CA2562069A1 - Therapeutic combination for treatment of alzheimers disease - Google Patents

Abstract

Pharmaceutical compositions useful for treating Alzheimer~s Disease are disclosed. Methods for treating Alzheimer~s Disease are also disclosed.

Description

THERAPEUTIC COMBINATION FOR TREATMENT OF ALZHEIMER'S
DISEASE
The present application claims priority under 35 U.S.C. section 119(e) to United States Provisional Application Serial Numbers 60,562,141 filed April 16, 2004.
FIELD OF THE INVENTION
The present invention relates to compositions useful for the treatment of Alzheimer's Disease. The invention further relates to methods of using such compositions to treat subjects, including humans, suffering from Alzheimer's Disease.
SACI~GROUND OF THE INVENTION
Alois Alzheimer in 1906 was the first to describe the unique neuropathologic features of what we now call Alzheimer's disease (AD), in the brain of a patient with progressive dementia (Alzheimer A. Ueber eine eigenartige erkrankung der hirnrinele. Z Gesamte Neurol Psyclaiat. 18:177; 1907). Over 5%
of individuals over the age of 65 are estimated to be affected by dementia (Hofman A, Rocca WA, Brayne C, Breteler MM, Clarke M, Cooper B, et al. The prevalence of dementia in Europe: A collaborative study of 1980-1990 findings.
EURODEM Prevalence Research Group. hit T Epidemiol, 20(3): 736-748; 1991).
Between 60 and 70% of dementias are attributed to Alzheimer's disease ("AD").
According to the Alzheimer's Association, one in ten people over 65 years of age, and nearly half of those over 85 years of age suffer from AD. Currently, over million Americans suffer from this disease. It is estimated that this number will increase to 14 million in the year 2050 (Brookmeyer R and Gray S. Methods for projecting the incidence and prevalence of chronic diseases in aging populations:
Application to Alzheimer's disease. Stat Med, 19(11-12): 1481-1493; 2000).
Alzheimer's disease is a chronic neurodegenerative disorder that is manifested by cognitive declines in learning and memory. It is accompanied by diffuse structural abnormalities in the brain. A growing body of evidence suggests that beta amyloid (A(3) plays an important role in this multifactorial degenerative process (De Strooper B and Annaert W. Proteolytic processing and cell biological functions of the amyloid precursor protein. J Cell Sci, 113:1857-1870; 2000).
However, in a review by Emmerling and co-workers (Emmerling MR, Spiegel K, Hall ED, LeVine H, Walker LC, Schwarz RD and Gracon S. Emerging strategies for the treatment of Alzheimer's disease at the Millennium. Errzerging Drugs, 4:35-86; 1999), they described AD as "...no longer viewed solely as a disease of neurotransmitter deficits or amyloid deposition. Rather, it is a combination of events (amyloidosis, neurofibrillary pathology, inflammation, oxidative stress and cerebral vascular insufficiency) that conspire to produce this dementia."
Acetylcholine esterase inhibitors are known to be useful in the treatment of AD. Examples of known acetylcholine esterase inhibitors include donepezil (Aricept°), tacrine (Cognex°), rivastigmine (Exelon°) and galantamine (Reminyl).
Aricept" is disclosed in the following U.S. patents, all of which are fully incorporated herein by reference: 4,895,841, 5,985,864, 6,140,321, 6,245,911 and 6,372,760. Exelori is disclosed in U.S. Patent Nos. 4,948,807 and 5,602,176 which are fully incorporated herein by reference.
Cognex ° is disclosed in U.S. Patent Nos. 4,631,286 and 4,816,456 (fully incorporated herein by reference). Remynil° is disclosed in U.S. Patent Nos.
4,663,318 and 6,099,863 which are fully incorporated herein by reference.
Cholesterol may play an important role in the development and progression of AD. The synthesis and secretion of various lipid particles occurs differentially in the periphery and the brain. Importantly, further research is needed to understand the potentially critical role of transport and metabolism of lipid particles both in the periphery and the brain in AD (Beisiegel U and Spector AA. Lipids and lipoproteins in the brain. Current Opinion iy~ Lipidology, 12:243-244; 2001).
Cholesterol modulates the processing of amyloid precursor protein (APP) and associated A(3 production as demonstrated through in vitro and animal model studies (Emmerling MR, Spiegel K, Hall ED, LeVine H, Walker LC, Schwarz RD
and Gracon S. Emerging strategies for the treatment of Alzheimer's disease at the Millennium. Emerging Drags, 4:35-86; 1999). Excess cholesterol in culture or animal diet results in an increase in processing of amyloid precursor protein (APP) and production of A/3. Removing cholesterol from culture or animal diets results in a reduction in the processing of APP and production of A[3 (Bergmann C, Runz H, Jakala P and Hartmann T. Diversification of gamma secretase versus beta-secretase inhibition by cholesterol depletion. Neurobiol Agif2g, 21:5278;
2000).
Statins inhibit de novo synthesis by blocking a critical step in the pathway, conversion of HMG-CoA to mevalonate. Lowering cholesterol through HMG-CoA-reductase inhibitors, known as statins, has a similar effect on the processing of APP and the production of A[3 (Austen BM, Frears ER and Davies H.
Cholesterol upregulatr es production of Abeta 1-40 and 1-42 in transfected cells.
Neurobiol Agifzg, 21:5254; 2000).
In normal human subjects treated with, for example, lovastatin, serum A(3 concentrations are reduced in a dose-dependent manner (Friedhoff LT, Cullen EI, Geoghagen NS, Buxbaum JD. Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A[3) peptide. Int J
Neuropsych~plZariaaacol., 4(2):127-30; June 2001). These data suggest that a lowering of serum cholesterol is correlated with a reduction in APP and (3 amyloid. Such reduction could result in a modification of disease progression and an improvement in cognitive and behavioral function.
It has been suggested that the role of serum ApoE in the development of AD may not be through cholesterol, but more directly on A[3 aggregation (Golde TE and Eckman CB. Cholesterol modulation as an emerging strategy for the treatment of Alzheimer's disease. Drug Discovery T~day, 6(2): 1049-1055;
2001).
Advancing age, female gender and family history are clear risk factors for AD.
Additional rislc factors include smoking, body mass, blood pressure, and lipid values. However, as the disease progresses, the relative importance of these risk factors may change (Corti MC, Guralnile JM, Salive ME, Harris T, Ferrucci L, Glynn RJ, Havlik RJ. Clarifying the direct relation between total cholesterol levels and death from coronary heart disease in older persons. Alan Intern Med, 126:753-760; 1997). In general, the diagnosis of AD is associated with raised serum cholesterol several decades earlier (Kivipelto M, Hellcala EL, Heanninen T and others. Midlife vascular,risk factors and late-life mild cognitive impairment -A
population-based study. Neurology, 322:1447-1451; 2001).
Early work by Sparks and co-workers (Sparks, DL, Hunsaker JC and others. Cortical senile plaques in coronary artery disease, aging and Alzheimer's disease. Neurobiology ofAgif2g, 11(6): 601-607; 1990) demonstrated AD-like neuropathologic lesions in non-demented CAD patients. Epidemiological work has demonstrated an association between high fat diets and the risk of AD
(Desmond DW, Tatemichi TK, Paik M, Stern Y. Risk factors for cerebrovascular disease as correlates of cognitive function in a stroke-free cohort. Arch Neurol, 50:162-166; 1993). Diets that are so-called cardioprotective have been shown to reduce the risk of developing AD (Forette F, Seux ML, Staessen JA and others.
Prevention of dementia in randomized double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Layzcet, 352:1347-1351; 1998).
' Recent retrospective studies point to a positive relationship between the use of cholesterol-lowering agents, namely statins, and a reduction in cholesterol and risk of developing AD (Dick H, Zornberg GL, Jick SS, Seshadri S and Drachman DA. Statins and the risk of dementia. Tlae LayZeet, 356:1627-1631;
2000).
Atorvastatin is a member of the statin class of lipid regulators for use in the treatment of hypercholesterolemia. United States Patent No. 4,681,893 (fully incorporated herein by reference) and United States Patent No. 5,273,995 (fully incorporated herein by reference) disclose atorvastatin (Lipitox°).
Other statins include lovastatin, fluvastatin, cerivastatin, pravastatin, simvastatin and rosuvastatin.

