  • the antimicrobial peptide comprises any one of SEQ ID NOs: 13-36.
  • the subject is cognitively impaired.
  • Attorney Docket Number 08061.0063-00304 12.
  • the method of embodiment 9, wherein the subject has one or more of a t-tau level in CSF that is above 400 ng/L, an A ⁇ 1-42 level in CSF that is below 550 ng/L, and a A ⁇ 1- 42/A ⁇ 1-40 ratio in CSF that is below 0.065.
  • the control is the level of AMP a biofluid (e.g., CSF) from an individual who does not have Alzheimer’s disease. 14.
  • a method of monitoring treatment efficacy in a subject having or suspected of having AD comprising: determining a first level of at least one antimicrobial peptide (AMP) in a biofluid, e.g., a cerebrospinal fluid (CSF), from the subject, wherein the first level of the AMP is altered in CSF from the subject as compared to a control, e.g., CSF from an individual who has not been diagnosed with AD, wherein the AMP is selected from any of those listed in Table 10; administering to the subject a first therapeutically effective dose of an AD therapy, e.g., an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody; and measuring a second level of the AMP in CSF from the subject, wherein a second level of the AMP that is different from the first level indicates effective treatment.
  • an AD therapy e.g., an anti-amyloid ⁇ (A ⁇ ) treatment
  • a ⁇ anti-a
  • the antimicrobial peptide comprises any one of SEQ ID NOs: 13-36. 17.
  • the subject has one or more of a t-tau level in CSF that is above 400 ng/L, an A ⁇ 1-42 level in CSF that is below 550 ng/L, and a A ⁇ 1- 42/A ⁇ 1-40 ratio in CSF that is below 0.065.
  • the control is the level of AMP a biofluid (e.g., CSF) from an individual who does not have Alzheimer’s disease.
  • the anti-A ⁇ protofibril antibody is lecanemab.
  • a method of diagnosing AD in a subject comprising: determining a level of one or more antimicrobial peptides (AMP) in a biofluid, e.g., a cerebrospinal fluid (CSF), from the subject, wherein the AMP is selected from any of those listed in Table 10, and comparing the level of the AMP to a control, e.g., CSF from an individual who has not been diagnosed with AD, wherein an altered level of the AMP in CSF from the subject as compared to the control indicates that the subject has AD.
  • AMP antimicrobial peptides
  • CSF cerebrospinal fluid
  • Figure 2 shows the de novo-assisted pipeline used to identify differential expression of 24 AMPs (q ⁇ 0.2) in the CSF of A ⁇ + demented subjects.
  • Figure 3 is a volcano plot using 320 CSF peptides in cognitively impaired subjects. 24/320 CSF AMP peptides were differentially regulated in subjects that are A ⁇ + (AD) vs A ⁇ - (non-AD) comparisons (q ⁇ 0.2).
  • Figure 4 shows a heat map showing 24 significantly altered AMPs (q ⁇ 0.2) in subjects that are A ⁇ + (AD) and A ⁇ - (non-AD) dementia.
  • Figure 5 shows a box plot showing increased expression of antimicrobial peptides from Clusterin (Fig.5A) and Chromogranin A (Fig.5B) proteins in CSF of A ⁇ -driven dementia.
  • Figure 6 shows MEGENA data-driven peptide co-expression network that consisted of 642 modules (Fig.6A).
  • CMGA peptide represented a hub in c1_16 and c1_179 modules and exhibited high correlation with a dementia-linked neurosecretory protein VGF (Fig.6B).
  • Gene Ontology analysis of c1_16 module proteins showed enrichment of many neurodegeneration associated pathways (Fig.6C).
  • AD Alzheimer’s disease
  • a ⁇ amyloid beta
  • NFTs tau neurofibrillary tangles
  • a ⁇ and tau have been proposed to play a central, even causative, role in the pathogenesis of AD. Acting either independently of each other or synergistically, A ⁇ plaques and tau tangles contribute to synaptic dysfunction, loss of neural connectivity, and neuronal death, as well as other associated pathologies.
  • Chronic neuroinflammation which may provide a link between A ⁇ plaques and NFTs (Chen and Yu, Journal of Neuroinflammation, 2023.20:165).
  • innate immune cells such as microglia and astrocytes contribute to chronic inflammation, e.g., through sustained activation that produces high levels of pro- inflammatory factors.
  • Innate immune cells appear to be both activated by and to enhance activation of A ⁇ and tau in feedback loops.
  • a ⁇ deposition may be an innate immune response to a challenge such as a microbial pathogen, as A ⁇ oligomers may trap pathogens to protect against infection.
  • the A ⁇ aggregates can be degraded and phagocytosed by microglia, however, in AD when A ⁇ levels are elevated, the microglia are in a chronically activated state that paradoxically leads to reduced A ⁇ clearance, further activates the microglia, and eventually leads to tangle formation and neurodegeneration (Prosswimmer et al., Scientific Reports, 2024.14:5376).
  • novel AMPs which may be used in a variety of methods for diagnosing, monitoring, and treating patients with AD, based on AMP levels in biofluid samples, e.g., CSF or blood.
  • the present disclosure relates to methods of diagnosing Alzheimer’s disease (AD), treating AD, and/or monitoring treatment efficacy, based on a determination of the levels of at least one antimicrobial peptide (AMP) in a biofluid from a subject having or suspected of having AD.
  • AD Alzheimer’s disease
  • AMP antimicrobial peptide
  • Antimicrobial Peptides One aspect of the present disclosure relates to an AMP selected from the 24 AMP listed in Table 10, any of which may be measured (alone or in combination) at any step of treating a subject who has, is suspected of having, or is at risk of developing AD.
  • the AMP may be used for selecting a subject for treatment with a therapeutically effective dose of an AD therapy, e.g., an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody, treating the subject with the AD therapy, reducing a brain A ⁇ level by administering the AD therapy, reducing a brain tau level by administering the AD therapy, monitoring efficacy of treatment, and/or altering a treatment regimen that comprises administration of AD therapy.
  • the AMP is selected from Table 10. Table 10 provides the sequence of the AMP and the human protein to which it maps.
  • the AMP is a peptide of Clusterin (CLUS), e.g., a peptide that is or comprises amino acids 69-79, 155-167, 259-276, 363-371, 386-395, 388-408, 391-408, or 418-425 of Clusterin.
  • the AMP is a peptide of Chromogranin A (CMGA), e.g., a peptide that is or comprises amino acids 19-27, 20-46, 21-27, or 78-88 of Chromogranin A.
  • CMGA Chromogranin A
  • the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2-microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Secretogranin-1 (SCG1), Ubiquitin-ribosomal protein eL40 Attorney Docket Number 08061.0063-00304 fusion protein (RL40), Ubiquitin-40S ribosomal protein S27A, Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC).
  • A4 Amyloid-beta precursor protein
  • B2MG Beta-2-microglobulin
  • CLUS Clusterin
  • CMGA Chromogranin-A
  • SCG1 Secretogranin-1
  • Ubiquitin-ribosomal protein eL40 Attorney Docket Number 08061.0063-00304 fusion protein (RL40), Ubiquitin-40S ribosomal protein S27A, Polyubiquitin-B (UBB),
  • the level (e.g., concentration, expression, quantity, etc.) of the AMP in a biofluid sample from a subject is increased relative to a control (e.g., an AMP level from an individual who does not have AD).
  • the AMP may be up- regulated in the biofluid sample from the subject.
  • the level (e.g., concentration, expression, quantity, etc.) of the AMP in a biofluid sample from a subject is decreased relative to a control (e.g., an AMP level from an individual who does not have AD).
  • the AMP may be down-regulated in the biofluid sample from the subject.
  • the difference between the AMP level in the biofluid sample from the subject and the AMP level in the biofluid sample from the control is used for the methods disclosed herein.
  • One aspect of the present disclosure relates to a method of selecting a subject for a treatment comprising an AD therapy, wherein the method comprises a) obtaining a measurement of a level of at least one antimicrobial peptide (AMP) in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; and b) selecting the subject for treatment if the level of at least one AMP is altered compared to a control sample, e.g., compared to an AMP level in an individual who does not have Alzheimer’s disease (AD).
  • AMP antimicrobial peptide
  • Another aspect of the present disclosure relates to a method of selecting a subject for a treatment comprising an AD therapy, wherein the method comprises a) obtaining a measurement of a level of at least one antimicrobial peptide (AMP) in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2-microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Secretogranin-1 (SCG1), Ubiquitin-ribosomal protein eL40 fusion protein (RL40), Ubiquitin-40S ribosomal protein S27A, Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC); and b) selecting the subject for treatment if the level of at least one antimicrobial peptide (AMP) is altered compared to a control sample, e.g.
  • the AMP is a peptide listed in Table 10.
  • Attorney Docket Number 08061.0063-00304 levels of two or more AMPs (e.g., from the AMPs listed in Table 10) may be obtained in a biofluid sample e.g., a CSF or blood sample, from the subject and compared to the levels of the two more AMPs in a control sample, e.g., in an individual who does not have AD.
  • levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 AMPs may be obtained from the subject and compared to levels in the control sample.
  • the level of at least one AMP among the two or more AMPs will show a change (e.g., an increase or a decrease) as compared to the level of the same AMP in a control sample.
  • the level of at least one AMP from the subject is increased as compared to the control.
  • the level of at least one AMP from the subject is decreased as compared to the control.
  • the AMP is about 10-100 amino acids in length, e.g, about 12-50 amino acids in length.
  • the peptide may correspond to any region of the full-length protein.
  • the AMP comprises any one of SEQ ID NOs: 27-50.
  • the subject having or suspected of having AD is cognitively impaired.
  • the individual may have dementia.
  • the subject may be A ⁇ +, for example, as determined by measurement of A ⁇ levels in a biofluid, or as determined by imaging, e.g., amyloid PET imaging.
  • the subject has one or more of a t-tau level in CSF that is above 400 ng/L, an A ⁇ 1-42 level in CSF that is below 550 ng/L, and a A ⁇ 1-42/A ⁇ 1-40 ratio in CSF that is below 0.065.
  • the level of at least one AMP in the biofluid (e.g., CSF) from the subject may be compared to the level of at least one AMP in a control.
  • the control is the level of AMP in CSF from an individual who does not have Alzheimer’s disease.
  • the individual is cognitively impaired.
  • the individual may have dementia.
  • the individual is A ⁇ -.
  • the individual does not have AD.
  • the biofluid is a cerebrospinal fluid (CSF).
  • the biofluid is blood.
  • the biofluid is one or more of CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that may be collected from a body.
  • AD therapy may be any treatment or therapeutic that is administered to a subject to reduce symptoms and/or progression of the AD.
  • AD therapy is an Attorney Docket Number 08061.0063-00304 anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody.
  • the anti-A ⁇ protofibril antibody comprises a CDR, a variable region, a heavy chain, a light chain, or a constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4.
  • the anti-A ⁇ protofibril antibody is lecanemab (also called BAN2401).
  • the AD therapy is an anti-tau antibody.
  • the anti-tau antibody comprises a CDR, a heavy chain variable region, a light chain variable region, or a constant region according to SEQ ID NOs: 15-24 in Tables 6-8. In some embodiments, the anti-tau antibody is E2814. In some embodiments, the subject has, is suspected of having, or is at risk for developing Alzheimer’s disease (AD).
  • AD Alzheimer’s disease
  • the subject may have symptoms of AD, such as cognitive impairment or high levels of amyloid PET or tau PET, or altered levels of one or more biomarkers in addition to in addition to the AMP (e.g., MTBR-tau243, A ⁇ 42, A ⁇ 40, A ⁇ 42/40 ratio, total tau, phosphorylated-tau (e.g., p-tau181, p-tau205, p-tau217, and/or p-tau231), the ratio of p-tau181/np-tau181, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231, and/or MTBR-tau243 indicate that the subject may have AD.
  • AD symptoms of AD
  • AMP e.g., MTBR-tau243, A ⁇ 42, A ⁇ 40, A ⁇ 42/40 ratio, total tau, phosphorylated-tau (e.g., p-tau
  • the individual may have additional risk factors for developing AD, such as family history, genetic background, gender, age over 60 years, head injury, co-morbidities (e.g., vascular disease and/or diabetes), or certain lifestyle factors such as smoking, consuming alcohol, or limiting physical activity.
  • the subject has severe AD.
  • the subject has moderate AD.
  • the subject has mild AD.
  • the subject has early-AD.
  • the subject has pre-AD.
  • the subject is amyloid positive.
  • the subject is amyloid positive and cognitively impaired. 2.
  • An aspect of the present disclosure relates to a method of monitoring treatment efficacy in a subject receiving a treatment comprising a therapeutically effective dose of an AD therapy, wherein the method comprises a) obtaining a first measurement of an AMP level in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; b) obtaining a second measurement of the AMP level in a biofluid sample in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first AMP level to the second AMP level, wherein a change in the second AMP level ratio as compared to first AMP level is an indicator of treatment efficacy.
  • a biofluid sample e.g., a CSF or blood sample
  • An aspect of the present disclosure relates to a method of monitoring treatment efficacy in a subject receiving a treatment comprising a therapeutically effective dose of an AD therapy, wherein the method comprises a) obtaining a first measurement of an AMP level in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2- microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Secretogranin-1 (SCG1), Ubiquitin-ribosomal protein eL40 fusion protein (RL40), Ubiquitin-40S ribosomal protein S27A, Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC); b) obtaining a second measurement of the AMP level in a biofluid sample in a second biofluid sample, wherein the AMP is a
  • the AMP is a peptide listed in Table 10.
  • levels of two or more AMPs may be obtained in the biofluid sample e.g., a CSF or blood sample, from the subject and compared to the levels of the two more AMPs in a control sample, e.g., in an individual who does not have AD.
  • levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 AMPs may be obtained from the subject and compared to levels in the control sample.
  • the level of at least one AMP among the two or more AMPs will show a change (e.g., an increase or a decrease) as compared to the level of the same AMP in a control sample. Changes in the two or more AMPs may be independent of each other (e.g., one may increase and the other decrease).
