MXPA06011969A

MXPA06011969A - Therapeutic combination for treatment of alzheimers disease.

Info

Publication number: MXPA06011969A
Application number: MXPA06011969A
Authority: MX
Inventors: Gregg H Larson
Original assignee: Warner Lambert Co
Priority date: 2004-04-14
Filing date: 2005-04-04
Publication date: 2006-12-15
Also published as: AU2005232447A1; NO20065196L; BRPI0509881A; IL178120A0; ZA200608239B; CA2562069A1; KR20060133008A; RU2006136361A; EP1737539A1; CN1960781A; JP2007532624A; TW200533341A; WO2005099823A1

Abstract

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

Description

The prevalence of dementia in Europe: A collaborative study of 1980-1990 findings. EURODEM Prevaience Research Group. Int. J. 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 10 people over 65 years of age, and about half of those who are above 85 years of age suffer AD. Currently, about 4 million Americans suffer from this disease. It is estimated that this number will increase to 14 million by 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 -1943; 2000). Alzheimer's disease is a chronic neurodegenerative disorder manifested by cognitive impairment in learning and memory. It is accompanied by diffuse structural abnormalities in the brain. A growing body of evidence suggests that beta amyloid (? ß) plays an important role in this degenerative multifactorial procedure (De Strooper B and Annaert W. Proteolytic processing and cell biological functions of the amyloid precursor protein J Cell Sci, 1 13: 1857 -1870; 2000). However, in a review by Emmerling and colleagues (Emmerling MR, Spiegel K, Hall ED, Le Vine H, Walker LC, Schwarz RD and Gracon S. Emerging strategies for the treatment of Alzheimer's disease at the Millenium. Emerging Drugs, 4: 35-86; 1999), describe AD as "not only seen as a disease of neurotransmitter deficit or amyloid deposition, but rather a combination of cases (amyloidosis, neurofibrillary pathology, inflammation, oxidative stress and cerebral vascular insufficiency). that conspires to produce this dementia. " Inhibitors of this acetylcholine esterase are known to be useful in the treatment of AD. Examples of known acetylcholine esterase inhibitors include donepezil, (Aricept ®), tacrine (Cognex ®), revastigmine (Exelon ®) and galantamine (Reminyi). Aricept ® is described in the following U.S.A.A patents, all of which are incorporated herein by reference in their entirety: 4,895,841, 5,985,864, 6,140,321, 6,245,911 and 6,372,760. Exelon ® is described in the following U.S. Patent Nos. 4,948,807 and 5,602,176 which are incorporated herein by reference in their entirety. Cognex ® is described in U.S. Patent Nos. 4,631, 286 and 4,816,456 (incorporated herein by reference in its entirety). Reminyi ® is described in U.S. Patent Nos. 4,663,318 and 6,099,863 which are incorporated herein by reference in their entirety. Cholesterol can 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. Considerably, additional research is needed to understand the potentially critical role of transport and metabolism of lipid particles in both the periphery and the brain in AD (Beisiegel U and Spector A Lipoids and lipoproteins in the brain. Lipidology, 12: 243-244, 2001).