SCARY OF THE INVENTION
The present invention provides a pharmaceutical composition comprising an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; an amount of atorvastatin or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.
The present invention further provides a method for treating a mammal suffering from Alzheimer's Disease comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof;
and a therapeutically effective amount of a second compound, said second compound being atorvastatin or a pharmaceutically acceptable salt thereof.
Further provided is a method for preventing Alzheimer's Disease in a mammal comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being atorvastatin or a pharmaceutically acceptable salt thereof.
Further provided is a method for treating a mammal which has been diagnosed as suffering from Alzheimer's Disease or the risk of Alzheimer's Disease, which would benefit from therapy by the combined administration of both (a) and (b) below, and therefore administration of both (a) and (b) has been prescribed, which comprises administering to said mammal so diagnosed and prescribed an amount of a first active ingredient (a), said first active ingredient (a) being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and an amount of a second active ingredient (b), said second active ingredient (b) being atorvastatin or a pharmaceutically acceptable salt thereof wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.
Further provided is a method for treating or preventing Alzheimer's Disease in a mammalwhich has been examined for Alzheimer's Disease by a medical practitioner and diagnosed as in need of therapy for said Alzheimer's Disease by the joint administration of the active ingredients designated as (a) and (b) below, which comprises a therapeutically effective amount of a first active ingredient (a), said first active ingredient (a) being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second active ingredient (b), said second active ingredient (b) being atorvastatin, or a pharmaceutically acceptable salt thereof;
wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.
Further provided is a kit for acheiving a therapeutic effect in a mammal comprising a therapeutically effective amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form; a therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form;
and container means for containing said first and second dosage forms.
Further provided is a first pharmaceutical composition for use with a second pharmaceutical compostion for achieving an Alzheimer's Disease-modifying effect in a mammal suffering from Alzheimer's Disease, which Alzheimer's Disease-modifying effect is greater than the sum of the effects achieved by administering said first and second pharmaceutical compositions separately wherein said first pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, and wherein said second pharmaceutical composition comprises and an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable carrier or diluent.
Further provided is a pharmaceutical composition comprising an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof;
an amount of a statin or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.
Further provided is a method for treating a mammal suffering from Alzheimer's Disease comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being a statin or a pharmaceutically acceptable salt thereof.
Further provided is a method for preventing Alzheimer's Disease in a mammal comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being a statin or a pharmaceutically acceptable salt thereof.
Further provided is a method for treating a mammal which has been diagnosed as suffering from Alzheimer's Disease or the risk of Alzheimer's Disease, which would benefit from therapy by the combined administration of both (a) and (b) below, and therefore administration of both (a) and (b) has been prescribed, which comprises administering to said mammal so diagnosed and prescribed an amount of a first active ingredient (a), said first active ingredient (a) being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and an amount of a second active ingredient (b), said second active ingredient (b) being a statin or a pharmaceutically acceptable salt thereof wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.
Further provided is a method for treating or preventing Alzheimer's Disease in a mammal which has been examined for Alzheimer's Disease by a medical practitioner and diagnosed as in need of therapy for said Alzheimer's Disease by the joint administration of the active ingredients designated as (a) and (b) below, which comprises a therapeutically effective amount of a first active ingredient (a), said first active ingredient (a) being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second active ingredient (b), said second active ingredient (b) being a statin, or a pharmaceutically acceptable salt thereof;
wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.

Further provided is a kit for acheiving a therapeutic effect in a mammal comprising a therapeutically effective amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form; a therapeutically effective amount of a statin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form;
and container means for containing said first and second dosage forms.
Further provided is a first pharmaceutical composition for use with a second pharmaceutical composition for achieving an Alzheimer's Disease-modifying effect in a mammal suffering from Alzheimer's Disease, which Alzheimer's Disease-modifying effect is greater than the sum of the effects achieved by administering said first and second pharmaceutical compositions separately wherein said first pharmaceutical composition comprises an amount of a statin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, and wherein said second pharmaceutical composition comprises and an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable carrier or diluent.
The present invention further provides a pharmaceutical composition comprising an amount of donepezil or a pharmaceutically acceptable salt thereof;
an amount of atorvastatin or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.
Further provided is a method for treating a mammal suffering from Alzheimer's Disease comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being donepezil or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being atorvastatin or a pharmaceutically acceptable salt thereof.
Further provided is a method for preventing Alzheimer's Disease in a mammal comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being donepezil or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being atorvastatin or a pharmaceutically acceptable salt thereof.