  • the first AMP level will show a change (e.g., an increase or a decrease) as compared to the second AMP level from the subject after treatment.
  • the first AMP level from the subject is increased as compared to the second AMP level, and this indicates that the treatment is effective.
  • the first AMP level from the subject is decreased as compared to the second AMP level, and this indicating that the treatment is not effective. In some embodiments, the first AMP level from the subject is increased as compared to the second AMP level, and this indicates that the treatment is not effective. In some embodiments, the first AMP level from the subject is decreased as compared to the second AMP level, and this indicating that the treatment is effective. In some embodiments, the first AMP level from the subject shows no change as compared to the second AMP level, and this indicates that the treatment is effective. Attorney Docket Number 08061.0063-00304 In some embodiments, the first AMP level from the subject shows no change as compared to the second AMP level, and this indicates that the treatment is not effective.
  • the measurement of the first AMP level may be obtained from the subject prior to treatment. In some embodiments, the measurement of the first AMP level is a measurement of the AMP level in a subject who had already begun treatment without having a prior measurement of the AMP level. In some embodiments, the steps b) obtaining a second measurement of the AMP level in a biofluid sample in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and step c) comparing the first AMP level to the second AMP level, of the method of monitoring treating efficacy may be repeated at least once in order to continue monitoring the treatment efficacy over time.
  • a biofluid sample in a second biofluid sample e.g., a CSF or blood sample
  • the method further comprises, after step c), obtaining a measurement of a third AMP level in a third biofluid sample, e.g., a CSF or blood sample, from the subject at a time point after obtaining the second biofluid sample and comparing the third AMP level to an earlier measurement of the AMP level (e.g., the first and/or the second AMP level), wherein a change in the third AMP level as compared to the earlier AMP level is an indicator of treatment efficacy.
  • steps b) and c) may be repeated for as long as the subject receives treatment.
  • steps b) and c) may be repeated at regular intervals, e.g., once weekly, biweekly, monthly, quarterly, semiannually, or yearly.
  • the method of monitoring treatment efficacy may further comprise, after step c), a further step of d) modifying the treatment by administering a modified treatment comprising a further therapeutically effective dose of the AD therapy.
  • the dose may be modified by increasing the size of the dose, increasing the frequency of administration, and/or changing the route of administration.
  • an additional therapeutic may be added, e.g., if the AD therapy comprises an anti-A ⁇ protofibril antibody (e.g., lecanemab), an anti-tau antibody (e.g., E2814) may be added.
  • the treatment is effective, the dose may be modified by decreasing the size of the dose, increasing the frequency of administration, and/or changing the route of administration.
  • the subject may be switched from a treatment administered according to a treatment dosing regimen to a treatment administered according to a maintenance dosing regimen. In some embodiments, the treatment may be discontinued.
  • steps b) and c) may be repeated for as long as the subject receives treatment, e.g., after the subject receives a modified treatment. In some embodiments, steps b) and c) may be repeated if the subject no longer Attorney Docket Number 08061.0063-00304 receives treatment, e.g., to continue monitoring treatment efficacy after the treatment has been discontinued.
  • the AMP is about 10-100 amino acids in length, e.g, about 12-50 amino acids in length.
  • the peptide may correspond to any region of the full-length protein.
  • the AMP comprises any one of SEQ ID NOs: 27-50.
  • the subject having or suspected of having AD is cognitively impaired.
  • the individual may have dementia.
  • the subject may be A ⁇ +, for example, as determined by measurement of A ⁇ levels in a biofluid, or as determined by imaging, e.g., amyloid PET imaging.
  • the subject has one or more of a t-tau level in CSF that is above 400 ng/L, an A ⁇ 1-42 level in CSF that is below 550 ng/L, and a A ⁇ 1-42/A ⁇ 1-40 ratio in CSF that is below 0.065.
  • the AMP level in the biofluid (e.g., CSF) from the subject may be compared to the AMP level in a control.
  • the control is the level of AMP in CSF from an individual who does not have Alzheimer’s disease.
  • the biofluid is a cerebrospinal fluid (CSF). In some embodiments, the biofluid is blood. In some embodiments, the biofluid is one or more of CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that may be collected from a body.
  • AD therapy may be any treatment or therapeutic that is administered to a subject to reduce symptoms and/or progression of the AD.
  • AD therapy is an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody.
  • the anti-A ⁇ protofibril antibody comprises a CDR, a variable region, a heavy chain, a light chain, or a constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4.
  • the anti-A ⁇ protofibril antibody is lecanemab (also called BAN2401).
  • the AD therapy is an anti-tau antibody.
  • the anti-tau antibody comprises a CDR, a heavy chain variable region, a light chain variable region, or a constant region according to SEQ ID NOSs: 15-24 in Tables 6-8. In some embodiments, the anti-tau antibody is E2814. In some embodiments, the subject has, is suspected of having, or is at risk for developing Alzheimer’s disease (AD).
  • AD Alzheimer’s disease
  • the subject may have symptoms of AD, such as cognitive impairment or high levels of amyloid PET or tau PET, or altered levels of Attorney Docket Number 08061.0063-00304 one or more biomarkers in addition to the AMP (e.g., MTBR-tau243, A ⁇ 42, A ⁇ 40, A ⁇ 42/40 ratio, total tau, and/or phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217, and/or p- tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., tau181/np-tau181, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), indicate that the subject may have AD.
  • the AMP e.g., MTBR-tau243, A ⁇ 42, A ⁇ 40, A ⁇ 42/40 ratio, total tau, and/or phosphorylated tau
  • the individual may have additional risk factors for developing AD, such as family history, genetic background, gender, age over 60 years, head injury, co-morbidities (e.g., vascular disease and/or diabetes), or certain lifestyle factors such as smoking, consuming alcohol, or limiting physical activity.
  • the subject has severe AD.
  • the subject has moderate AD.
  • the subject has mild AD.
  • the subject has early-AD.
  • the subject has pre-AD.
  • the subject is amyloid positive.
  • the subject is amyloid positive and cognitively impaired. 3.
  • An aspect of the present disclosure relates to a method of adjusting a treatment regimen in a subject receiving a treatment comprising a therapeutically effective dose of an AD therapy, wherein the method comprises a) obtaining a measurement of a level of at least one AMP in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; b) comparing the level of at least one AMP to a control sample, e.g., an AMP level in an individual who does not have Alzheimer’s disease (AD); and c) adjusting the treatment regimen, e.g., by adjusting the size of the dose, the frequency of administration, and/or the route of administration, if the AMP level differs from the control sample.
  • a biofluid sample e.g., a CSF or blood sample
  • the AMP is selected from any of those listed in Table 10
  • a control sample e.g., an AMP level in
  • a further aspect of the present disclosure relates to a method of adjusting a treatment regimen in a subject receiving a treatment comprising a therapeutically effective dose of an AD therapy, wherein the method comprises a) obtaining a measurement of a level of at least one AMP in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2-microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Secretogranin-1 (SCG1), Ubiquitin-ribosomal protein eL40 fusion protein (RL40), Ubiquitin- 40S ribosomal protein S27A, Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC); b) comparing the level of at least one AMP to a control sample, e.g., an AMP level in an individual who
  • the AMP is a peptide listed in Table 10.
  • levels of two or more AMPs may be obtained in a biofluid sample e.g., a CSF or blood sample, from the subject and compared to the levels of the two more AMPs in a control sample, e.g., in an individual who does not have AD.
  • levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 AMPs may be obtained from the subject and compared to levels in the control sample.
  • the level of at least one AMP among the two or more AMPs will show a change (e.g., an increase or a decrease) as compared to the level of the same AMP in a control sample. Changes in the two or more AMPs may be independent of each other (e.g., one may increase and the other decrease).
  • the control sample is a measurement of an AMP level (e.g., the same at least one AMP measured in a subject) obtained from a biofluid sample, e.g., a CSF or blood sample, from a control subject.
  • the control subject may be an individual who does not have AD.
  • control sample is a measurement of a previous AMP level obtained from a biofluid sample, e.g., a CSF or blood sample from the subject receiving the treatment.
  • the control sample may have been obtained from the subject prior to the treatment, or at an earlier time during the course of treatment, prior to performing the steps of the method.
  • the measurement of the AMP level may be obtained prior to treatment.
  • the measurement of the AMP level is a first measurement of the AMP level in a subject who had already begun treatment without having a prior measurement of the AMP level.
  • the treatment regimen (also called a “dosing regimen” or “treatment dosing regimen”), comprises a schedule specifying doses of the AD therapy administered per unit of time, including the number of doses over a given time period and the elapsed time between doses.
  • the treatment regimen comprises administering the AD therapy at a specified dose, according to a schedule (e.g., on a repetitive basis).
  • adjusting the treatment regimen comprises increasing the size of the dose, increasing the frequency of administration, and/or changing the route of administration of the AD therapy if the AMP level is higher than the control sample.
  • an additional therapeutic may be added.
  • adjusting the treatment regimen comprises decreasing the size of the dose, decreasing the frequency of administration, and/or changing the route of administration if the AMP level is lower than the control sample.
  • the subject may be switched from a treatment comprising administration of a therapeutically effective dose of the AD therapy (e.g., an initiation dose) administered according to an initiation dosing regimen to a treatment comprising administration of a therapeutically effective dose of the AD therapy (e.g., a maintenance dose) administered according to a maintenance dosing regimen.
  • the treatment may be discontinued.
  • the steps of a) obtaining a measurement of a level of at least one AMP in a biofluid sample, e.g., a CSF or blood sample, from the subject, and b) comparing the level of at least one AMP to a control sample, e.g., an AMP level in an individual who does not have Alzheimer’s disease (AD) of the method of adjusting a treatment regimen may be repeated at least once in order to monitor the efficacy of the adjusted treatment regimen and optionally, to further adjust the treatment regimen.
  • a biofluid sample e.g., a CSF or blood sample
  • the method further comprises, after step c), obtaining a further measurement of a level of at least one AMP in a further biofluid sample, e.g., a CSF or blood sample, from the subject at a time point after adjusting the treatment regimen, and comparing the further measurement to the measurement of the level of at least one AMP obtained prior to adjusting the treatment regimen or to a control sample (e.g., an AMP level in an individual who does not have AD).
  • a control sample e.g., an AMP level in an individual who does not have AD.
  • the treatment may be adjusted further.
  • the steps a) and b) may be repeated for as long as the subject receives the treatment or the adjusted treatment.
  • steps b) and c) may be repeated if the subject no longer receives treatment, e.g., to continue monitoring treatment efficacy after the treatment has been discontinued. In some embodiments, steps b) and c) may be repeated at regular intervals, e.g., once weekly, biweekly, monthly, quarterly, semiannually, or yearly.
  • the AMP is about 10-100 amino acids in length, e.g, about 12-50 amino acids in length.
  • the peptide may correspond to any region of the full-length protein.
  • the AMP comprises any one of SEQ ID NOs: 27-50.
  • the subject having or suspected of having AD is cognitively impaired. For example, the individual may have dementia.
  • the subject may be A ⁇ +, for example, as determined by measurement of A ⁇ levels in a biofluid, or as determined by imaging, e.g., amyloid PET imaging.
  • the subject has one or more of a Attorney Docket Number 08061.0063-00304 t-tau level in CSF that is above 400 ng/L, an A ⁇ 1-42 level in CSF that is below 550 ng/L, and a A ⁇ 1-42/A ⁇ 1-40 ratio in CSF that is below 0.065.
  • the AMP level in the biofluid (e.g., CSF) from the subject may be compared to the AMP level in a control.
  • the control is the level of AMP in CSF from an individual who does not have Alzheimer’s disease.
  • the individual is cognitively impaired.
  • the individual may have dementia.
  • the individual is A ⁇ -.
  • the individual does not have AD.
  • the biofluid is a cerebrospinal fluid (CSF).
  • the biofluid is blood.
  • the biofluid is one or more of CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that may be collected from a body.
  • AD therapy may be any treatment or therapeutic that is administered to a subject to reduce symptoms and/or progression of the AD.
  • AD therapy is an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody.
  • the anti-A ⁇ protofibril antibody comprises a CDR, a variable region, a heavy chain, a light chain, or a constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4.
  • the anti-A ⁇ protofibril antibody is lecanemab (also called BAN2401).
  • the AD therapy is an anti-tau antibody.
  • the anti-tau antibody comprises a CDR, a heavy chain variable region, a light chain variable region, or a constant region according to SEQ ID NOSs: 15-24 in Tables 6-8. In some embodiments, the anti-tau antibody is E2814. In some embodiments, the subject has, is suspected of having, or is at risk for developing Alzheimer’s disease (AD).
  • AD Alzheimer’s disease
  • the subject may have symptoms of AD, such as cognitive impairment or high levels of amyloid PET or tau PET, or altered levels of one or more biomarkers in addition to the AMP (e.g., MTBR-tau243, A ⁇ 42, A ⁇ 40, A ⁇ 42/40 ratio, total tau, and/or phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217, and/or p- tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., tau181/np-tau181, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231) indicate that the subject may have AD.
  • AD cognitive impairment or high levels of amyloid PET or tau PET
  • biomarkers in addition to the AMP e.g., MTBR-tau243, A ⁇ 42, A ⁇ 40, A ⁇ 42/40 ratio, total tau
  • the individual may have additional risk factors for developing AD, such as family history, genetic background, gender, age over 60 years, head injury, co-morbidities (e.g., vascular disease and/or diabetes), or certain lifestyle factors such as smoking, consuming alcohol, or limiting physical activity.
  • the subject has severe AD.
  • the subject has moderate AD.
  • the subject has mild AD.
  • the subject has early-AD.
  • the subject has pre-AD.
  • the subject is amyloid positive.
  • the subject is amyloid positive and cognitively impaired. 4.
  • An aspect of the present disclosure relates to a method of detecting a decrease in a brain A ⁇ level in a subject receiving a treatment comprising a therapeutically effective dose of an AD therapy, wherein the method comprises a) obtaining a measurement of a first AMP level in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment, wherein the AMP is selected from any of those listed in Table 10; b) obtaining a measurement of a second AMP level in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second AMP levels, wherein a change in the AMP level in the second sample relative to the first sample indicates a decrease of a brain A ⁇ level in the subject.