Cholesterol modulates the processing of the amyloid precursor protein (APP) and associated ß-β production as demonstrated through in vitro studies and in animal models (Emmerling MR, Spiegel K, Hall ED, Le Vine H, Walker LC, Schwarz RD and Gracon S. Emerging strategies for the treatment of Alzheimer's disease at the Millenium, Emerging Drugs, 4: 35-86: 1999). Excess cholesterol in culture or the diet of animals results in an increase in the processing of amyloid precursor protein (APP) and the production of? ß. Removal of cholesterol from the culture or from animal diets results in a reduction in APP processing and the production of? ß (Bergmann C, Runz H, Jakala P and Hartmann T. Diversification of gamma secretase versus beta-secretase inhibition by depletion of cholesterol Neurobiol Aging, 21: S278; 2000). Statins inhibit de novo synthesis by blocking a critical step in the pathway, converting HMG-CoA to mevalonate. The reduction of cholesterol by the inhibitors of HMG-CoA reductase, known as statins, has a similar effect on the processing of APP and the production of? ß (Austen BM, Frears ER and Davies H. Cholesterol upregular is production of abeta 1 -40 and 1-42 in transfected cells, Neurobiol Aging, 21: S254, 2000). In normal human ects treated with, for example, lovastatin, serum ß-ß concentrations are reduced in a dose-dependent manner (Friedhoff LT, Cullen EI, Geohagen NS, Buxbaum JD Treatment with controlled - lovastatin decreases serum concentrations of human beta - amyloid (? ß) peptide Int J Neuropsychopharmacol., 4 (2): 127-30; June 2001). These data suggest that a reduction in serum cholesterol is correlated with a reduction in APP and β-amyloid. Such a reduction could result in a modification of the progression of the disease and an improvement in cognitive and behavioral function. It has been suggested that the role of ApoE in serum in the development of AD may not be through cholesterol, but more directly on the aggregation of ββ (Golge TE and Eckman CB) Cholesterol modulation as an emerging strategy for the treatment of Alzheimer's disease, Drug Discovery Today, 6, (2): 1049-1055, 2001). Advanced age, female gender and family history are clear risk factors for AD. Additional risk 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, Guralnik JM, Salive ME, Harris T, Ferrucci L, Glynn RJ, Havlik R. J. Clarifyng the direct relationship between total cholesterol levéis and death from coronary heart disease in older persons, Ann Intem Med, 126: 753-760, 1997). In general, the diagnosis of AD is associated with an increase in serum cholesterol several decades earlier (Kivipelto M, Helkala EL, Heanninen T and others). 322: 1447-1451, 2001). A previous work by Sparks et al. (Sparks, DL, Hunsaker JC et al., Cortical senile plaques coronary artery disease, aging and Alzheimer's disease, Neurobiology of Aging, 1 1 (6): 601-607; 1990) demonstrated neuropathological lesions. type AD in non-demented CAD patients. Epidemiological work has shown an association between high-fat diets and 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: 162-66, 1993). Diets that are called cardioprotective have been shown to reduce the risk of developing AD. (Forette F, Seux M L, Staessen J A et al., Prevention of dementia in randomized double blind placebo - controlled systolic Hypertension in Europe (Syst-Eur) trial, Lancet, 352: 1347-1351, 1998). Recent retrospective studies point to a positive relationship between the use of cholesterol-lowering agents, specifically statins, and a reduction in cholesterol and risk of developing AD (Jick H, Zomberg GL, Jick SS, Seshadri S and Drachman D A. Statins and the risk of dementia, The Lancet, 356: 1627-1631, 2000). Atorvastatin is a member of the statin class of lipid regulators for use in the treatment of hypercholesterolemia. U.S. Patent No. 4,681, 893 (incorporated herein by reference in its entirety) and U.S. Patent No. 5,273,995 (incorporated herein by reference in its entirety) disclose atorvastatin (Lipitor®). Other statins include lovastatin, fluvastatin, cervivastatin, pravastatin, simvastatin, and rosuvastatin.