Further provided is a method for treating a mammal which has been diagnosed as suffering from Alzheimer's Disease or the risk of Alzheimer's Disease, which would benefit from therapy by the combined administration of both (a) and (b) below, and therefore administration of both (a) and (b) has been prescribed, which comprises administering to said mammal so diagnosed and prescribed, an amount of a first active ingredient (a), said first active ingredient (a) being donepezil or a pharmaceutically acceptable salt thereof; and an amount of a second active ingredient (b), said second active ingredient (b) being atorvastatin or a pharmaceutically acceptable salt thereof wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.
Further provided is a method for treating Alzheimer's Disease in a mammal which has been examined for Alzheimer's Disease by a medical practitioner and diagnosed as in need of therapy for said Alzheimer's Disease by the joint administration of the active ingredients designated as (a) and (b) below, which comprises a therapeutically effective amount of a first active ingredient (a), said first active ingredient (a) being donepezil or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second active ingredient (b), said second active ingredient (b) being atorvastatin, or a pharmaceutically acceptable salt thereof; wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.
Further provided is a kit for acheiving a therapeutic effect in a mammal comprising a therapeutically effective amount of donepezil or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form; a therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and container means for containing said first and second dosage forms.
Further provided is a first pharmaceutical composition for use with a second pharmaceutical compostion for achieving an Alzheimer's Disease-modifying effect in a mammal suffering from Alzheimer's Disease, which Alzheimer's Disease-modifying effect is greater than the sum of the effects achieved by administering said first and second pharmaceutical compositions separately wherein said first pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, and wherein said second pharmaceutical composition 5 comprises and an amount of donepezil or a pharmaceutically acceptable carrier or diluent.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a pharmaceutical composition comprising an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; an amount of atorvastatin or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.
Further provided is the above composition comprising the hemicalcium salt of atorvastatin.
Further provided is the above composition comprising from about 0.2 mg.
to about 20 mg. of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof and about 5 mg. to about 80 mg. of atorvastatin or a pharmaceutically acceptable salt thereof.
Further provided is the pharmaceutical composition comprising a fixed combination selected from the group consisting of: atorvastatin calcium, 5 mg active and an acetylcholine esterase inhibitor, 10 mg active; atorvastatin calcium, 10 mg active and an acetylcholine esterase inhibitor, 10 mg active;
atorvastatin calcium, 20 mg active and an acetylcholine esterase inhibitor, 10 mg active;
atorvastatin calcium, 40 mg active and an acetylcholine esterase inhibitor, 10 mg active; atorvastatin calcium, 80 mg active and an acetylcholine esterase inhibitor, 10 mg active; atorvastatin calcium, 5 mg active and an acetylcholine esterase inhibitor, 5 mg active; atorvastatin calcium, 10 mg active and an acetylcholine esterase inhibitor, 5 mg active; atorvastatin calcium, 20 mg active and an acetylcholine esterase inhibitor, 5 mg active; atorvastatin calcium, 40 mg active and an acetylcholine esterase inhibitor, 5 mg active; and atorvastatin calcium, 80 mg active and an acetylcholine esterase inhibitor, 5 mg active.
Further provided is a method for treating a mammal suffering from Alzheimer's Disease comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being atorvastatin or a pharmaceutically acceptable salt thereof.
Further provided is a method for preventing Alzheimer's Disease in a mammal comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being atorvastatin or a pharmaceutically acceptable salt thereof.
Further provided is a method for treating a mammal which has been diagnosed as suffering from Alzheimer's Disease or the risk of Alzheimer's Disease, which would benefit from therapy by the combined administration of both (a) and (b) below, and therefore administration of both (a) and (b) has been prescribed, which comprises administering to said mammal so diagnosed and prescribed an amount of a first active ingredient (a), said first active ingredient (a) being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and an amount of a second active ingredient (b), said second active ingredient (b) being atorvastatin or a pharmaceutically acceptable salt thereof wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.
Further provided is a method for treating or preventing Alzheimer's Disease in a mammal which has been examined for Alzheimer's Disease by a medical practitioner and diagnosed as in need of therapy for said Alzheimer's Disease by the joint administration of the active ingredients designated as (a) and (b) below, which comprises a therapeutically effective amount of a first active ingredient (a), said first active ingredient (a) being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second active ingredient (b), said second active ingredient (b) being atorvastatin, or a pharmaceutically acceptable salt thereof;
wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.
Further provided is a kit for acheiving a therapeutic effect in a mammal comprising a therapeutically effective amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form; a therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form;
and container means for containing said first and second dosage forms.
Further provided is a first pharmaceutical composition for use with a second pharmaceutical compostion for achieving an Alzheimer's Disease-modifying effect in a mammal suffering from Alzheimer's Disease, which Alzheimer's Disease-modifying effect is greater than the sum of the effects achieved by administering said first and second pharmaceutical compositions separately wherein said first pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, and wherein said second pharmaceutical composition comprises and an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable carrier or diluent.
Further provided is a method for stabilizing symptoms of Alzheimer's Disease i~ a mammal requiring stabilization comprising administering to said mammal a stabilizing amount of the above-described pharmaceutical composition.
Further provided is the method wherein said stabilization is assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).
Further provided is the method wherein said stabilization is assessed by the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change scale (ADCS-CGIC).
Still further, the present invention provides a pharmaceutical composition comprising an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; an amount of a statin or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.
Further provided is the above pharmaceutical composition comprising from about 0.2 mg. to about 20 mg. of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof and about 5 mg. to about 80 mg. of a statin or a. pharmaceutically acceptable salt thereof.
Further provided is the above pharmaceutical composition comprising a fixed combination selected from the group consisting of: a statin, 5 mg active and an acetylcholine esterase inhibitor, 10 mg active; a statin, 10 mg active and an acetylcholine esterase inhibitor, 10 mg active; a statin, 20 mg active and an acetylcho>line esterase inhibitor, 10 mg active; atorvastatin calcium, 40 mg active and an acetylcholine esterase inhibitor, 10 mg active; a statin, 80 mg active and an acetylcholine esterase inhibitor, 10 mg active; a statin, 5 mg active and an acetylcholine esterase inhibitor, 5 mg active; a statin, 10 mg active and an acetylcholine esterase inhibitor, 5 mg active; a statin, 20 mg active and an acetylcholine esterase inhibitor, 5 mg active; a statin, 40 mg active and an acetylcholine esterase inhibitor, 5 mg active; and a statin, 80 mg active and an acetylcholine esterase inhibitor, 5 mg active.
Further provided is a method for treating a mammal suffering from Alzheimer's Disease comprising administering to said mammal:a therapeutically effective amount of a first compound, said first compound being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being a statin or a pharmaceutically acceptable salt thereof.
Further provided is a method for preventing Alzheimer's Disease in a mammal comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being a statin or a pharmaceutically acceptable salt thereof.
Further provided is a method for treating a mammal which has been diagnosed as suffering from Alzheimer's Disease or the risk of Alzheimer's Disease, which would benefit from therapy by the combined administration of both (a) and (b) below, and therefore administration of both (a) and (b) has been prescribed, which comprises administering to said mammal so diagnosed and prescribed an amount of a first active ingredient (a), said first active ingredient (a) being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and an amount of a second active ingredient (b), said second active ingredient (b) being a statin or a pharmaceutically acceptable salt thereof wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.
Further provided is a method for treating or preventing Alzheimer's Disease in a mammal which has been examined for Alzheimer's Disease by a medical practitioner and diagnosed as in need of therapy for said Alzheimer's Disease by the joint administration of the active ingredients designated as (a) and (b) below, which comprises a therapeutically effective amount of a first active ingredient (a), said first active ingredient (a) being an acetylcholine esterase 5 inhibitor or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second active ingredient (b), said second active ingredient (b) being a statin, or a pharmaceutically acceptable salt thereof; wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically 10 acceptable carrier or diluent.
Further provided is a kit for acheiving a therapeutic effect in a mammal comprising a therapeutically effective amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable Garner or diluent in a first unit dosage form; a therapeutically effective 15 amount of a statin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form;
and container means for containing said first and second dosage forms.
Further provided is a first pharmaceutical composition for use with a second pharmaceutical composition for achieving an Alzheimer's Disease-modifying effect in a mammal suffering from Alzheimer's Disease, which Alzheimer's Disease-modifying effect is greater than the sum of the effects achieved by administering said first and second pharmaceutical compositions separately wherein said first pharmaceutical composition comprises an amount of a statin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or d.iluent, and wherein said second pharmaceutical composition comprises and an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable carrier or diluent.
Further provided is a method for stabilizing symptoms of Alzheimer's Disease in a mammal requiring stabilization comprising administering to said mammal a stabilizing amount of the above-described pharmaceutical composition.
Further provided is the above method wherein said stabilization is assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).