  • a first biofluid sample e.g., a CSF or blood sample
  • An aspect of the present disclosure relates to a method of detecting a decrease in a brain A ⁇ level in a subject receiving a treatment comprising a therapeutically effective dose of an AD therapy, wherein the method comprises a) obtaining a measurement of a first AMP level in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment, wherein the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2-microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Secretogranin-1 (SCG1), Ubiquitin-ribosomal protein eL40 fusion protein (RL40), Ubiquitin-40S ribosomal protein S27A, Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC); b) obtaining a measurement of a second AMP level in a second biofluid sample, e
  • the AMP is a peptide listed in Table 10.
  • levels of two or more AMPs may be obtained in a biofluid sample e.g., a CSF or blood sample, from the subject and compared to the levels of the two more AMPs in a control sample, e.g., in an individual who does not have AD.
  • levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 AMPs may be obtained from the subject and compared to levels in the control sample.
  • the level of at least one AMP among the two or more AMPs will show a change (e.g., an increase or a decrease) as compared to the Attorney Docket Number 08061.0063-00304 level of the same AMP in a control sample. Changes in the two or more AMPs may be independent of each other (e.g., one may increase and the other decrease).
  • the first AMP level will show a change (e.g., an increase or a decrease) as compared to the second AMP level from the subject after treatment.
  • the first AMP level from the subject is increased as compared to the second AMP level, and this indicates that the brain A ⁇ level is decreased.
  • the first AMP level from the subject is decreased as compared to the second AMP level, and this indicates that the brain A ⁇ level is decreased. In some embodiments, the first AMP level from the subject is increased as compared to the second AMP level, and this indicates that the brain A ⁇ level is not decreased. In some embodiments, the first AMP level from the subject is decreased as compared to the second AMP level, and this indicates that the brain A ⁇ level is not decreased.
  • An aspect of the present disclosure relates to a method of detecting a decrease in a brain tau level (e.g., a reduction in tau tangles) in a subject receiving a treatment comprising a therapeutically effective dose of an anti-tau antibody, wherein the method comprises a) obtaining a measurement of a first AMP level in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment with the anti-tau antibody wherein the AMP is selected from any of those listed in Table 10; b) obtaining a measurement of a second AMP level in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second AMP levels, wherein a change in the AMP level in the second sample relative to the first sample indicates a decrease of a brain A ⁇ level in the subject.
  • a first biofluid sample e.g., a CSF
  • An aspect of the present disclosure relates to a method of detecting a decrease in a brain tau level in a subject receiving a treatment comprising a therapeutically effective dose of an AD therapy, wherein the method comprises a) obtaining a measurement of a first AMP level in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment, wherein the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2-microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Secretogranin-1 (SCG1), Ubiquitin-ribosomal protein eL40 fusion protein (RL40), Ubiquitin-40S ribosomal protein S27A, Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC); b) obtaining a measurement of a second AMP level in a second biofluid sample, e.
  • the first AMP level from the subject is increased as compared to the second AMP level, and this indicates that the brain tau level is decreased.
  • a decrease in a brain tau level is a decrease in tau tangles.
  • the first AMP level from the subject is decreased as compared to the second AMP level, and this indicates that the brain tau level is decreased.
  • the first AMP level from the subject is increased as compared to the second AMP level, and this indicates that the brain tau level is not decreased.
  • the first AMP level from the subject is decreased as compared to the second AMP level, and this indicates that the brain tau level is not decreased.
  • the AMP is about 10-100 amino acids in length, e.g, about 12-50 amino acids in length.
  • the peptide may correspond to any region of the full-length protein.
  • the AMP comprises any one of SEQ ID NOs: 27-50.
  • the subject having or suspected of having AD is cognitively impaired.
  • the individual may have dementia.
  • the subject may be A ⁇ +, for example, as determined by measurement of A ⁇ levels in a biofluid, or as determined by imaging, e.g., amyloid PET imaging.
  • the subject has one or more of a t-tau level in CSF that is above 400 ng/L, an A ⁇ 1-42 level in CSF that is below 550 ng/L, and a A ⁇ 1-42/A ⁇ 1-40 ratio in CSF that is below 0.065.
  • the AMP level in the biofluid (e.g., CSF) from the subject may be compared to the AMP level (e.g., the same at least one AMP as measured in the subject) in a control.
  • the control is the level of AMP in CSF from an individual who does not have Alzheimer’s disease.
  • the individual is cognitively impaired.
  • the individual may have dementia.
  • the individual is A ⁇ -. In some embodiments, the individual does not have AD.
  • the biofluid is a cerebrospinal fluid (CSF). In some embodiments, the biofluid is blood. In some embodiments, the biofluid is one or more of CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that may be collected from a body.
  • AD therapy may be any treatment or therapeutic that is administered to a subject to reduce symptoms and/or progression of the AD. In some embodiments, AD therapy is an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody.
  • a ⁇ anti-amyloid ⁇
  • the anti-A ⁇ protofibril antibody comprises a CDR, a variable region, a heavy chain, a light chain, or a constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4.
  • the anti-A ⁇ protofibril antibody is lecanemab (also called BAN2401).
  • the AD therapy is an anti-tau antibody.
  • the anti-tau antibody comprises a CDR, a heavy chain variable region, a light chain variable region, or a constant region according to SEQ ID NOSs: 15-24 in Tables 6-8.
  • the anti-tau antibody is E2814.
  • the subject has, is suspected of having, or is at risk for developing Alzheimer’s disease (AD).
  • AD Alzheimer’s disease
  • the subject may have symptoms of AD, such as cognitive impairment or high levels of amyloid PET or tau PET, or altered levels of one or more biomarkers in addition to the AMP (e.g., MTBR-tau243, A ⁇ 42, A ⁇ 40, A ⁇ 42/40 ratio, total tau, and/or phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217, and/or p- tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., tau181/np-tau181, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231) indicate that the subject may have AD.
  • AMP e.g., MTBR-tau243, A ⁇ 42, A ⁇ 40, A
  • the individual may have additional risk factors for developing AD, such as family history, genetic background, gender, age over 60 years, head injury, co-morbidities (e.g., vascular disease and/or diabetes), or certain lifestyle factors such as smoking, consuming alcohol, or limiting physical activity.
  • the subject has severe AD.
  • the subject has moderate AD.
  • the subject has mild AD.
  • the subject has early-AD.
  • the subject has pre-AD.
  • the subject is amyloid positive.
  • the subject is amyloid positive and cognitively impaired. 5.
  • a further aspect of the present disclosure relates to a method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising a) obtaining a measurement of a first AMP level in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-tau protofibril antibody if the a first AMP level is changed as compared to a control sample, e.g., compared to an AMP level in an individual who does not have Alzheimer’s disease (AD); and c) obtaining a measurement of a second AMP level, wherein a change in the second AMP level as compared to the first AMP level indicates a reduction in tau tangles, optionally wherein the anti-tau antibody comprises three heavy Attorney Docket
  • a further aspect of the present disclosure relates to a method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising a) obtaining a measurement of a first AMP level in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2-microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Secretogranin-1 (SCG1), Ubiquitin-ribosomal protein eL40 fusion protein (RL40), Ubiquitin-40S ribosomal protein S27A, Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC); b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-tau protofibril antibody if the a first
  • the AMP is a peptide listed in Table 10.
  • levels of two or more AMPs may be obtained in a biofluid sample e.g., a CSF or blood sample, from the subject and compared to the levels of the two more AMPs in a control sample, e.g., in an individual who does not have AD.
  • levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 AMPs may be obtained from the subject and compared to levels in the control sample.
  • the level of at least one AMP among the two or more AMPs will show a change (e.g., an increase or a decrease) as compared to the level of the same AMP in a control sample. Changes in the two or more AMPs may be independent of each other (e.g., one may increase and the other decrease).
  • tangles are reduced by preventing, reducing, and/or slowing formation of new Attorney Docket Number 08061.0063-00304 tau tangles; and/or by promoting, increasing, and/or speeding up breakdown of existing tau tangles, as evidenced by a reduction in an AMP level in a sample taken after treatment.
  • tau tangles may be measured by tau PET imaging, e.g., using a radioligand.
  • tau PET imaging may be used, e.g., together with the change in the AMP level (e.g., an increase or a decrease in the AMP level), to establish and/or confirm the reduction in tau tangles.
  • a method for identifying tau tangles in a subject comprises a) obtaining a measurement of a level of at least one AMP in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) identifying tau tangles in the subject if the level of at least one AMP is changed as compared to a control sample, e.g., compared to a level of an AMP in an individual who does not have Alzheimer’s disease (AD).
  • a treatment comprising a therapeutically effective dose of an anti-tau antibody (e.g., E2814) may be administered to the subject in whom tau tangles have been identified.
  • an anti-tau antibody e.g., E2814
  • a treatment comprising a therapeutically effective dose of an anti-A ⁇ protofibril antibody may be administered to the subject in whom tau tangles have been identified.
  • measurements of further level of at least one AMP may be obtained from further biofluid samples (e.g., a further CSF or blood sample) in order to determine if the treatment has changed the level of at least one AMP.
  • a change in the level of at least one AMP over time indicates that the treatment is reducing tau tangles.
  • the efficacy of the treatment may be determined by further measurements of the level of at least one AMP in a biofluid sample (e.g., a CSF or blood sample) in the subject obtained during the time course of treatment, and optionally, the treatment may be adjusted.
  • the subject may be switched to a maintenance dose of the AD therapy, e.g., a maintenance dose of the anti-tau antibody or a maintenance dose of the anti-A ⁇ protofibril antibody.
  • the first AMP level will show a change (e.g., an increase or a decrease) as compared to the second AMP level from the subject after treatment.
  • the first AMP level from the subject is increased as compared to the second AMP level, and this indicates that the tau tangles are decreased.
  • the first AMP level from the subject is decreased as compared to the second AMP level, and this indicates that the tau tangles are decreased.
  • the first AMP level from the subject is increased as compared to the second AMP level, and this indicates that the tau tangles are not decreased.
  • the first AMP level from the subject is decreased as compared to the second AMP level, and this indicates that the tau tangles are not decreased.
  • the AMP is about 10-100 amino acids in length, e.g, about 12-50 amino acids in length.
  • the peptide may correspond to any region of the full-length protein.
  • the AMP comprises any one of SEQ ID NOs: 27-50.
  • the subject having or suspected of having AD is cognitively impaired.
  • the individual may have dementia.
  • the subject may be A ⁇ +, for example, as determined by measurement of A ⁇ levels in a biofluid, or as determined by imaging, e.g., amyloid PET imaging.
  • the subject has one or more of a t-tau level in CSF that is above 400 ng/L, an A ⁇ 1-42 level in CSF that is below 550 ng/L, and a A ⁇ 1-42/A ⁇ 1-40 ratio in CSF that is below 0.065.
  • the AMP level in the biofluid (e.g., CSF) from the subject may be compared to the AMP level (e.g., the same at least one AMP as measured in the subject) in a control.
  • the control is the level of AMP in CSF from an individual who does not have Alzheimer’s disease.
  • the individual is cognitively impaired.
  • the individual may have dementia.
  • the individual is A ⁇ -. In some embodiments, the individual does not have AD.
  • the biofluid is a cerebrospinal fluid (CSF). In some embodiments, the biofluid is blood. In some embodiments, the biofluid is one or more of CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that may be collected from a body.
  • AD therapy may be any treatment or therapeutic that is administered to a subject to reduce symptoms and/or progression of the AD. In some embodiments, AD therapy is an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody.
  • a ⁇ anti-amyloid ⁇
  • the anti-A ⁇ protofibril antibody comprises a CDR, a variable region, a heavy chain, a light chain, or a constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4.
  • the anti-A ⁇ protofibril antibody is lecanemab (also called BAN2401).
  • the AD therapy is an anti-tau antibody.
  • the anti-tau antibody comprises a CDR, a heavy chain variable region, a light chain variable region, or a constant region according to SEQ ID NOSs: 15-24 in Tables 6-8.
  • the anti-tau antibody is E2814.
  • the subject has, is suspected of having, or is at risk for developing Alzheimer’s disease (AD).
  • AD Alzheimer’s disease
  • the subject may have symptoms of AD, Attorney Docket Number 08061.0063-00304 such as cognitive impairment or high levels of amyloid PET or tau PET, or altered levels of one or more biomarkers in addition to the AMP (e.g., MTBR-tau243, A ⁇ 42, A ⁇ 40, A ⁇ 42/40 ratio, total tau, and/or phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217, and/or p- tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., tau181/np-tau181, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231) indicate that the subject may have AD.
  • AMP e.g., MTBR-t
  • the individual may have additional risk factors for developing AD, such as family history, genetic background, gender, age over 60 years, head injury, co-morbidities (e.g., vascular disease and/or diabetes), or certain lifestyle factors such as smoking, consuming alcohol, or limiting physical activity.
  • the subject has severe AD.
  • the subject has moderate AD.
  • the subject has mild AD.
  • the subject has early-AD.
  • the subject has pre-AD.
  • the subject is amyloid positive.
  • the subject is amyloid positive and cognitively impaired. 6.
  • a method of treating a subject relates to method of treating a disorder in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), wherein the method comprises: a) obtaining a measurement of a level of at least one AMP in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; and b) administering to the subject a treatment comprising a therapeutically effective dose of an AD therapy if the level of at least one AMP is altered compared to a control sample, e.g., compared to an AMP level in an individual who does not have Alzheimer’s disease (AD).
  • a biofluid sample e.g., a CSF or blood sample
  • An aspect of the present disclosure relates to method of treating a disorder in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), wherein the method comprises: a) obtaining a measurement of a level of at least one AMP in a biofluid sample, e.g., a CSF or blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2- microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Secretogranin-1 (SCG1), Ubiquitin-ribosomal protein eL40 fusion protein (RL40), Ubiquitin-40S ribosomal protein S27A, Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC); and b) administering to the subject a treatment comprising a therapeutically effective dose of an AD therapy if the level of at least one AMP is altered
  • the AMP is a peptide listed in Table 10.