Further provided is the method wherein said stabilization is assessed by the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change scale (ADCS-CGIC).
Still further, the present invention provides a pharmaceutical composition comprising an amount of donepezil or a pharmaceutically acceptable salt thereof;
an amount of atorvastatin or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable Garner or diluent.
Further provided is the above pharmaceutical composition comprising the hemicalcium salt of atorvastatin. Further provided is the composition comprising donepezil HCl.
Further provided is the above pharmaceutical composition comprising from about 0.2 mg. to about 20 mg. of donepezil or a pharmaceutically acceptable salt thereof and about 5 mg. to about 80 mg. of atorvastatin or a pharmaceutically acceptable salt thereof.
Further provided is the above pharmaceutical composition comprising a fixed combination selected from the group consisting of atorvastatin calcium, mg active and donepezil, 10 mg active; atorvastatin calcium, 10 mg active and donepezil, 10 mg active; atorvastatin calcium, 20 mg active and donepezil, 10 mg active; atorvastatin calcium, 40 mg active and donepezil, 10 mg active;
atorvastatin calcium, 80 mg active and donepezil, 10 mg active; atorvastatin calcium, 5 mg active and donepezil, 5 mg active; atorvastatin calcium, 10 mg active and donepezil, 5 mg active; atorvastatin calcium, 20 mg active and donepezil, 5 mg active; atorvastatin calcium, 40 mg active and donepezil, 5 mg active; and atorvastatin calcium, 80 mg active and donepezil, 5 mg active.
Further provided is a method for treating a mammal suffering from Alzheimer's Disease comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being donepezil or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being atorvastatin or a pharmaceutically acceptable salt thereof.
Further provided is a method for preventing Alzheimer's Disease in a mammal comprising administering to said mammal a therapeutically effective amount of a first compound, said first compound being donepezil or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second compound, said second compound being atorvastatin or a pharmaceutically acceptable salt thereof.
Further provided is the above method comprising the hemicalcium salt of atorvastatin. Further provided is the method comprising donepezil HCI.
Further provided is a method for treating a mammal which has been diagnosed as suffering from Alzheimer's Disease or the risk of Alzheimer's Disease, which would benefit from therapy by the combined administration of both (a) and (b) below, and therefore administration of both (a) and (b) has been prescribed, which comprises administering to said mammal so diagnosed and prescribed an amount of a first active ingredient (a), said first active ingredient (a) being donepezil or a pharmaceutically acceptable salt thereof; and an amount of a second active ingredient (b), said second active ingredsent (b) being atorvastatin or a pharmaceutically acceptable salt thereof wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.
Further provided is the above method wherein the active ingredient (b) is the hemicalcium salt of atorvastatin. Further provided is the method wherein the active ingredient (a) is donepezil HCI.
Further provided is a method for treating Alzheimer's Disease in a mammal which has been examined for Alzheimer's Di sease by a medical practitioner and diagnosed as in need of therapy for said Alzheimer's Disease by the joint administration of the active ingredients designated as (a) and (b) below, which comprises a therapeutically effective amount of a first active ingredient (a), said first active ingredient (a) being donepezil or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a second active ingredient (b), said second active ingredient (b) being atorvastatin, or a pharmaceutically acceptable salt thereof; wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.
Further provided is the above method wherein the active ingredient (b) is the hemicalcium salt of atorvastatin. Further provided is the method wherein the active ingredient (a) is donepezil HCI.

Further provided is a kit for acheiving a therapeutic effect in a mammal comprising a therapeutically effective amount of donepezil or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form; a therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and container means for containing said first and second dosage forms.
Further provided is a first pharmaceutical composition for use with a second pharmaceutical compostion for achieving an Alzheimer's Disease-modifying effect in a mammal suffering from Alziheimer's Disease, which Alzheimer's Disease-modifying effect is greater than the sum of the effects achieved by administering said first and second pharmaceutical compositions separately wherein said first pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, and wherein said second pharmaceutical composition comprises and an amount of donepezil or a pharmaceutically acceptable carrier or diluent.
Further provided is a method for stabilizing symptoms of Alzheimer's Disease in a mammal requiring stabilization comprising administering to said mammal a stabilizing amount of the above-described pharmaceutical composition.
Further provided is the above method whe:~rein said stabilization is assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).
Further provided is the above method wherein said stabilization is assessed by the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change scale (ADCS-CGIC).
One embodiment of the present invention is an improved method for stabilizing symptoms of Alzheimer's disease in a mammal in need of stabilization comprising administering atorvastatin plus the acatylcholinesterase inhibitor donepezil, which is improved over treatment with a donepezil alone, as measured by cognition and global function, in particular as assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change scale (ADCS-CGIC), respectively. As used herein, "stabilizing" means no further decline in the above referenced measures (ADAS-Cog and ADCS-CGIC) over t>Eme.
A further embodiment of the invention is a pharmaceutical formulation of combined statin, for example, atorvastatin plus an acetylcholinesterase inhibitor (for example, donepezil) having an AD-disease-modifying effect.
A further embodiment of this invention is a pharmaceutical formulation of a combination of a statin, for example, atorvastatin, plus an acetylcholine esterase inhibitor, for example, donepezil, that siginificantly slows the progression and reduces the deterioration of Alzheimer's Disease.
"Combined treatment" as used herein means administering a statin, for example, atorvastatin and an acetylcholine esterase inhibitor, for example, donepezil together in a single pharmaceutical compositon with a pharmaceutically acceptable carrier or diluent.
"Alzheimer's Disease modifying effect" or "stabilization" as used herein means no further decline in AD symptoms in a mammal suffering from AD. An "Alzheimer's Disease stabilizing amount" as used herein means the dosage required to achieve such stabilization of AD symptioms in such mammal.
Other clinical measures of AD as well as the disease-modifying effects of an AD treatment regime include the following: behavior, as measured by the Neuropsychiatric Inventory (NPI); general cognitive status, as measured by the Mini Mental Status Examination (MMSE); overall dementia severity as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB); and daily function as assessed by the Alzheimer's Disease Functional Assessment and Change Scale (ADFACS).
Further, measuring brain volume and metabolism through MRI and MRS
provides indication of disease modifying effects of an AD treatment regime.
MRI
measures include whole brain, ventricular, and hippocampal volumes. MRS
measures include N-acetylaspartate (NAA) and myoinositol (MI). Evidence of disease modification is demonstrated by differences between treatment groups in these measures.

Further, measuring peripheral biomarkers of AD, specifically plasma levels of ~i-amyloid peptide (A(31-40, A(31-42), cerebrosterol (24S-hydroxycholesterol), and S 100b provide indication of disease-modifying effects of an AD treatment regime. Evidence of disease modification is demonstrated by 5 differences between treatment groups in these measures.
As used herein, the term "patient" means all mammals including humans.
Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits.
A "therapeutically effective amount" is an amount of a compound of the 10 present invention that when administered to a patient ameliorates a symptom of AD.
The term "a pharmaceutically acceptable salt" refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolati on 15 and purification of the compounds or by separately reacting the purified compound in its free form with a suitable organic or inorganic acid or base and isolating the salt thus formed. Representative salts include the hydrobromid_e, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, 20 maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate~
lactobionate, and laurylsulphonate salts, and the like. These may include canons based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine rations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, Berge S.M., et al., "Pharmaceutical Salts," J. Plaann. Sri., 1977;66:1-19, which is incorporated herein by reference.) The free base form may be regenerated by contacting the salt form with a base. While the free base may differ from the salt form in terms of physical properties, such as solubility, the salts are equivalent to their respective free bases for the purposes of the present invention.

The compositions of the present invention are suitable to be administered to a patient for the treatment, control, or prevention of Alzheimer's Disease.
The terms "treatment", "treating", "controlling", "preventing" and the like, refers to reversing, alleviating, or inhibiting the progress of the disease or condition to which such term applies, or one or more symptoms of such disease or condition.
As used herein, these terms also encompass, depending on the condition of the patient, preventing the onset of a disease or condition or of symptoms associated with a disease or condition, including reducing the severity of a disease or condition or symptoms associated therewith prior to affliction with said disease or condition. Such prevention or reduction prior to affliction refers to administration of the compound of the invention to a subject that is not at the time of administration afflicted with the disease or condition. "Preventing" also encompasses preventing the recurrence of a disease or condition or of symptoms associated therewith. Accordingly, the compositions of the present invention can be administered to a patient alone or as part of a composition that contains other components such as excipients, diluents, and carners, all of which are well-known in the art. The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, as for example paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite;
and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, .
polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
In general, statins are administered in the following dosage amounts:
simvastatin, generally about 2.5 mg to about 160 mg and preferably about 10 mg to about 40 mg; pravastatin, generally about ~.5 mg to about 160 mg and preferably about 10 mg to about 40 mg; cerivastatin, generally about 25 micrograms to about 5 mg and preferably about 1 mg to about 3.2 mg;
fluvastatin, generally about 2.5 mg to about 160 mg and preferably about 20 mg to about 80 mg; lovastain, generally about 2.5 mg to about 160 mg and preferably about 10 mg to about 80 mg; and atorvastatin, generally about 2.5 mg to about 160 mg and preferably about 10 mg to about 80 mg.
The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well-known to those skilled in the art.
Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).
Since the present invention has an aspect that related to the treatment of the disease/conditions described herein with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositins: a compound of the present inventino, a prodrug thereof or a salt of such compound or prodrug and a second compound as described above. The hit comprises means for containing the separate compositions such as a container, a divided bottle or a divided foil packet.
Typically, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and paxenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparetn plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shpae of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the stheet of relatively stiff material is sealed against the plastic foil at the fact of the foil which is opposite from the direction in which the recesses were formed.
As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such taht the tablets or 5 capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess.
The tablet or capsule can then be removed via said opening.
It mat be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the 10 days of the regimen which the tablets or capsules so specified should be ingested.
Another example of such a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, ...etc... Second Week, Monday, Tuesday,..." etc. Other variations of memory aids will be readily apparent. A
"daily dose" can be a single tablet or capsule or several pills or capsules to be 15 taken on a given day, Also, a daily dose of compounds of the present invention can consist of one tablet or capsule whit a daily dose of the second compound can consist of several tablets or capusles and vice versa. The memory aid should reflect this.
In another specific embodiment of the invention, a dispenser designed to 20 dispense the daily doses one at a time in the order of their inteded use i s provided.
Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed.
Another example of such a memory-aid is a battery-powered micro-chip memory 25 coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
FORMULATIONS
The compositions of the present invention can be administered alone or in combination with one or more therapeutic agents. These include, for example, other agents for treating, preventing or controlling Alzheimer's Disease.

The compositions are thus well suited for convenient administration to mammals for the prevention and treatment of AD.
The following examples further illustrate typical formulations of the compositions provided by the invention. As used herein, "compound" means an acetylcholine esterase inhibitor or a statin, including donepezil and atorvastatin, respectively.
Formulation 1 Ingredient Amount compound 1 5 to 80 mg compound 2 5 to 80 mg sodium benzoate 5 mg isotonic saline 1000 mL

The above ingredients are mixed and dissolved in the saline for IV
administration to a patient.
Formulation 2 Ingredient Amount compound 1 5 to 80 mg compound 2 5 to 80 mg cellulose, microcrystalline400 mg stearic acid 5 mg silicon dioxide 10 mg sugar, confectionery50 mg The above ingredients are blended to uniformity and pressed into a tablet that is well suited for oral administration to a patient.
Formulation 3 Amount In redient compound 1 5 to 80 mg compound 2 5 to 80 mg Starch, dried 250 mg magnesium stearate 10 mg The above ingredients are combined and milled to afford material suitable for filling hard gelatin capsules administered to a patient.
Formulation 4 Ingredient Amount % wt./(total wt.) Compound 1 5 to 80 mg Compound 2 5 to 80 mg 32 to 75 Polyethylene lyco11000 Polyethylene glycol 4000 16 to 25 The above ingredients are combined via melting and then poured into molds.
While embodiments of the invention have been illustrated and described, it is not intended that these embodiments illustrate and describe all possible forms of the invention. Rather, the words used in the specification are words of description rather than limitation, and it is understood that various changes may be made without departing from the spirit and scope of the invention.
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Coy) The ADAS-Cog is an 11-item scale designed to assess the severity of cognitive impairments in AD patients. Items include word recall, naming objects and fingers, following commands, constructional praxis, ideational praxis, orientation, word recognition, spoken language ability, comprehension of spoken language, word finding difficulty in spontaneous speech, and remembering test instructions. Total scores range from 0-70, with 70 indicating worse cognition.
For this study, two additional items have been added to the ADAS-Cog. These are delayed word recall and concentration/distractibility. When these two additional items are combined with the original 11-item ADAS-Cog, the instrument will be referred to as the Modified ADAS-Cog.