  • levels of two or more AMPs may be obtained in a biofluid sample e.g., a CSF or blood sample, from the subject and compared to the levels of the two more AMPs in a control sample, e.g., in an individual who does not have AD.
  • levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 AMPs may be obtained from the subject and compared to levels in the control sample.
  • the level of at least one AMP among the two or more AMPs will show a change (e.g., an increase or a decrease) as compared to the level of the same AMP in a control sample. Changes in the two or more AMPs may be independent of each other (e.g., one may increase and the other decrease).
  • the first AMP level will show a change (e.g., an increase or a decrease) as compared to the second AMP level from the subject after treatment.
  • the AMP level from the subject is increased as compared to the control.
  • the AMP level from the subject is decreased as compared to the control.
  • the disorder is Alzheimer’s disease (AD).
  • AD Alzheimer’s disease
  • the disorder is mild AD.
  • the disorder is early AD.
  • the disorder is moderate AD.
  • the disorder is severe AD.
  • the disorder is pre-AD.
  • the disorder is a neurological disorder (e.g., a neurodegenerative disorder or disease) characterized by A ⁇ peptide-containing soluble and/or insoluble A ⁇ aggregates.
  • Exemplary disorders include but are not limited to Down’s Syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, and Lewy Body Dementia.
  • treating the disorder comprises at least one of inhibiting the disorder, slowing progression of the disorder, delaying progression, arresting its development, reversing progression of disorder (e.g., reversing aggregation of tau), preventing the onset or development of the disorder, relieving or ameliorating one or more symptoms or underlying condition(s) of the disorder, curing the disorder, improving one or more clinical metrics, or preventing reoccurrence of one or more symptoms of the disorder.
  • treating a disorder comprises at least one of reducing a brain A ⁇ level, reducing a brain tau level, improving cognition, and altering biomarkers associated with AD pathology.
  • the method of treating the disorder further comprises steps of monitoring treatment efficacy and/or adjusting a treatment regimen.
  • Attorney Docket Number 08061.0063-00304 the method further comprises, after steps of a) obtaining a measurement of an AMP level in a biofluid sample, e.g., a CSF or blood sample, from the subject; and b) administering to the subject a treatment comprising a therapeutically effective dose of an AD therapy, applying further step c) obtaining a further measurement of the level of at least one AMP (e.g., a further AMP level) in a second biofluid sample, e.g., a CSF or blood sample, from the subject; d) determining that the further AMP level has changed as compared the level of at least one AMP obtained prior to administration of the AD therapy; and e) administering a further therapeutically effective dose of the AD therapy to the subject.
  • a biofluid sample e.g., a CSF or blood sample
  • the first AMP level is increased as compared to the second AMP level. In some embodiments, the first AMP level is decreased as compared to the second AMP level.
  • the further therapeutically effective dose is an adjusted dose (e.g., the size of the dose, the frequency of administration, and/or the route of administration is adjusted as compared to the treatment first administered to the subject). In some embodiments, the further therapeutically effective dose is an adjusted dose administered as part of an initiation dosing regimen, wherein both the treatment first administered to the subject and the further therapeutically effective dose are part of the initiation dosing regimen. In some embodiments, the AMP is about 10-100 amino acids in length, e.g, about 12-50 amino acids in length.
  • the peptide may correspond to any region of the full-length protein.
  • the AMP comprises any one of SEQ ID NOs: 27-50.
  • the subject having or suspected of having AD is cognitively impaired.
  • the individual may have dementia.
  • the subject may be A ⁇ +, for example, as determined by measurement of A ⁇ levels in a biofluid, or as determined by imaging, e.g., amyloid PET imaging.
  • the subject has one or more of a t-tau level in CSF that is above 400 ng/L, an A ⁇ 1-42 level in CSF that is below 550 ng/L, and a A ⁇ 1-42/A ⁇ 1-40 ratio in CSF that is below 0.065.
  • the AMP level in the biofluid (e.g., CSF) from the subject may be compared to the AMP level in a control.
  • the control is the level of AMP in CSF from an individual who does not have Alzheimer’s disease.
  • the individual is cognitively impaired.
  • the individual may have dementia.
  • the individual is A ⁇ -.
  • the individual does not have AD.
  • the biofluid is a cerebrospinal fluid (CSF).
  • the biofluid is blood.
  • the biofluid is one or more of CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that may be collected from a body.
  • AD therapy may be any treatment or therapeutic that is administered to a subject to reduce symptoms and/or progression of the AD.
  • AD therapy is an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody.
  • the anti-A ⁇ protofibril antibody comprises a CDR, a variable region, a heavy chain, a light chain, or a constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4.
  • the anti-A ⁇ protofibril antibody is lecanemab (also called BAN2401).
  • the AD therapy is an anti-tau antibody.
  • the anti-tau antibody comprises a CDR, a heavy chain variable region, a light chain variable region, or a constant region according to SEQ ID NOSs: 15-24 in Tables 6-8.
  • the anti-tau antibody is E2814.
  • the subject has, is suspected of having, or is at risk for developing Alzheimer’s disease (AD).
  • the subject may have symptoms of AD, such as cognitive impairment or high levels of amyloid PET or tau PET, or altered levels of one or more biomarkers in addition to the AMP (e.g., MTBR-tau243, A ⁇ 42, A ⁇ 40, A ⁇ 42/40 ratio, total tau, and/or phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217, and/or p- tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., tau181/np-tau181, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231) indicate that the subject may have AD.
  • AD cognitive impairment or high levels of amyloid PET or tau PET
  • biomarkers in addition to the AMP e.g., MTBR-tau243, A ⁇ 42, A ⁇ 40, A ⁇ 42/40 ratio, total tau
  • the individual may have additional risk factors for developing AD, such as family history, genetic background, gender, age over 60 years, head injury, co-morbidities (e.g., vascular disease and/or diabetes), or certain lifestyle factors such as smoking, consuming alcohol, or limiting physical activity.
  • the subject has severe AD.
  • the subject has moderate AD.
  • the subject has mild AD.
  • the subject has early-AD.
  • the subject has pre-AD.
  • the subject is amyloid positive.
  • the subject is amyloid positive and cognitively impaired.
  • an AD therapy disclosed herein e.g., an anti-tau antibody such as E2814 or an antibody comprising the CDRs and/or variable domains from E2814, and/or an anti-A ⁇ protofibril antibody such as lecanemab or an antibody comprising the CDRs and/or variable domains from lecanemab
  • a level of at least one AMP in a biofluid sample, e.g., a CSF or blood sample, from the subject is changed (e.g., increased or decreased) compared to a control sample, e.g., compared to a level of at least one AMP (e.g., the same at least one AMP measured in the subject) in an individual who does not have Alzheimer’s disease (AD).
  • the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier.
  • an AD therapy disclosed herein e.g., an anti-tau antibody such as E2814 or an antibody comprising the CDRs and/or variable domains from E2814, and/or an anti-A ⁇ protofibril antibody such as lecanemab or an antibody comprising the CDRs and/or variable domains from lecanemab
  • a level of at least one AMP concentration in a biofluid sample e.g., a CSF or blood sample
  • a control sample e.g., compared to a level of at least one AMP (e.g., the same at least one AMP measured in the subject) concentration in an individual who does not have Alzheimer’s disease (AD).
  • an anti-tau antibody such as E2814 or an antibody comprising the CDRs and/or variable domains from E2814, and/or an anti-A ⁇ protofibril antibody such as lecanemab or an antibody comprising the CDRs and/or variable domains from lecanemab
  • a level of at least one AMP in a biofluid sample e.g., a CSF or blood sample
  • a control sample e.g., compared to a level of at least one AMP (e.g., the same at least one AMP measured in the subject) in an individual who does not have Alzheimer’s disease (AD).
  • a method of treatment for Alzheimer’s disease relates to method of treating Alzheimer’s disease (AD) in a subject having or suspected of having AD, comprising: determining an altered level of at least one antimicrobial peptide (AMP) in a biofluid, e.g., a cerebrospinal fluid (CSF), from the subject as compared to a control, e.g., CSF from an individual who has not been diagnosed with AD, wherein the AMP is selected from any of those listed in Table 10, and administering to the subject a therapeutically effective dose of an AD therapy, e.g., an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody.
  • an AD therapy e.g., an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody.
  • a further aspect of the present disclosure relates to method of treating Alzheimer’s disease (AD) in a subject having or suspected of having AD, comprising: determining an altered level of at least one antimicrobial peptide (AMP) in a biofluid, e.g., a cerebrospinal fluid (CSF), from the subject as compared to a control, e.g., CSF from an individual who has not been diagnosed with AD, wherein the AMP is a peptide of a human protein selected from Amyloid-beta precursor protein (A4), Beta-2-microglobulin (B2MG), Clusterin (CLUS), Chromogranin-A (CMGA), Secretogranin-1 (SCG1), Ubiquitin-ribosomal protein eL40 fusion protein (RL40), Ubiquitin-40S ribosomal protein S27A, Polyubiquitin-B (UBB), and Polyubiquitin-C (UBC), and administering to the subject
  • AMP antimicrobial peptide
  • a protein may be known by other aliases, or may be known by the name of a gene encoding the protein.
  • Secretogranin-1 SCG1
  • SCG1 secretogranin-1
  • RPS27A gene may be known as Ribosomal Protein S27a, as Ubiquitin Carboxyl Extension Protein 80, UBCEP80, Ubiquitin-40S Ribosomal Protein S27a, UBCEP1, Uba80, or UBA80.
  • the AMP is about 10-100 amino acids in length, e.g, about 12-50 amino acids in length.
  • the peptide may correspond to any region of the full-length protein.
  • the AMP comprises any one of SEQ ID NOs: 27-50.
  • the subject having or suspected of having AD is cognitively impaired.
  • the individual may have dementia.
  • the subject may be A ⁇ +, for example, as determined by measurement of A ⁇ levels in a biofluid, or as determined by imaging, e.g., amyloid PET imaging.
  • the subject has one or more of a t-tau level in CSF that is above 400 ng/L, an A ⁇ 1-42 level in CSF that is below 550 ng/L, and a A ⁇ 1-42/A ⁇ 1-40 ratio in CSF that is below 0.065.
  • the AMP level in the biofluid (e.g., CSF) from the subject may be compared to the AMP level in a control.
  • the control is the level of AMP in CSF from an individual who does not have Alzheimer’s disease.
  • the individual has not been diagnosed with AD.
  • the individual is cognitively impaired.
  • the individual may have dementia.
  • the individual is A ⁇ -.
  • the individual does not have AD.
  • an altered level in an AMP in the biofluid is an increased level of the AMP.
  • the subject having or suspected of having AD may have an increased level of the AMP in the biofluid as compared to the level of the AMP in the control.
  • the altered level in an AMP in the biofluid is a decreased level Attorney Docket Number 08061.0063-00304 of the AMP, e.g., the subject having or suspected of having AD may have an increased level of the AMP in the biofluid as compared to the level of the AMP in the control.
  • the biofluid is a cerebrospinal fluid (CSF).
  • the biofluid is blood.
  • the biofluid is one or more of CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that may be collected from a body.
  • AD therapy may be any treatment or therapeutic that is administered to a subject to reduce symptoms and/or progression of the AD.
  • AD therapy is an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody.
  • the anti-A ⁇ protofibril antibody comprises a CDR, a variable region, a heavy chain, a light chain, or a constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4.
  • the anti-A ⁇ protofibril antibody is lecanemab (also called BAN2401).
  • the AD therapy is an anti-tau antibody.
  • the anti-tau antibody comprises a CDR, a heavy chain variable region, a light chain variable region, or a constant region according to SEQ ID NOSs: 15-24 in Tables 6-8.
  • the anti-tau antibody is E2814. 8. Evaluating treatment efficacy An AMP level may be obtained at different time points. For example, the AMP level in the biofluid of a subject may be determined at two or more time points, wherein a first time point may be prior to treatment for AD or early during the treatment regimen, while a second time point may be at later time in the treatment regimen.
  • a further aspect of the present disclosure relates to a method of treating Alzheimer’s disease (AD) in a subject having or suspected of having AD, comprising determining a first level of at least one antimicrobial peptide (AMP) in a biofluid, e.g., a cerebrospinal fluid (CSF), from the subject, wherein the first level of the AMP is altered in CSF from the subject as compared to a control, e.g., CSF from an individual who has not been diagnosed with AD, wherein the AMP is selected from any of those listed in Table 10; administering to the subject a first therapeutically effective dose of an AD therapy, e.g., an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody; determining a second level of the AMP in CSF from the subject; and administering a second therapeutically effective dose of the AD therapy if there is a change from the first level of the AMP to the second level of the AMP
  • the AMP is about 10-100 amino acids in length, e.g, about 12-50 amino acids in length.
  • the peptide may correspond to any region of the full-length protein.
  • the AMP comprises any one of SEQ ID NOs: 27-50.
  • the subject having or suspected of having AD is cognitively impaired.
  • the individual may have dementia.
  • the subject may be A ⁇ +, for example, as determined by measurement of A ⁇ levels in a biofluid, or as determined by imaging, e.g., amyloid PET imaging.
  • the subject has one or more of a t-tau level in CSF that is above 400 ng/L, an A ⁇ 1-42 level in CSF that is below 550 ng/L, and a A ⁇ 1-42/A ⁇ 1-40 ratio in CSF that is below 0.065.
  • the AMP level in the biofluid (e.g., CSF) from the subject may be compared to the AMP level in a control.
  • the control is the level of AMP in CSF from an individual who does not have Alzheimer’s disease.
  • the individual is cognitively impaired.
  • the individual may have dementia.
  • the individual is A ⁇ -.
  • an altered level in an AMP in the biofluid is an increased level of the AMP.
  • the subject having or suspected of having AD may have an increased level of the AMP in the biofluid as compared to the level of the AMP in the control.
  • the altered level in an AMP in the biofluid is a decreased level of the AMP, e.g., the subject having or suspected of having AD may have an increased level of the AMP in the biofluid as compared to the level of the AMP in the control.
  • the biofluid is a cerebrospinal fluid (CSF).
  • the biofluid is blood.
  • the biofluid is one or more of CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that may be collected from a body.
  • AD therapy may be any treatment or therapeutic that is administered to a subject to reduce symptoms and/or progression of the AD.
  • AD therapy is an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody.
  • the anti-A ⁇ protofibril antibody comprises a CDR, a variable region, a heavy chain, a light chain, or a constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4.
  • the anti-A ⁇ protofibril antibody is lecanemab (also called BAN2401).
  • a further aspect of the present disclosure relates to a method of monitoring treatment efficacy in a subject having or suspected of having AD, comprising determining a first level of at least one antimicrobial peptide (AMP) in a biofluid, e.g., a cerebrospinal fluid Attorney Docket Number 08061.0063-00304 (CSF), from the subject, wherein the first level of the AMP is altered in CSF from the subject as compared to a control, e.g., CSF from an individual who has not been diagnosed with AD, wherein the AMP is selected from any of those listed in Table 10; administering to the subject a first therapeutically effective dose of an AD therapy, e.g., an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody; and measuring a second level of the AMP in CSF from the subject, where
  • treatment may be changed if a difference between the first level of the AMP and the second level of the AMP indicates effective treatment. For example, a treatment may be reduced, e.g., in dosage and/or frequency of administration. In some embodiments, treatment may not be changed if the first level of the AMP is not different from the second level of the AMP. For example, a treatment may be continued.
  • the AMP is about 10-100 amino acids in length, e.g, about 12-50 amino acids in length.
  • the peptide may correspond to any region of the full-length protein.
  • the AMP comprises any one of SEQ ID NOs: 27-50.
  • the subject having or suspected of having AD is cognitively impaired.
  • the individual may have dementia.
  • the subject may be A ⁇ +, for example, as determined by measurement of A ⁇ levels in a biofluid, or as determined by imaging, e.g., amyloid PET imaging.
  • the subject has one or more of a t-tau level in CSF that is above 400 ng/L, an A ⁇ 1-42 level in CSF that is below 550 ng/L, and a A ⁇ 1-42/A ⁇ 1-40 ratio in CSF that is below 0.065.
  • the AMP level in the biofluid (e.g., CSF) from the subject may be compared to the AMP level in a control.
  • the control is the level of AMP in CSF from an individual who does not have Alzheimer’s disease.
  • the individual is cognitively impaired.
  • the individual may have dementia.
  • the individual is A ⁇ -.
  • the individual does not have AD.
  • an altered level in an AMP in the biofluid is an increased level of the AMP.
  • the subject having or suspected of having AD may have an increased level of the AMP in the biofluid as compared to the level of the AMP in the control.
  • the altered level in an AMP in the biofluid is a decreased level of the AMP, e.g., the subject having or suspected of having AD may have an increased level of the AMP in the biofluid as compared to the level of the AMP in the control.
  • Attorney Docket Number 08061.0063-00304 the biofluid is a cerebrospinal fluid (CSF).
  • the biofluid is blood.
  • the biofluid is one or more of CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that may be collected from a body.
  • AD therapy may be any treatment or therapeutic that is administered to a subject to reduce symptoms and/or progression of the AD.
  • AD therapy is an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody.
  • the anti-A ⁇ protofibril antibody comprises a CDR, a variable region, a heavy chain, a light chain, or a constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4.
  • the anti-A ⁇ protofibril antibody is lecanemab (also called BAN2401).
  • the AD therapy is an anti-tau antibody.
  • the anti-tau antibody comprises a CDR, a heavy chain variable region, a light chain variable region, or a constant region according to SEQ ID NOSs: 15-24 in Tables 6-8. In some embodiments, the anti-tau antibody is E2814. 9.
  • a method of diagnosis for AD An aspect of the present disclosure relates to a method of diagnosing AD in a subject, comprising determining a level of one or more antimicrobial peptides (AMP) in a biofluid, e.g., a cerebrospinal fluid (CSF), from the subject, wherein the AMP is selected from any of those listed in Table 10, and comparing the level of the AMP to a control, e.g., CSF from an individual who has not been diagnosed with AD, wherein an altered level of the AMP in CSF from the subject as compared to the control indicates that the subject has AD.
  • the AMP is about 10-100 amino acids in length, e.g, about 12-50 amino acids in length.
  • the peptide may correspond to any region of the full-length protein.
  • the AMP comprises any one of SEQ ID NOs: 27-50.
  • the subject having or suspected of having AD is cognitively impaired.
  • the individual may have dementia.
  • the subject may be A ⁇ +, for example, as determined by measurement of A ⁇ levels in a biofluid, or as determined by imaging, e.g., amyloid PET imaging.
  • the subject has one or more of a t-tau level in CSF that is above 400 ng/L, an A ⁇ 1-42 level in CSF that is below 550 ng/L, and a A ⁇ 1-42/A ⁇ 1-40 ratio in CSF that is below 0.065.
  • the AMP level in the biofluid (e.g., CSF) from the subject may be compared to the AMP level in a control.
  • the control is the level of AMP in CSF from an individual who does not have Alzheimer’s disease.
  • the individual Attorney Docket Number 08061.0063-00304 who has not been diagnosed with AD.
  • the individual is cognitively impaired.
  • the individual may have dementia.
  • the individual is A ⁇ -.
  • the individual does not have AD.
  • the biofluid is a cerebrospinal fluid (CSF).
  • the biofluid is blood.
  • the biofluid is one or more of CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that may be collected from a body.
  • AD therapy may be any treatment or therapeutic that is administered to a subject to reduce symptoms and/or progression of the AD.
  • AD therapy is an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody.
  • the anti-A ⁇ protofibril antibody comprises a CDR, a variable region, a heavy chain, a light chain, or a constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4.
  • the anti-A ⁇ protofibril antibody is lecanemab (also called BAN2401).
  • the AD therapy is an anti-tau antibody.
  • the anti-tau antibody comprises a CDR, a heavy chain variable region, a light chain variable region, or a constant region according to SEQ ID NOSs: 15-24 in Tables 6-8.
  • the anti-tau antibody is E2814.
  • Alzheimer’s Disease Therapy Alzheimer’s disease (AD) therapy may be any treatment or therapeutic that is administered to a subject to reduce symptoms and/or progression of the AD.
  • AD therapy may be any treatment that delays progression of amyloid pathology, tau pathology, and/or clinical symptoms in a subject who has, is suspected of having, or is at risk for developing AD.
  • the AD therapy is administered to a subject based on measurements of antimicrobial peptides (AMPs) in a biofluid sample from the subject.
  • the AD therapy comprises an antibody.
  • the AD therapy is an anti-A ⁇ protofibril antibody (e.g., lecenemab).
  • the AD therapy is an anti-tau antibody (e.g., E2814).
  • the AD therapy is a combination of an anti-A ⁇ protofibril antibody (e.g., lecenemab) and an anti-tau antibody (e.g., E2814).
  • the AD therapy may be administered according to an initiation dosing regimen, and optionally, a maintenance dosing regimen.
  • Exemplary dosage Attorney Docket Number 08061.0063-00304 regimens for lecanemab, E2814, and a combination thereof are disclosed in WO2023/111618, WO2023/114586, and PCT/US2024/033125, which are incorporated herein by reference. a.
  • Anti-A ⁇ protofibril antibodies when an AMP level from a biofluid sample (e.g., a CSF sample or a blood sample) differs from an AMP level from a control (e.g., a biofluid sample from a subject who does not have AD), AD therapy comprising an anti-amyloid ⁇ (A ⁇ ) treatment, e.g., an anti-A ⁇ protofibril antibody, may be administered.
  • the anti-A ⁇ protofibril antibody comprises a CDR, a variable region, a heavy chain, a light chain, or a constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4.
  • the anti-A ⁇ protofibril antibody is lecanemab (also called BAN2401).
  • the anti-A ⁇ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1 , HCDR2, and HCDR3) comprising amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3) (Table 1).
  • the anti-A ⁇ protofibril antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8 (Table 2). In some embodiments, the anti-A ⁇ protofibril antibody comprises human heavy and light chain variable region frameworks. In some embodiments, the anti-A ⁇ protofibril antibody comprises a human IgG1 heavy chain constant region, and a human Ig kappa light chain constant region. In some embodiments, the anti-A ⁇ protofibril antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 9 and a light chain comprising an amino acid sequence of SEQ ID NO: 10 (Table 3).
  • CDRs used herein in the context of an antibody sequence or structure refers to complementarity determining regions, which provide the main determinants of antigen binding.
  • the antigen-binding site has six CDRs; three in the VH (HCDR1, HCDR2, HCDR3), and three in the VL (LCDR1, LCDR2, LCDR3).
  • the CDRs may be determined according to the Kabat numbering scheme. which may be determined by according to the Kabat numbering scheme (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991, hereafter referred to as “Kabat report”).
  • the at least one anti-A ⁇ protofibril antibody comprises a human constant region.
  • the human constant region of the at least one anti-A ⁇ protofibril antibody comprises a heavy chain constant region chosen from IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgE, and any allelic variation thereof as disclosed in the Kabat report. Any one or more of such sequences may be used in the present disclosure.
  • the heavy chain constant region is chosen from IgG1 and allelic variations thereof.
  • the amino acid sequence of human IgG1 constant region is known in the art and set out in SEQ ID NO: 11 (Table 4).
  • the human constant region of the at least one anti-A ⁇ antibody comprises a light chain constant region chosen from ⁇ - ⁇ -chain constant regions and any allelic variation thereof as discussed in the Kabat report. Any one or more of such sequences may be used in the present disclosure.
  • the light chain constant region is chosen from ⁇ and allelic variations thereof.
  • the amino acid sequence of human ⁇ chain constant region is known in the art and set out in SEQ ID NO: 12 (Table 4). b.
  • Anti-tau antibodies when an AMP level from a biofluid sample (e.g., a CSF sample or a blood sample) differs from an AMP level from a control (e.g., a biofluid sample from a subject who does not have AD), AD therapy comprising an anti-tau treatment, e.g., an anti-tau antibody, may be administered.
  • the anti-tau antibody comprises a CDR, a heavy chain variable region, a light chain variable region, or a constant region according to SEQ ID NOSs: 15-24 in Tables 6-8.
  • the anti-tau antibody is E2814.
  • the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3), as defined by Kabat (Table 6).
  • the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) from a heavy chain variable region of SEQ ID NO: 21 and a light chain variable region of SEQ ID NO: 22 (e.g., as defined by Kabat or IMGT).
  • the anti-tau antibody comprises a heavy chain variable region of SEQ ID NO: 21 and a light chain variable region of SEQ ID NO: 22 (Table 7).
  • the anti-tau antibody comprises a human constant region.
  • the human constant region comprises a heavy chain constant region Attorney Docket Number 08061.0063-00304 chosen from IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgE, and any allelic variation thereof as disclosed in the Kabat report. Any one or more of such sequences may be used in the present disclosure.
  • the heavy chain constant region comprises SEQ ID NO: 23 (Table 8).
  • the human constant region of the anti-tau antibody comprises a light chain constant region chosen from ⁇ and ⁇ -chain constant regions and any allelic variation thereof as discussed in the Kabat report. Any one or more of such sequences may be used in the present disclosure.
  • the light chain constant region comprises SEQ ID NO: 24 (Table 8).
  • the anti-tau antibody comprises E2814 or an antigen binding fragment thereof.
  • E2814 is disclosed in US 2019/0112364 A1, incorporated by reference in its entirety, and which discloses E2814 as clone 7G6-HCzu25/LCzu18, the sequences of which are incorporated by reference herein.
  • the anti-tau antibody is any of those disclosed in US 2019/0112364 A1, the disclosure of which is fully incorporated herein by reference.
  • the anti-tau antibody comprises the CDR and/or variable region sequences from antibody clone 7G6-HCzu25/LCzu18 as disclosed in US 2019/0112364 A1, the sequences of which are incorporated by reference herein.
  • the anti-tau antibody is produced by antibody-producing cells deposited with the American Type Culture Collection (10801 University Boulevard., Manassas, Va.20110-2209) on Oct.11, 2017, with Accession No. PTA-124524.
  • a subject in addition to a change in the levels of one more more AMPs, a subject shows a change and/or difference in a measurement of one or more biomarkers associated with AD pathology prior to and/or during an AD treatment, e.g., a treatment disclosed herein.
  • the change and/or difference in the measurement is selected from (a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), (b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), (c) decreased cerebrospinal fluid levels of ratio of A ⁇ 1-42/1-40 and/or increased total tau, phosphorylated tau (e.g., p- tau181, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non- phosphorylated tau (e.g., tau181/np-tau181, tau205/np-tau205, p-tau217/np-tau217 and/or Attorney Docket Number 08061.0063-00304 tau231/np-t
  • the subject shows a change and/or difference in a measurement of one or more biomarkers associated with AD pathology during and/or after treatment.
  • the change and/or difference in the measurement is selected from (a) decreased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), (b) decreased tau in the brain, e.g., as measured by positron emission tomography (PET), (c) increased cerebrospinal fluid levels of ratio of A ⁇ 1-42/1-40 and/or decreased total tau, phosphorylated tau (e.g., p- tau181, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non- phosphorylated tau (e.g., tau181/np-tau181, tau205/np-tau205),
  • amyloid PET
  • Amyloid PET PET imaging enables visualization of amyloid plaques in the brain, which were previously detected only by examining the brain at autopsy. Amyloid PET is a valuable tool for diagnosing AD and monitoring progression of the disease, as it has a high predictive accuracy for the presence of AD pathology. Amyloid PET may be used in conjunction with other biomarker measures, including any of those disclosed herein, preferably a blood or CSF marker, e.g. an AMP in blood or CSF. In some embodiments, the AMPs disclosed herein may be used to estimate (e.g., as a proxy) amyloid PET measurements. As used herein, the term “Amyloid PET” refers to Amyloid positron emission tomography imaging.