Alzheimer's Disease Cooperative Study Clinical Global Impression of Change scale (ADCS-CGIC) The ADCS-CGIC is the ADCS version of a clinician's interview based impression of change plus caregiver input (CIBIC-Plus). It is a global rating of change in patient function derived through comprehensive interviews of the subject and caregiver by an independent clinician.
Clinical Dementia Rating-Sum of Boxes (CDR-SB) The CDR-SB is a measure of dementia severity in six domains that assess cognition and function: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.
Neuropsychiatric Inventory (NPI) The Neurogsychiatric Inventory (NPI) is a 12-item scale of behavioral disturbances commonly occurring in dementia subjects: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritabilityllability, aberrant motor activity, sleep, and appetite and eating disorders. Through a structured interview with the caregiver, each of the 12 behaviors is assessed. The frequency (0-4) and severity (0-3) of each behavior are determined and multiplied for a total score of 0-144.
Higher scores indicate more psychopathology. In addition, the degree of caregiver distress (0-5) is also determined for each behavior.
Alzheimer's Disease Functional Assessment and Change Scale (ADFACS) The ADFACS is a 16-item functional assessment instrument based on instrumental and basic activities of daily living (ADL) scales commonly used in clinical research. It includes 6 basic ADLs (toileting, feeding, dressing, personal hygiene and grooming, bathing and walking) and 10 instrumental ADLs (ability to use the telephone, household tasks, using household appliances, handling money, shopping, food preparation, ability to get around inside and outside home, hobbies and leisure activities, handling personal mail, and grasp of situations or explanations). The assessment of each item is based on an interview of the subject's caregiver. Each of the basic ADL items is scored on a scale of 0 (no impairment) to 4 (very severe impairment), giving a basic ADL total score of 0-24. Each of the instrumental ADL items is scored on a scale of 0 (no impairment) to 3 (severe impairment) giving an instrumental ADL total score of 0-30. The overall 16 item ADFACS therefore has a total score range of 0 -54.
Mini-Mental State Examination (MMSE):
The MMSE is a brief, widely used test for assessing overall cognitive state. The MMSE measures selected aspects of cognition such as memory, orientation, attention, language, and praxis on a scale of 0-30. Lower scores indicate greater cognitive impairment.
Modified Alzheimer's Disease Assessment Scale-Cognitive Subscale (Modified ADAS-Coy):
The Modified ADAS-Cog is the same instrument as the 11-item ADAS-Cog described above with the addition of two items - Delayed Word Recall and Concentration/Distractibility.
Clinical Dementia Rating-Sum of Boxes (CDR-SB):
The CDR-SB is a measure of dementia severity in six domains that assess cognition and function: memory, orientation, judgment and problem solving, community affairs, and home and hobbies. The rating for each domain will be agreed upon by the subject's assessment team (excluding the clinician conducting the ADCS-CGIC) after consideration of the results from all tests conducted during a clinic visit. The CDR-SB consensus discussion should include the interview notes and rating of the ADCS-CGIC interviewer, but the ADCS-CGIC interviewer does not participate in the CDR-SB discussion. The ratings in each of the domains are summed to provide a global clinical measure, the Sum of the Boxes.
Neuropsychiatric Inventory (NPI):
The Neuropsychiatric Inventory (NPI) is a 12-item scale of behavioral disturbances commonly occurring in dementia subjects: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathylindifference, disinhibition, irritability/lability, aberrant motor activity, sleep, and appetite and eating. Through a structured interview with the caregiver, each of the 12 behaviors is assessed. The frequency (0-4) and severity (0-3) of each behavior are determined and multiplied for a total score of 0-144. Higher scores indicate more psychopathology. In addition, the degree of caregiver distress (0-5) is also determined for each behavior.
Alzheimer's Disease Functional Assessment and Change Scale 5 (ADFACS):
The ADFACS is a 16-item functional assessment instrument based on instrumental and basic activities of daily living (ADL) scales commonly used in clinical research. It includes 6 basic ADLs (toileting, feeding, dressing, personal hygiene and grooming, bathing and walking) and 10 instrumental ADLs (use of 10 telephone, household tasks, using household appliances, managing money, shopping, food preparation, ability to get around inside and outside home, hobbies and leisure activities, handling personal mail, and grasp of situations or explanations). The assessment of each item is based on an interview of the subject's caregiver. Each of the basic ADL items is scored on a scale of 0 (no 15 impairment) to 4 (very severe impairment), giving a basic ADL total score of 0-24. Each of the instrumental ADL items is scored on a scale of 0 (no impairment) to 3 (severe impairment) giving an instrumental ADL total score of 0-30. The overall 16 item ADFACS therefore has a total score range of 0 -54.
Disease Modification 20 Withdrawal Phase:
The randomized withdrawal design has been proposed (Leber 1996, 1997) as a study design to assess drug-induced changes in the progression of AD
(Leber P. Observations and suggestions on antidementia drug development. Alzheimer 25 Disease afzd Associated Disorders, 10(1):S31-535; 1996). The International Working Group on the Harmonization of Guidelines (in AD) endorsed this concept (Bodick N, Forette F, Hadler D, et al. Protocols to demonstrate the slowing of Alzheimer's disease progression. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines. The Disease 30 Progression Sub-Group. Alzlzei>7zer Dis Assoc Disord, 11 (suppl 3): 50-3;
1997.) In the randomized withdrawal design, following treatment with a potential disease-modifying agent for sufficient duration, active treatment is withdrawn (subgroup of subjects remain on active treatment, and a subgroup is withdrawn). If the treatment, (for example, in this case atorvastatin), has only a symptomatic effect, then the performance of subjects switched to placebo would be expected to decrease to the level of performance of the subject group that was on placebo from the very beginning. There has been at least one published clinical trial in AD
utilizing this design (Rother M, Erkinjuntti T, Roessner M et al..
Propentofylline in the treatment of Alzheimer's disease and vascular dementia: A review of Phase III trials. Dement Geriatr Cogrz Disord, 9(1):36-43; 1998).
MRI / MRS Substudy: Neuroimaging: Magnetic Resonance Imaging (MRI) / Magnetic Resonance Spectroscopy (MRS) As cognitive decline in AD advances, commensurate changes in brain volume occur, leading to progressive atrophy. Histopathological and radiological studies have shown that there are significant differences between the size of certain brain structures as well as the rate of atrophy between patients with AD and normal controls. As the severity of disease progresses, these changes can be monitored through the use of MRI to measure structural volume as an in vivo measure of gross atrophy (Kesslalc, JP, Nalcioglu O, Cotman CW. Quantification of magnetic resonance scans for hippocampal and parahippocampal atrophy in Alzheimer's disease. Neurology, 41: 57; 1991).