  • PET imaging also referred to as a PET scan
  • amyloid pathology Hansson et al., Nature Medicine, 2021.27: 954– Attorney Docket Number 08061.0063-00304 963; Therriault et al., Nature Reviews Neurology, 2024.20: 232–244.
  • amyloid PET is assessed with a PET tracer and uses the same tracer in follow-up assessments.
  • the amyloid beta plaque levels in the brain are evaluated using PET imaging.
  • the PET imaging uses an amyloid PET tracer.
  • the PET imaging uses florbetaben (e.g., 18F-Florbetaben (Neuraceq®)), florbetapir (e.g., 18F-Florbetapir (Amyvid®)), and/or flutametamol (e.g., 18F-Flutemetamol (Vizamyl®))
  • florbetaben e.g., 18F-Florbetaben (Neuraceq®)
  • florbetapir e.g., 18F-Florbetapir (Amyvid®)
  • flutametamol e.g., 18F-Flutemetamol (Vizamyl®)
  • the PET imaging uses a florbetapir tracer.
  • the PET imaging used a flutemetamol tracer.
  • the PET imaging uses a florbetaben tracer.
  • different tracers may yield different results.
  • the adjusted mean reduction threshold is dependent upon the tracer used.
  • a subject’s brain amyloid level is determined by visual reads of amyloid PET images and expressed as a PET standard uptake value ratio (SUVr value).
  • a brain amyloid level is reduced after administration of an AD therapy (e.g., an anti-A ⁇ protofibril antibody such as lecanemab or an anti-tau antibody such as E2814), concomitant with a change in a measurement of an AMP from Table 10.
  • AD therapy e.g., an anti-A ⁇ protofibril antibody such as lecanemab or an anti-tau antibody such as E2814
  • Tau PET PET imaging enables visualization of tau accumulation in the brain, which was previously detected only by examining the brain at autopsy.
  • Tau PET is a valuable tool for diagnosing AD and monitoring progression of the disease, particularly as the tau NFT burden is strongly correlated with severity of clinical AD symptoms (Hansson et al., Nature Medicine, 2021.27: 954–963; Therriault et al., Nature Reviews Neurology, 2024.20: 232– 244).
  • Tau PET may be used in conjunction with other biomarker measures, including any of those disclosed herein, preferably a blood or CSF marker, e.g. an AMP in blood or CSF.
  • the AMPs disclosed herein may be used to estimate (e.g., as a proxy) amyloid PET measurements.
  • tau PET refers to tau positron emission tomography.
  • PET imaging e.g., a PET scan
  • tau PET is assessed with a PET tracer and uses the same tracer in follow-up assessments.
  • a subject’s brain tau level is determined by visual reads of tau PET images and expressed as a PET standard uptake value ratio (SUVr value).
  • a brain tau level is reduced after administration of an AD therapy (e.g., an anti- A ⁇ protofibril antibody such as lecanemab or an anti-tau antibody such as E2814), concomitant with a change in a measurement of an AMP from Table 10.
  • an AD therapy e.g., an anti- A ⁇ protofibril antibody such as lecanemab or an anti-tau antibody such as E2814
  • Subjects having AD, suspected of having AD, or at risk of developing AD include those having AD or suspected of having AD.
  • the subject shows changes (e.g., an increase, a decrease, a change in the rate and/or extent of an increase, or a change in the rate and/or extent of the decrease) in one or more biomarkers associated with AD pathology (e.g., the AMPs described herein), as compared with a reference measurement.
  • the reference measurement may be a measurement taken from the same subject, e.g., at an earlier point in time, or a measurement in a part of the subject’s body, tissue, or fluids where the biomarkers levels do not change in response to AD pathology.
  • the reference measurement may be a measurement taken from another subject, such as a healthy control subject, or may be an average of measurements taken from more than one reference subject.
  • the subject may show a change and/or a difference in a measurement of an AMP level prior to treatment, e.g., an increase or a decrease in the AMP level as compared to the reference measurement, e.g., as compared to an earlier measurement in the subject or as compared to a control subject who does not have AD.
  • the subject may show a change and/or a difference in a measurement of one or more biomarkers associated with AD pathology prior to treatment, e.g., one or more of (a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), (b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), (c) decreased cerebrospinal fluid levels of A ⁇ 1-42 (e.g., a decreased ratio of A ⁇ 1-42/1-40) and/or increased total tau, phosphorylated tau (e.g., p- tau181, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non- phosphorylated tau (e.g., tau
  • the subject may show a change in the ratio of phosphorylated to non- phosphorylated Tau 217 (P-Tau217/NP-Tau217 ratio, also called P-Tau217R or pTau217R) in blood plasma or serum, e.g., the ratio may be increased in subjects who have, are suspected of having, or are at risk of developing AD.
  • P-Tau217/NP-Tau217 ratio also called P-Tau217R or pTau217R
  • the ratio may be increased in subjects who have, are suspected of having, or are at risk of developing AD.
  • biomarkers as disclosed herein may be effective for predicting amyloid PET status (Rissman et al., 2024, Alzheimers & Dementia, 20(2): 1214-1224; Janelidze et al., 2022, Alzhimer’s & Dementia, 18:283-293) and for detecting and diagnosing AD (Hampel et al., 2023, Neuron, 111(18):2781-2799).
  • at least one of p-tau217/np-tau217, A ⁇ 42/A ⁇ 40, and p-tau181/np-tau181 may be used to predict amyloid PET status.
  • a measurement of p-tau217 and/or A ⁇ 42/A ⁇ 40 may be used to predict amyloid PET status.
  • a combination of p-tau217 and A ⁇ 42/A ⁇ 40 may be used to predict amyloid PET status.
  • the ratios of p-tau217/np-tau217 and A ⁇ 42/A ⁇ 40 may be used in combination to predict amyloid PET status.
  • the subject is amyloid-positive, e.g., as indicated by a PET assessment, a CSF assessment of A ⁇ (1-42), MRI, and/or retinal amyloid accumulation.
  • a subject has AD, e.g., has been diagnosed with AD.
  • the subject may have been diagnosed with (a) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood and/or has been diagnosed as having mild Alzheimer’s disease dementia; (b) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by National Institute of Aging – Alzheimer’s Association (NIA-AA) core clinical criteria; (c) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a CDR global score of 0.5 and a Memory Box score of 0.5 or greater before treatment; (d) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a history of subjective memory decline with gradual onset and slow progression over the last 1 year before treatment, e.g., as corroborated by an informant; (e) mild Alzheimer’s disease dementia by the NIA-AA core clinical criteria for probable Alzheimer’s disease dementia; or (f) mild Alzheimer’s disease dementia by a CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or greater before
  • the subject has early AD.
  • the subject with early AD may have symptoms ranging in severity from mild cognitive impairment due to AD – intermediate likelihood to mild Alzheimer’s disease dementia.
  • subjects with early AD have MMSE scores of 22 to 30 and Clinical Dementia Rating (CDR) global range 0.5 to 1.0.
  • CDR Clinical Dementia Rating
  • the subject has a low tau PET level in a global brain measurement, for example, as measured by tau PET.
  • a low level of tau PET may refer to a low level of tau aggregation as imaged by PET scan imaging, e.g., a low level of cortical tau aggregation.
  • a subject with low tau PET also has accumulation of tau in certain brain regions, e.g., one or more early Braak regions or a composite of regions where tau accumulates in early AD.
  • a subject may be classified as having a low level of tau if a level of tau as measured by PET using an MK tracer (e.g., MK6240) is below about 1.1, e.g., below about 1.0.
  • MK tracer e.g., MK6240
  • a patient may be classified as having a low level of tau if the tau PET level as measured using an MK tracer is below 1.06.
  • a patient may be classified as having an intermediate level of tau if the tau PET level as measured by MK tracer is between about 1.1 and 3.0, e.g., between 1.06 and 2.91.
  • a patient may be classified as having a high level of tau if the tau PET level as measured by MK tracer is above about 3.0, e.g., above 2.91.
  • a subject is suspected of having AD, e.g., based on one or more biomarkers and/or cognitive symptoms of dementia.
  • a subject is at risk for developing AD but has not yet exhibited cognitive symptoms of dementia.
  • a subject may have risk factors for AD, wherein the risk factors are related to age or genetic mutations.
  • the subject is ApoE4- positive. In some embodiments, the subject is at least 65 years old, e.g., 65 to 80 years old. In some embodiments, the subject is 55 to 64 years old and has at least one risk factor chosen from: (i) a first degree relative diagnosed with dementia onset before age 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid according to PET or cerebrospinal fluid (CSF) testing. In some embodiments, a subject at risk for AD has elevated brain amyloid, e.g., as measured by and/or confirmed by PET assessment, but does not exhibit any detectable cognitive symptoms.
  • APOE4 apolipoprotein E4 variant
  • CSF cerebrospinal fluid
  • a subject at risk for AD has a change in a biomarker such as amyloid PET; tau in the brain, e.g., as measured by positron emission tomography (PET), cerebrospinal fluid levels of one or more of A ⁇ 1-42 (or a ratio of A ⁇ 1-42/1-40 in the cerebrospinal fluid), total tau, phosphorylated tau (e.g., p- tau181, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non- phosphorylated tau (e.g., tau181/np-tau181, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, neurogranin, and neurofilament light chain (NfL), and/or a change in a blood serum or plasma levels of one or more of A ⁇ 1-4
  • a subject at risk for developing AD may have pre-AD (also referred to as preclinical AD, in which subjects are cognitively unimpaired but have elevated amyloid in the brain, e.g., as based on a change in one or more biomarkers associated with AD pathology).
  • pre-AD also referred to as preclinical AD, in which subjects are cognitively unimpaired but have elevated amyloid in the brain, e.g., as based on a change in one or more biomarkers associated with AD pathology.
  • the subject may show a change in one or more biomarkers associated with AD pathology, but no cognitive impairment, e.g., as measured by clinical symptoms of AD.
  • the subject has a Global Clinical Dementia Rating (CDR) score of 0.
  • MMSE Mini-Mental State Examination
  • the subject has a Wechsler Memory Scale-IV Logical Memory (subscale) II (WMS-IV LMII) score better than one standard deviation below age-adjusted mean in the WMS-IV LMII; namely a score of greater than 15 for a subject of age ranging from 50 to 64 years, of greater than 12 for a subject of age ranging from 65 to 69 years, of greater than 11 for a subject of age ranging from 70 to 74 years, of greater than 9 for a subject of age ranging from 75 to 79 years, and of greater than 7 for a subject of age ranging from 80 to 90 years.
  • WMS-IV LMII Wechsler Memory Scale-IV Logical Memory II
  • the subject has a genetic mutation for a dominantly inherited Alzheimer’s disease, e.g., wherein the subject a genetic mutation in at least one of three genes — PSEN1, PSEN2, or APP. In some embodiments, the subject has a mutation in APP. In some embodiments, the subject has a dominantly inherited Alzheimer’s disease (DIAD). In some embodiments, the subject has mild-to-moderate AD, e.g., where mild AD may be associated with Mini-Mental State Examination [MMSE] scores ⁇ 20) and may be characterized by forgetfulness and difficulties with activities of daily living (ADLs).
  • MMSE Mini-Mental State Examination
  • Moderate AD may be associated with MMSE scores of about 10–19 and may be characterized by marked memory loss and a requirement for significant assistance with ADLs.
  • Attorney Docket Number 08061.0063-00304 As used herein, the singular terms “a,” “an,” and “the” include the plural reference unless the context clearly indicates otherwise.
  • the phrase “and/or,” as used herein, means “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases.
  • “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in some embodiments, to A only (optionally including elements other than B); in other embodiments, to B only (optionally including elements other than A); in yet other embodiments, to both A and B (optionally including other elements); etc.
  • “at least one” means one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified.
  • “at least one of A and B” can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • “about” when used in connection with doses, amounts, or ratios include the value of a specified dose, amount, or ratio or a range of the dose, amount, or ratio that is recognized by one of ordinary skill in the art to provide a therapeutic effect equivalent to that obtained from the specified dose, amount, or ratio.
  • the term “about” may refer to an acceptable error for a particular value as determined by one of skill in the art, which depends in part on how the values is measured or determined. In some embodiments, the term “about” means within 5% of a given value or range.
  • MMRM linear mixed-effects model
  • an antimicrobial peptide also called a host defense peptide (HDP)
  • HDP host defense peptide
  • AMPs may play a role in the innate immune response.
  • the level of an AMP refers the concentration, and/or quantityof the AMP in a measured sample or in a subject.
  • Amyloid ⁇ 1-42 (A ⁇ 42) refers to an amyloid beta monomer from amino acid 1 to 42 of the full-length protein (Table 5, SEQ ID NO:13).
  • Amyloid ⁇ 1-40 (A ⁇ 1-40) refers to an amyloid beta monomer from amino acid 1 to 42 of the full-length protein (Table 5, SEQ ID NO:14).
  • P-tau181 is human tau protein phosphorylated at threonine in position 181.
  • P- tau217 is human tau protein phosphorylated at threonine in position 217.
  • P-tau231 is human tau protein phosphorylated at threonine in position 231.
  • P-tau205 is a human tau protein phosphorylated at threonine in position 205.
  • Total tau or t-tau as used herein is a measure of total tau in a sample, e.g. a CSF sample, a plasma sample, a serum sample.
  • MTBR-tau 243 is a peptide fragment of tau, spanning residues 243-254 in the microtubule-binding region of tau and is enriched in tau aggregates. MTBR-tau243 may be measured in a biofluid sample, e.g., CSF or blood, as a correlate of tau tangles, tau PET, and cognitive impairment.
  • Preclinical AD patients with “preclinical AD” or “pre-AD” as described herein (also called patients who are “asymptomatic” for AD), are cognitively normal individuals with intermediate or elevated levels of amyloid in the brain and can be identified by asymptomatic stages with or without memory complaints and emerging episodic memory and executive function deficits.
  • Cognitively normal can include individuals who are CDR 0, or individuals within the normal ranges of cognitive test scores (MMSE, International Shopping List Task, Attorney Docket Number 08061.0063-00304 Logical Memory, etc.).
  • Preclinical AD occurs prior to significant irreversible neurodegeneration and cognitive impairment and is typically characterized by the appearance of in vivo molecular biomarkers of AD and the absence clinical symptoms.
  • Preclinical AD biomarkers that may suggest the future development of Alzheimer’s disease include, but are not limited to, one or more of intermediate or elevated levels of amyloid in the brain by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20- 32), fluorodeoxyglucose (FDG) PET, or tau positron emission tomography (PET), cerebrospinal fluid level of A ⁇ 1-42 and/or A ⁇ 1-42/1-40 ratio, cerebrospinal fluid level of total tau, cerebrospinal fluid level of microtubule binding region (MTBR)-tau, cerebrospinal fluid level of neurogranin, cerebrospinal fluid level of neurofilament light chain (NfL), and blood biomarkers as measured in the serum or plasma (e.g.
  • amyloid PET e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20- 32
  • a ⁇ 1-42/1-40 ratio e.g., a ratio of between about 0.092-0.094 or below about 0.092
  • plasma levels of plasma total tau T-tau
  • levels of phosphorylated tau P-tau or p-tau isoforms (including tau phosphorylated at 181 (P-tau181), at 205, (P-tau205), 217 (P-tau217), and 231 (P-tau231)
  • GFAP glial fibrillary acidic protein
  • NfL neurofilament light chain
  • “Early AD” or “early Alzheimer’s disease,” as used herein, is a continuum of AD severity from mild cognitive impairment due to AD – intermediate likelihood to mild Alzheimer’s disease dementia.
  • Subjects with early AD include subjects with mild Alzheimer’s disease dementia as defined herein and subjects with mild cognitive impairment Attorney Docket Number 08061.0063-00304 (MCI) due to AD – intermediate likelihood as defined herein.
  • MCI Attorney Docket Number 08061.0063-00304
  • subjects with early AD have MMSE scores of 22 to 30 and Clinical Dementia Rating (CDR) global range 0.5 to 1.0.
  • NIA-AA National Institute of Aging-Alzheimer’s Association
  • NIA-AA National Institute of Aging-Alzheimer’s Association
  • a subject with early AD has evidence of elevated amyloid in the brain or a positive amyloid load.
  • elevated amyloid in the brain or a positive amyloid load is indicated and/or confirmed by PET assessment.
  • elevated amyloid in the brain or a positive amyloid load is indicated and/or confirmed by a CSF assessment of markers such as A ⁇ 1-42 (e.g., a soluble CSF biomarker analysis).
  • elevated amyloid in the brain or a positive amyloid load is indicated and/or confirmed by measuring the level of p-tau181.
  • elevated amyloid in the brain or a positive amyloid load is indicated and/or confirmed by an MRI.
  • elevated amyloid in the brain or a positive amyloid load is indicated by retinal amyloid accumulation. In some embodiments, more than one assessment method is used.
  • Amyloid refers to fibers that are unbranched, usually extracellular, and found in vivo; in addition, the fibers bind the dye Congo Red and then show green birefringence when viewed between crossed polarizers. Amyloid-forming proteins have been identified and associated with serious diseases, including amyloid- ⁇ peptide (A ⁇ ) with Alzheimer’s disease (AD), islet amyloid polypeptide (IAPP) with diabetes type 2, and prion protein (PrP) with the spongiform encephalopathies. As used herein, “amyloid,” “brain amyloid,” and “amyloid- ⁇ peptide (A ⁇ )” are used interchangeably.
  • a ⁇ exists in various conformational states: monomers, oligomers (e.g., different forms of A ⁇ oligomers such as dimers, trimers, tetramers, pentamers, hexamers, nonamers, dodecamers), a paranucleus (e.g., a partially- folded monomer that forms a nucleus for fibril elongation), protofibrils (e.g., soluble, pre- fibrillar intermediates), and insoluble fibrils (plaques).
  • monomers e.g., different forms of A ⁇ oligomers such as dimers, trimers, tetramers, pentamers, hexamers, nonamers, dodecamers
  • a paranucleus e.g., a partially- folded monomer that forms a nucleus for fibril elongation
  • protofibrils e.g., soluble, pre- fibrillar intermediates
  • insoluble fibrils plaque
  • Protofibrils are formed as intermediate species when A ⁇ monomers aggregate into insoluble fibrils, and various species of soluble Attorney Docket Number 08061.0063-00304 protofibrils have been implicated in AD pathogenesis (Hampel et al., Mol Psychiatry, 2021: 26, 5481–550).
  • a ⁇ peptides generally exist in a dynamic continuum of conformational states such that species tend to progress from monomeric A ⁇ , to soluble A ⁇ assemblies that include a range of low molecular weight oligomers to higher molecular weight protofibrils, and finally to insoluble fibrils (plaques).
  • the subject has “elevated amyloid” or “intermediate amyloid.”
  • amyloid levels from amyloid PET can be reported using the Centiloid method in “centiloid” units (CL).
  • CL centiloid units
  • the Centiloid method measures a tracer on a scale of 0 CL to 100 CL, where 0 is deemed the anchor-point and represents the mean in young healthy controls and 100 CL represents the mean amyloid burden present in subjects with mild to moderate severity dementia due to AD.
  • centiloid thresholds may vary, for example may be refined, based on new or additional scientific information. (See, e.g., http://www.gaain.org/centiloid-project.)
  • An elevated level of amyloid can be set relative to a baseline threshold in a healthy control determined according to methods known to a person of ordinary skill in the art (POSA).
  • POSA methods known to a person of ordinary skill in the art
  • a centiloid value of 32.5 can be used as a threshold value for “elevated amyloid,” and an “intermediate amyloid” level refers to an A ⁇ amyloid PET in the range of 20-32.5 CL (e.g., 30 CL).
  • a centiloid value of 40 can be used as a threshold value for “elevated amyloid,” and an “intermediate amyloid” level refers to an A ⁇ amyloid PET in the range of 20-40 CL.
  • tau refers to tau proteins, which belong to the family of microtubule-associated proteins (MAPs), and are mainly expressed in neurons and found in the axons and dendrites. Tau proteins play an important role in the assembly of tubulin monomers into microtubules to constitute the cytoskeleton and serve as tracks for axonal transport.
  • MAPs microtubule-associated proteins
  • Tau proteins are translated from a single gene located on chromosome 17, with alternative mRNA splicing leading to the formation of 6 different central nervous system tau isoforms, of which 5 are found in the human adult brain.
  • the isoforms differ, having either 3 (Rl, R3, and R4) or 4 (R1-R4) repeat-regions in the carboxy (C)-terminal part and variable occurrence of microtubule binding region (MTBR).
  • the amino (N)-terminal domain which establishes links between microtubules and other parts of the cytoskeleton, or the plasma membrane, has a variable occurrence of 0, 1, or 2 inserts of 29 amino acids.
  • tau pathology refers to pathological forms of tau, such as intracellular fibrillary tangles and components thereof, which are described in Alzheimer’s disease (AD) and other neurodegenerative disorders, referred to as tauopathies. Aggregation of hyperphosphorylated tau into insoluble paired helical filaments (PHF) that accumulate in neurons to form neurofibrillary tangles (NFTs) are hallmarks of tau pathology. In AD, NFTs occur in a neuroanatomically characteristic pattern of increasing severity, generally defined according to the Braak stages 1 to 6, which correlate well with progressive neuronal loss and clinical decline. Extracellular tau seeds are also a pathological form of tau. Some tau seeds contain the tau MTBR.
  • Subjects with “mild Alzheimer’s disease dementia,” or “mild AD dementia” as used herein, are subjects meeting the National Institute of Aging-Alzheimer’s Association (NIA-AA) core clinical criteria for probable Alzheimer’s disease dementia in McKhann, G.M. 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.
  • NIA-AA National Institute of Aging-Alzheimer’s Association
  • Subjects with “MCI due to AD – intermediate likelihood,” as used herein are those identified as such in accordance with the NIA-AA core clinical criteria for mild cognitive impairment due to Alzheimer’s disease – intermediate likelihood (see McKhann supra).
  • a subject may be symptomatic but not demented, with evidence of brain amyloid pathology making them less heterogeneous and more similar to mild Alzheimer’s disease dementia subjects in cognitive and functional decline as measured by the ADCOMS Composite Clinical Score defined herein.
  • a “control subject”, “untreated AD subject”, or an “untreated control subject” is a subject that is not being treated or has been treated for Alzheimer’s disease. In some embodiments, a control subject has Alzheimer’s disease.
  • the control subject has early Alzheimer’s disease, or pre-Alzheimer’s disease. In some embodiments, the control subject has Alzheimer’s disease and is not treated with an anti-A ⁇ protofibril antibody.
  • patient and “subject” are used interchangeably.
  • MMSE refers to the Mini-Mental State Examination, a cognitive instrument commonly used for screening purposes, but also often measured longitudinally in AD clinical trials having a 30 point scale with higher scores indicating less impairment and lower scores indicating more impairment, ranging from 0 (most impaired) to 30 (no impairment).
  • ADAS-Cog refers to Alzheimer’s Disease Assessment Scale- Cognitive.
  • the ADAS-Cog is a widely used cognitive scale in Alzheimer's disease trials having a structured scale that evaluates memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing letter in envelope) and constructional praxis (copying geometric designs).
  • word recall word recall
  • delayed word recall and word recognition
  • reasoning following commands
  • language naming, comprehension
  • orientation ideational praxis
  • ideational praxis placing letter in envelope
  • constructional praxis constructional praxis (copying geometric designs).
  • ADAS-Cog refers to the use of the Alzheimer Disease Assessment Scale-Cognitive Subscale14 (ADAS-Cog14).
  • a modified version may be used herein and is scored from 0 to 90 points with a score of 0 indicating no impairment, and a score of 90 indicating maximum impairment.
  • the ADAS–Cog14 tasks include memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing letter in envelope), constructional praxis (copying geometric designs), spoken language, language comprehension, word finding difficulty, ability to remember test instructions, maze, and number cancellation (Rosen et al, 1984).
  • CDR-SB refers to clinical dementia rating - sum of boxes.
  • the CDR is a clinical scale that describes 5 degrees of impairment in performance on each of 6 categories of function including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.
  • a sum of boxes score provides a measure of change where each category has a maximum possible score of 3 points and the total score is a sum of the category scores giving a total possible score of 0 to 18 with higher scores indicating more impairment.
  • CDR global As used herein, “CDR global”, “global CDR” score and “global rating of dementia CDR” score is used interchangeably.
  • CDR global score is a rating of the degree of impairment obtained on each of the 6 categories of function from the 6 categories of the CDR scale and is synthesized into 1 global rating of dementia CDR score, (ranging from 0 to 3) where 0 indicates no cognitive impairment, 0.5 indicates mild cognitive impairment, and 1-3 indicates mild, moderate, severe dementia respectively.
  • the global CDR score may be used as a clinical measure of severity of dementia.
  • a global CDR score may be used to determine if a patient has progressed or maintained a stage of AD, e.g., a higher score on a subsequent evaluation indicating progression of AD, e.g., an unchanged score indicating no progression of AD.
  • ADCOMS refers to Alzheimer’s Disease Composite Score, a composite clinical score based on an analysis of four ADAS-Cog items (delayed word recall, orientation, word recognition, and word finding difficulty), two Mini Mental State Examination (MMSE) items (orientation to time, and drawing), and all six CDR-SB items (personal care, community affairs, home and hobbies, memory, orientation, and judgment and problem solving), as discussed in the Examples and in Wang, J.
  • ADCOMS a composite clinical outcome for prodromal Alzheimer’s disease trials. J. Neurol. Neurosurg. Psychiatry.2016; 87:993-999.
  • ADCOMS was developed to be particularly sensitive to disease progression during early stages of AD (i.e., preclinical AD or early AD).
  • ADCOMS can be calculated using the following formula: ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ where ⁇ ⁇ ⁇ ⁇ , ⁇ ⁇ ⁇ ⁇ and items from ADAS- cog, reversed MMSE scores, and CDR-SB, respectively (Wang, J.
  • ADCOMS a composite clinical outcome for prodromal Alzheimer’s disease trials.
  • ADCOMS is particularly sensitive to disease progression during early stages of AD, i.e., prodromal and mild AD.
  • ADCS MCI-ADL refers to the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL).
  • the ADCS MCI-ADL is a clinical scale that assesses the competence level of a patient at six Attorney Docket Number 08061.0063-00304 basic activities of daily living. Additional examples are discussed in Kreutzer J.S., DeLuca J., Caplan B. (eds) Encyclopedia of Clinical Neuropsychology. Springer, New York, NY.
  • modified iADRS or “iADRS” refers to a composite tool that combines scores from the ADAS Cog14 (all items) and the ADCS MCI-ADL (all items).
  • ApoE4-positive subjects and “ApoE4 carriers” refer to subjects who harbor the ⁇ 4 variant of the apolipoprotein (APOE) gene.
  • the ⁇ 4 variant is one of several major alleles of the apolipoprotein gene. The gene is generally responsible for metabolism of fats.
  • a subject treated herein is a heterozygous carrier of the apolipoprotein E ⁇ 4 gene allele.
  • the subject is a homozygous carrier of the apolipoprotein E ⁇ 4 gene allele.
  • the terms “ApoE4-negative” and “ApoE4 non- carriers” are used interchangeably.
  • whether an early AD subject is “amyloid positive” or “amyloid negative” may be determined based on whether the subject has a positive amyloid load.
  • a subject is determined to be amyloid-positive or amyloid-negative as indicated by longitudinal positron emission tomography (PET) assessment of an imaging agent uptake into the brain, e.g., an amyloid imaging agent or a tau imaging agent.
  • PET longitudinal positron emission tomography
  • a subject is determined to be amyloid-positive or amyloid-negative by evaluation of a tau PET imaging assessment.
  • the subject is “amyloid negative” if PET SUVr negativity is below a threshold determined for an amyloid PET tracer.
  • the amyloid PET tracer may be florbetaben (e.g., 18F-Florbetaben (Neuraceq®)), florbetapir (e.g., 18F-Florbetapir (Amyvid®)), and/or flutametamol (e.g., 18F- Flutemetamol (Vizamyl®)).