These differences are most marked in areas associated with memory and other cognitive functions. Studies have highlighted the utility of medial temporal lobe structures, and particularly hippocampus, as well as ventricular and whole brain volume to monitor disease progression (Friedhoff LT, Cullen EI, Geoghagen NS, Buxbaum JD. Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A[3) peptide. I~zt J
Neuropsyclzopharmacol., 4(2):127-30; June 2001). Specifically, hippocampal atrophy has been demonstrated to be a sensitive and early indicator of AD, and studies have shown the ability to differentiate between mild to moderate AD
and normal controls with sensitivity and specificity of about 90% each. Moreover, degree of hippocampal atrophy has been shown to correlate with severity of ' memory loss (Laaslco MP, Soininen H, Partanen K et al. MRI of the hippocampus in Alzheimer's disease: sensitivity, specificity and analysis of the incorrectly classified subjects. Neurolobiol Aging, 19: 23-31; 1998).
As treatments for AD are developed, the question remains as to whether such therapies are only symptomatic, or also disease modifying.
With the use of an MRI scanner and specific software, Magnetic Resonance Spectroscopy (MRS) can measure biochemical metabolites in a brain region of interest. In AD, studies have demonstrated particular changes in two metabolites: N-acetyl aspartate (NAA) and myoinositol (MI). NAA, produced primarily by neurons, is a marker of neuronal mitochondrial metabolism and thus neuronal integrity, has been shown to be decreased in various brain regions in AD
patients (Klunk, W, Panchalingam K, Moosy J, McClure R, Pettigrew J. N-acetyl-L aspartate and other amino acid metabolites in Alzheimer's disease brain:
a preliminary proton nuclear magnetic resonance study. Neurology, 42: 1578-1585; 1992). Conversely, MI, generated in astrocytes and a marker of gliosis, has been shown to be increased in this population. Taken together, studies have shown high sensitivity and specificity for identifying patients with mild to moderate AD (Shonk TK, Moats R, Gifford P, Michaelis T, Mandingo JC, Izumi J, Ross BD. Probable Alzheimer's disease: diagnosis with proton MR
spectroscopy. Radiology, 195:65-72; 1995). Thus, such measures could serve as a monitor of disease progression and response to therapy.
The measures of interest from the MRI are global brain atrophy and regional brain atrophy (hippocampal atrophy) as defined by the rate of change in the global or regional volumes, wolumeltime. The measures of interest for the MRS are the change in N-acetylaspartate to creatine (NAA/Cr) and normalized NAA levels in the frontal cortex and occipital cortex, as well as MIICr and MI/NAA and normalized MI levels.
"Peripheral Biomarkers", as used herein, refers to proteins, peptides and lipids, which are found in blood and are implicated in the pathophysiology of Alzheimer's disease.
Peripheral Biomarkers, specifically plasana levels of (3-amyloid peptide (A(31-40, A(31-42), cerebrosterol (24S-hydroxycholesterol), and S 100b are evidence for disease modifying effects of combined statin, e.g., for example, atorvastatin plus an acetylcholinesterase inhibitor (for example, donepezil).
Apolipoprotein B (ApoB), Apolipoprotein E (ApoE) (Davignon T, Gregg RE, Sing CE. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis, 8:1-21;
1988), serum total cholesterol, serum LDL-C, serum VLDL-C, cerebrosterol, triglycerides and HDL-C] and RBC acetylcholinesterase inhibition (RBC AChE-I) are further l~iomarkers of disease modification or progress.
Plasma biomarkers of interest include plasma (3-amyloid peptide (A(31-40, A(31-42), S 100b and 24-hydroxycholesterol (cerebrosterol).
Plasma A(3 levels are elevated in several familial forms of AD and in first-degree relatives of AD patients prior to the onset of disease (Golde TE, Eckman CB, Younlcin SG. Biochemical detection of Abeta isoforms: implications for pathogenesis, diagnosis, and treatment of Alzheimer's disease. Bioclzim Biophys Acta., 26; 1502(1):172-87; 26-July-2000). These findings imply an association of elevated plasma A[3 levels and with risk of AD. A retrospective study in an aged population (average age > 80 years) revealed that subjects with higher plasma A(3 levels had an increased risk for an AD diagnosis over the next 3 years (Mayeux R, Tang MX, Jacobs DM, Manly J, Bell K, Merchant C, Small SA, Stern Y, Wisniewski HM, Mehta PD. Plasma amyloid beta-peptide 1-42 and incipient Alzheimer's disease. Aran Neurol., 46(3): 412-6; Sep 1999). A recent study indicates that the level of plasma A(3 can be reduced in human subjects by treatment with an HMG-CoA reductase inhibitor (Friedhoff LT, Cullen EI, Geoghagen NS, Buxbaum JD. Treatment with controlled-release lovastatin decreases serum concentrations of human beta-amyloid (A[3) peptide. Ifat J
Neuropsychopharrraacol., 4(2):127-30; June 2001).
Cerebrosterol (24 S-hydroxycholesterol) is mostly produced in the brain (Bjorkhem I, Lutjohann D, Diczfalusy U, Stahle L, Ahlborg G, and Wahren J.
Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesteroal and evidence for a cerebral origin of most of this oxysterol in the circulation. J
Lipid Res, 39:1594-1600; 1998), (Bretillon L, Lutjohann D, Stahle L, Widhe T, Bindl L, Eggertsen G, Diczfalusy U, Bjorkhem I), moves across the blood-brain barrier (~lLutjohann D, Breuer O, Ahlborg G and others. Cholesterol homeostasis in human brain: eveidence for an age-dependent flux of 24S-hydroxycholesterol fro~rn the brain into the circulation. Proc Natl Acad Sci USA, 93:9799-9804;
1996) and is found in higher concentrations in the plasma of patients with early-onset AD (Lutjohann D, Papassotiropoulos A, Bjorkhem I and others. Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J Lipid Res, 41:195-198; 2000). Locatelli and co-workers (Locatelli S, Lutjohann D, Schmidt HH, Otto C, Beisiegel U, von Bergmann K.
Reduction of plasma 24S-hydroxycholesterol (cerebrosterol) levels using high-dosage simvastatin in patients with hypercholesterolemia: evidence that simvastatin affects cholesterol metabolism in the human brain. Arch Neurol., 592): 213-6; Feb 2002.) demonstrated that simvastatin reduced total cholesterol and cerebrosterol in the plasma of hypercholesterolemic patients.
S 100b is an intercellular signaling molecule, involved in the regulation of calcium levels (Mrak RE, Griffin WS. The role of activated astrocytes and of the neurotrophic cytokine S 100B in the pathogenesis of Alzheimer's disease.
Neurobiol Agihg, 22(6): 915-22. Review; Nov-Dec 2001). Activated astrocytes hare elevated levels of S 100b resulting from brain injury and inflammation.
The level of S 100b in CSF of mild to moderate AD patients is elevated relative to age-matched control subjects (Peskind ER, Griffin WS, Alcama KT, Raskind MA, Van Eldik LJ. Cerebrospinal fluid S 100B is elevated in the earlier stages of Alzheimer's disease. Neuroche»a lyat., 39(5-6): 409-413; Nov-Dec 2001). An increase in S 100b in brain can also result in elevated levels of S 100b in blood.