  • the threshold for PET SUVr for an amyloid PET tracer is about 1.17, and a measurement below this threshold may indicate that the subject is “amyloid negative.”
  • the florbetapir amyloid PET SUVr threshold is about 1.17.
  • the florbetaben amyloid PET SUVr threshold is about 1.17. In some embodiments, the flutemetamol amyloid PET SUVr threshold is about 1.17.
  • a subject is determined to be amyloid-positive or amyloid- negative by evaluation of the level of a biomarker in a sample (e.g., a A ⁇ 42/40 ratio) from a subject, alone or in combination with another method such as PET measurement of brain Attorney Docket Number 08061.0063-00304 amyloid. In some embodiments, a subject is “amyloid negative” if the A ⁇ 42/40 ratio in a sample is at or about above 0.092-0.094 e.g., at about 0.092.
  • a subject is “amyloid negative” if the A ⁇ 42/40 ratio in a sample is above 0.092.
  • a subject is determined to be amyloid-positive or amyloid-negative by a CSF assessment of the presence of amyloid pathology using assessments of markers such as p-tau181, alone or in combination with another method such as PET measurement of brain amyloid.
  • a qualitative visual read of PET scans may be used to determine amyloid positive and amyloid negative by categorizing subjects as having either “normal” or “abnormal” uptake on the basis of the PET image pattern.
  • a threshold will be set for quantitatively determining from a biomarker (e.g., serum or CSF) and/or PET scan whether an A ⁇ brain load indicates a subject is amyloid-positive or negative.
  • a subject is determined to be amyloid- positive or amyloid-negative by an imaging method. An imaging method may be used to determine, calculate, or predict whether a subject is amyloid-positive or negative, even when the imaging method is not used to visualize amyloid directly.
  • the method uses MRI), and/or combines MRI and other imaging modalities such as PET.
  • a subject is determined to be amyloid-positive or amyloid-negative by retinal amyloid accumulation.
  • a subject is determined to be amyloid-positive or amyloid-negative by behavioral/cognitive phenotypes.
  • digital, computerized, and/or conventional (e.g., pen and paper) cognitive tests may be used to detect early cognitive changes that may signal mild cognitive impairment and/or a risk for developing dementia, and thus may be used to identify subject in need of treatment as disclosed herein. Such tests, for example, may screen for cognitive impairment, and potentially identify individuals with MCI.
  • Tests may use artificial intelligence to analyze cognitive test results to determine whether a case of mild cognitive impairment will escalate into Alzheimer’s within a year. Diagnosing the condition early, before symptoms have begun to appear, may be used to assist physicians identify subjects in need of treatment as disclosed herein sooner, potentially delaying onset or lessening the severity of the neurodegenerative disease.
  • the term “treat” refers to any administration or application of a therapeutic agent for a disease or disorder in a subject, and includes inhibiting the disease, slowing progression of the disease, delaying progression, arresting its development, reversing Attorney Docket Number 08061.0063-00304 progression of disease (e.g., reversing build up of A ⁇ fibrils), preventing the onset or development of the disease, relieving or ameliorating one or more symptoms or underlying condition(s) of the disease, curing the disease, improving one or more clinical metrics, or preventing reoccurrence of one or more symptoms of the disease.
  • treatment of AD in a subject comprises an administration, e.g., an intravenous infusion, of an anti-amyloid ⁇ (A ⁇ ) protofibril antibody.
  • treatment of AD in a subject comprises a therapeutically effective dose by administration, e.g., an intravenous infusion, of an anti-amyloid ⁇ (A ⁇ ) protofibril antibody.
  • the term “infusion” refers to an active administration of one or more agents with an infusion time of, for example, approximately 60 minutes.
  • an anti-amyloid ⁇ (A ⁇ ) protofibril antibody, described herein is systemically administered to a human subject via infusion.
  • an anti-amyloid ⁇ (A ⁇ ) protofibril antibody is alternatively administered to the human subject, e.g., by subcutaneous injection.
  • the subcutaneous injection is a weekly injection.
  • the subcutaneous injection is a biweekly injection.
  • an anti-amyloid ⁇ (A ⁇ ) protofibril antibody is administered to the human subject by intravenous infusion.
  • the subject is administered a maintenance dose of a treatment.
  • the term “maintenance dose” refers to a dosage administered to a subject to maintain the desired therapeutic effect.
  • the maintenance dose is administered weekly, every two weeks, monthly, every two months, or every three months (quarterly) or every 24 weeks (every six months or semi-annually).
  • the maintenance dose comprises an anti-A ⁇ protofibril antibody.
  • the maintenance dose is administered as an intravenous infusion.
  • the intravenous infusion is a 10 mg/kg dose of lecanemab administered monthly.
  • the maintenance dose is administered subcutaneously, orally, or nasally.
  • the maintenance dose is administered subcutaneously.
  • the maintenance dose is administered as a subcutaneous injection.
  • the maintenance dose is administered as a weekly, subcutaneous injection.
  • the maintenance dose is administered as a biweekly, subcutaneous injection. In some embodiments, the maintenance dose is administered as a monthly, subcutaneous injection. In some embodiments, the maintenance dose is administered as a quarterly, subcutaneous injection. In some embodiments, the maintenance dose is administered weekly or less frequently, e.g., every two weeks Attorney Docket Number 08061.0063-00304 (biweekly), every four weeks, monthly, every six weeks, every eight weeks (2 months), every three months (quarterly) or every six monthly (semi-annually). In some embodiments, the maintenance dose is administered as a biweekly, subcutaneous injection of 500 mg, 360 mg, or 250 mg.
  • the maintenance dose is administered as a biweekly, subcutaneous injection of 500 mg comprising two concurrent, e.g., sequential, injections of 250 mg (e.g., 2 x 1.25 mL of 400 mg/2 mL) of the subcutaneous formulation.
  • the subcutaneous dose is administered in a single injection of 360 mg (e.g., 1 x 1.8 mL of 400 mg/2 mL) of the subcutaneous formulation.
  • the subcutaneous dose of 250 mg is administered in a single injection of 250 mg (e.g., 1 x 1.25 mL of 400 mg/2 mL) of the subcutaneous formulation.
  • the subcutaneous dose is administered by a vial-syringe method or by an auto-injector (AI). In some embodiments, a subcutaneous dose of 500 mg, 360 mg, or 250 mg is administered using an auto-injector.
  • the maintenance dose is administered once or multiple times. In some embodiments, the maintenance dose is administered at a lower dose than during an earlier course of treatment and/or is administered less frequently than during the earlier course of treatment.
  • a subject’s biomarker levels may indicate increasing levels of amyloid in the brain. In some embodiments, after switching to a maintenance dose, a subject’s biomarker levels may begin to worsen, e.g.
  • a subject on a maintenance dose may have a decrease in the A ⁇ 42/40 ratio.
  • a subject is put on a maintenance dose chosen such that the subject may have a decrease in the A ⁇ 42/40 ratio but the A ⁇ 42/40 ratio may remain above the threshold for amyloid positivity, e.g. for at least one year (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years).
  • levels of a subject’s biomarker e.g., MTBR-tau243 from a biofluid sample (e.g., CSF or blood) may increase.
  • a subject’s biomarker levels may begin to worsen, e.g. an increasing CSF MTBR-tau243.
  • a subject is put on a maintenance dose chosen such that the subject may have a decrease in the MTBR- tau243 concentration and maintain the concentration at a level comparable to a healthy control for at least one year (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years).
  • Attorney Docket Number 08061.0063-00304 In some embodiments, after switching to a maintenance dose, a subject’s biomarker levels, e.g. a MTBR-tau243 concentration or a tau PET level, may begin to increase or a rate of increase may increase.
  • such a subject may be moved back to a treatment regimen.
  • a subject may remain on a maintenance dose, e.g., if the increase remains below a tau PET level or rate of increase seen in a control subject who has AD but does not receive an anti-A ⁇ protofibril antibody.
  • the term “prevent” refers to obtaining beneficial or desired results including, but not limited to, prophylactic benefit.
  • the composition may be administered to a subject at risk of developing Alzheimer’s disease, to a subject having one or more preclinical symptoms but not clinical symptoms of Alzheimer’s disease, or to a subject reporting one or more of the physiological symptoms of Alzheimer’s disease, even though a clinical diagnosis of having Alzheimer’s has not been made.
  • prevention may further include therapeutic benefit, by which is meant eradication or amelioration of the underlying condition being treated or of one or more of the physiological symptoms associated therewith.
  • the term “ARIA” refers to amyloid-related imaging abnormality as evaluated using MRI.
  • ARIA includes amyloid related imaging abnormality edema/effusion (ARIA-E).
  • ARIA includes amyloid related imaging abnormality hemorrhage (ARIA-H).
  • ARIA-H amyloid related imaging abnormality hemorrhage
  • subjects with ARIA experience headache, confusion, and/or seizure and these may be used to identify a subject with ARIA or to indicate further evaluation for ARIA.
  • ARIA is evaluated at specified intervals during treatment.
  • ARIA is evaluated when the subject experiences symptoms of ARIA.
  • maximum serum concentration (Cmax) of anti-A ⁇ protofibril antibody can be used as a predictor of the risk of ARIA-E.
  • the use of a subcutaneous formulation may provide a reduced risk of ARIA-E (e.g., due to a lower Cmax) compared to an IV administration.
  • clinical decline refers to a worsening of one or more clinical symptoms of AD.
  • Methods for measuring clinical decline may employ the tests and assays specified herein.
  • clinical decline is determined by a worsening of ADCOMS.
  • clinical decline is determined by a worsening of MMSE.
  • clinical decline is determined by a worsening of ADAS-Cog.
  • clinical decline is determined by a worsening of FAQ.
  • clinical decline is determined by a worsening of CDR-SB.
  • clinical decline is determined by a worsening of Wechsler Memory Scale-IV Attorney Docket Number 08061.0063-00304 Logical Memory (subscale) I and/or (subscale) II.
  • clinical decline is determined by a worsening of CDR score.
  • clinical decline refers to a worsening in one or more biomarkers of AD or brain measurement (e.g., by PET or MRI), e.g., of brain atrophy and/or amyloid accumulation.
  • blood sample or “blood” refers to a sample of blood, including serum and/or blood plasma from a human subject.
  • blood will be collected from subjects to evaluate potential biomarkers of AD that may include amyloid fragments and isoforms, tau, and other protein biomarkers (e.g., anti-microbial peptides, neurofilament light chain or NfL) for association with AD diagnosis, amyloid or tau load, or disease modification.
  • potential biomarkers of AD may include amyloid fragments and isoforms, tau, and other protein biomarkers (e.g., anti-microbial peptides, neurofilament light chain or NfL) for association with AD diagnosis, amyloid or tau load, or disease modification.
  • subjects are required to fast if possible before collection at Week 96 and Week 216. In other embodiments and/or at other time points, subjects do not require fasting.
  • Pre-AD biomarker levels that may suggest the development of Alzheimer’s disease include, but are not limited to, brain amyloid level, cerebrospinal fluid level of A ⁇ 1-42, cerebrospinal fluid level of total tau, cerebrospinal fluid level of neurogranin, and cerebrospinal fluid level of neurofilament light chain (NfL).
  • Mass spectrometry (MS) data obtained from a published study (PRIDE archive PXD016278; Bader et al., Mol Syst Biol, 2020;16(6):e9356) was used to compare peptides in the CSF from subjects with cognitively impaired A ⁇ + (AD) and A ⁇ - (non-AD) individuals.
  • Subjects with AD were classified based on t-tau levels above 400 ng/L, A ⁇ 1-42 levels below 550 ng/L, and a A ⁇ 1-42/A ⁇ 1-40 ratio below 0.065.
  • the t-tau criterion and at least one of the A ⁇ criteria had to be met for a patient to be classified as AD.
  • MS files were analyzed using a novel platform integrating a de novo-based- workflow with a custom human protein database integrating AMP sequences to enable the identification of antimicrobial peptides in CSF samples.
  • Non-tryptic, semi-tryptic, and fully- tryptic peptides were selected.
  • AMPs When AMPs are generated, they may not be fully-tryptic peptides (e.g., with K and R amino acid resides at their ends, resulting from the sites where trypsin cuts). Accordingly, selection strategies for non-tryptic and semi-tryptic peptides may enable selection of diverse peptides, including those which do not have K and R amino acids at the ends.
  • Figure 2 shows the workflow used to obtain 24 AMPs.
  • the UniProt ID refers to the protein to which the peptides map (e.g., proteins from which the Attorney Docket Number 08061.0063-00304 peptides are produced) and the AMP_ID refers to the ID number in the public AMP databases (dbAMP, https://awi.cuhk.edu.cn/dbAMP/ and UDAMP, https://aps.unmc.edu/).
  • Peptide raw peak area intensities were quantile normalized and log2 transformed to reduce technical variation and ensure distribution symmetry. Differentially expressed peptides were identified via analysis of covariance after adjusting for age and gender, with the significance criteria set at 20% false discovery rate.
  • Figure 3 is a volcano plot using 320 CSF peptides in cognitively impaired subjects.
  • 24/320 CSF AMP peptides were differentially regulated in subjects that are A ⁇ + (AD) vs A ⁇ - (non-AD) comparisons (q ⁇ 0.2).
  • Figure 4 shows a heat map showing 24 significantly altered AMPs (q ⁇ 0.2) in subjects that are A ⁇ + (AD) and A ⁇ - (non-AD) dementia.
  • Figure 5 shows a box plot showing increased expression of antimicrobial peptides from Clusterin (Fig.5A) and Chromogranin A (Fig.5B) proteins in CSF of A ⁇ -driven dementia.
  • MEGENA Multiscale Embedded Gene Co-expression Network Analysis

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Abstract

L'invention concerne des méthodes de diagnostic, de sélection, de surveillance et de traitement de sujets atteints de la maladie d'Alzheimer (MA) ou suspectés d'être atteints de la MA, sur la base de la présence de peptides antimicrobiens (PAM) à des niveaux qui diffèrent de ceux observés chez des individus témoins.
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