As used herein, the following terms have the meanings shown.
AChE Acetylcholinesterase AD Alzheimer's Disease 5 ADAS-Cog Alzheimer's Disease Assessment Scale - Cognitive Subscale ADCS-CGIC Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change ADFACS Alzheimer's Disease Functional Assessment and Change 10 Scale ADL Activities of daily living ADRDA-NINCDS Alzheimer's Disease Diagnostic Criteria for Dementia of the Alzheimer's Type Muliple Cognitive Deficits AE Adverse Event 15 APP Amyloid precursor protein FDA Food and Drug Administration ALT Alanine aminotransferase (ALAT) = Glutamate pyruvate transaminase (GPT) ANCOVA Analysis of covariance 20 ANOVA Analysis of Variance ApoE Apolipoprotein E

AST Aspartate aminotransferase (ASAT) = Glutamate oxalacetate transaminase (GOT) BP Blood pressure 25 BPM Beats per minute BLTN Blood urea nitrogen CAD Coronary artery disease CDR-SB Clinical Dementia Rating-Sum of Boxes CFR Code of Federal Regulations 30 CI Confidence interval CIBIC-Plus Clinician's Interviewed-Based Impression of Change plus caregiver input CGIC Clinical Global Impression of Change CPK Creatinine phosphokinase CRF Case Report Form CRO Clinical Research Organisation CRP C-reactive protein CSF Cerebrospinal fluid CT Cranial computerized tomography CVA Cerebrovascular accident DSM-IV Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association, Fourth Edition -Revised 1987 DNA Deoxyribonucleic acid ECG Electrocardiogram ECT Electro-convulsive therapy EDTA Ethylene diamine tetraacetate EEG Electroencephalogram ELISA Enzyme-linked immunosorbent assay GCP Good Clinical Practice HAM-D Hamilton Depression Scale HDL High density lipoprotein HIS Hachinski Ischemia Scale HIV Human immonodeficiency virus HMG-CoA Hydrox ymethylglutaryl Co-enzyme A

ICH International Conference on Harmonisation IEC Independent Ethics Committee IPI International Product Information IRB Institutional Review Board LDL Low density lipoprotein LOCF Last observation carried forward MANOVA Multivariate Analysis of Variance MDD Major Depressive Disorder MI Myoino sitol MTTT Modified intent to treat population MMSE Mini Mental Status Examination MRI Magnetic resonance imaging MRS Magnetic resonance spectroscopy NAA N-acetylaspartate NAAICr N-acetylaspartate to creatine NPH Normal pressure hydrocephalus NPI Neuropsychiatric Inventory NSAID Nonsteroidal anti-inflammatory drug PI Package Insert PRN pro re nata = on an as needed basis QD Daily RBC Red blood cell count RBC AChE-I Red blood cell count acetylcholinesterase inhibition ROI Region of Interest RPR Rapid plasma regain RR Risk Ratio SAE Serious Adverse Event SOP Standard Operation Procedure TSH Thyroid stimulating hormone TFT Thyroid function test ULN Upper limit of normal DSM-IV DIAGNOSTIC CRITERIA FOR DEMENTIA OF THE ALZ

Claims (10)

1. A pharmaceutical composition comprising:
a. an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof;
b. an amount of a statin or a pharmaceutically acceptable salt thereof;
and c. a pharmaceutically acceptable carrier or diluent.

2. The pharmaceutical composition of claim 1 comprising a fixed combination selected from the group consisting of:
a statin, 5 mg active and an acetylcholine esterase inhibitor, 10 mg active;
a statin, 10 mg active and an acetylcholine esterase inhibitor, 10 mg active;
a statin, 20 mg active and an acetylcholine esterase inhibitor, 10 mg active;
atorvastatin calcium, 40 mg active and an acetylcholine esterase inhibitor, mg active;
a statin, 80 mg active and an acetylcholine esterase inhibitor, 10 mg active;
a statin, 5 mg active and an acetylcholine esterase inhibitor, 5 mg active;
a statin, 10 mg active and an acetylcholine esterase inhibitor, 5 mg active;
a statin, 20 mg active and an acetylcholine esterase inhibitor, 5 mg active;
a statin, 40 mg active and an acetylcholine esterase inhibitor, 5 mg active;
and a statin, 80 mg active and an acetylcholine esterase inhibitor, 5 mg active.

3. The pharmaceutical composition of Claim 1 or Claim 2 comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition of Claim 3 comprising an amount of donepezil or a pharmaceutically acceptable salt thereof

5. A pharmaceutical composition comprising from about 0.20 mg. to about 20 mg. of donepezil or a pharmaceutically acceptable salt thereof; about 5 mg. to about 80 mg. of atorvastatin or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.

6. A first pharmaceutical composition for use with a second pharmaceutical compostion for achieving an Alzheimer's Disease-modifying effect in a mammal suffering from Alzheimer's Disease, which Alzheimer's Disease-modifying effect is greater than the sum of the effects achieved by administering said first and second pharmaceutical compositions separately wherein said first pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, and wherein said second pharmaceutical composition comprises and an amount of donepezil or a pharmaceutically acceptable carrier or diluent.

7. The use of the pharmaceutical composition as defined in any one of claims 1-6 respectively, for the manufacture of a medicament to treat Alzheimer's Disease.

8. The use of the pharmaceutical composition as defined in any one of claims 1-6 respectively, for the manufacture of a medicament for stabilizing symptoms of Alzheimer's Disease in a mammal requiring stabilization.

9. The use as defined in claim 8 wherein said stabilization is assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale, (ADAS-Cog), or by the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale, (ARCS-CGIC).

10. A method for treating or preventing a mammal which has been diagnosed as suffering from Alzheimer's Disease or the risk of Alzheimer's Disease, which would benefit from therapy by the combined administration of both (a) and (b) below, and therefore administration of both (a) and (b) has been prescribed, which comprises administering to said mammal so diagnosed and prescribed 1. an amount of a first active ingredient (a), said first active ingredient (a) being an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof; and 2. an amount of a second active ingredient (b), said second active ingredient (b) being atorvastatin or a pharmaceutically acceptable salt thereof.
wherein said first active ingredient (a) and said second active ingredient (b) are administered together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.