BRIEF 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. 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. same; 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 a mammal suffering from Alzheimer's disease with 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. Additionally, a method is provided for treating a mammal that has been diagnosed as suffering from Alzheimer's disease or the risk of Alzheimer's disease, which would benefit from the therapy by the combined administration of both (a) and (b) below, so both the administration of both (a) and (b) has been prescribed, which comprises administering to said mammal thus diagnosed and prescribed an amount of a first active ingredient (a), said first active ingredient (a) being an inhibitor of acetylcholine esterase 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. Additionally, a method for treating or preventing Alzheimer's disease is provided in a mammal that has been examined for Alzheimer's disease by an attending physician and has been diagnosed as in need of therapy for said Alzheimer's disease by co-administration of the active ingredients designated as (a) and (b) below, comprising a therapeutically effective amount of a first active ingredient (a), said first active ingredient (a) being an inhibitor of acetylcholine esterase 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. Additionally, a kit is provided to achieve 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. Additionally, a first pharmaceutical composition is provided for use with a second pharmaceutical composition to achieve a modifying effect of Alzheimer's disease in a mammal suffering from Alzheimer's disease., said modifying effect of Alzheimer's disease 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 an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable carrier or diluent. In addition, a pharmaceutical composition comprising an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof is provided.; in 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 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. Additionally, a method is provided for treating a mammal that has been diagnosed as suffering from Alzheimer's disease or the risk of Alzheimer's disease, which would benefit from the therapy by combined administration of both (a) and (b) below, and by therefore the administration of both (a) and (b) has been prescribed, comprising administering to said mammal thus diagnosed and prescribed, comprising the administration of an amount of a first active ingredient (a) an acetylcholine inhibitor esterase 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. Additionally, a method for treating or preventing Alzheimer's disease in a mammal that has been examined for Alzheimer's disease by an optional physician and has been diagnosed as in need of therapy for said Alzheimer's disease by co-administration of the active ingredients is provided. designated as (a) and (b) below, comprising a therapeutically effective amount of a first active ingredient (a) said first active ingredient (a) being an inhibitor of acetylcholine esterase 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. Additionally, a kit is provided to achieve 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. Additionally, a first pharmaceutical composition is provided for use with a second pharmaceutical composition to achieve a modifying effect of Alzheimer's disease in a mammal suffering from Alzheimer's disease, said modifying effect of Alzheimer's disease being 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 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. Additionally 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 donepezil compound 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 donepezil compound or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount thereof. a second compound, said second compound being atorvastatin or a pharmaceutically acceptable salt thereof. Additionally, a method is provided for treating a mammal that has been diagnosed as suffering from Alzheimer's disease or the risk of Alzheimer's disease, which would benefit from the therapy by the combined administration of both (a) and (b) below, and therefore the administration of both (a) and (b) comprising administering to said mammal thus diagnosed and prescribed, of an amount of a first active ingredient (a), said first active ingredient (a) donepezil, has been prescribed. 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. Additionally, a method for treating Alzheimer's disease in a mammal that has been examined for Alzheimer's disease by an attending physician is provided and has been diagnosed in need of therapy for said Alzheimer's disease by co-administration of the active ingredients designated as ( a) and (b) below, comprising 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.

Additionally, a kit is provided to achieve 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. Additionally, a first pharmaceutical composition is provided for use with a second pharmaceutical composition to achieve a modifying effect of Alzheimer's disease in a mammal suffering from Alzheimer's disease, said modifying effect of Alzheimer's disease being 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 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. Additionally, the above composition comprising the hemicalcium salt of atorvastatin is provided. Additionally, the above composition comprising between about 0.2 mg and about 20 mg of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof and between about 5 mg and about 80 mg of atorvastatin or a pharmaceutically acceptable salt thereof is provided. Additionally provided is the pharmaceutical composition comprising a fixed combination selected from the group consisting of: calcium atorvastatin, active 5 mg and an acetylcholine esterase inhibitor, active 10 mg; calcium atorvastatin, 10 mg active and an acetylcholine esterase inhibitor, 10 mg active; calcium atorvastatin, 20 mg active and an acetylcholine esterase inhibitor, 10 mg active; calcium atorvastatin, 40 mg active and an acetylcholine esterase inhibitor, 10 mg active; calcium atorvastatin, active 80 mg and an acetylcholine esterase inhibitor, 10 mg active; calcium atorvastatin, 5 mg active and an acetylcholine esterase inhibitor, 5 mg active; calcium atorvastatin, 10 mg active and an acetylcholine esterase inhibitor, 5 mg active; calcium atorvastatin, 20 mg active and an acetylcholine esterase inhibitor, 5 mg active; calcium atorvastatin, 40 mg active and an acetylcholine esterase inhibitor, 5 mg active; and calcium atorvastatin, active 80 mg and an inhibitor of acetylcholine esterase, 5 mg active. Additionally 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 salt thereof; and a therapeutically effective amount of a second compound, said second compound being atorvastatin or a pharmaceutically acceptable salt thereof. Additionally 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. Additionally, a method is provided for treating a mammal that has been diagnosed as suffering from Alzheimer's disease or the risk of Alzheimer's disease, which would benefit from the therapy by the combined administration of both (a) and (b) below. , and therefore the administration of both (a) and (b) has been prescribed, which comprises administering to said mammal thus diagnosed and prescribed, an amount of a first active ingredient (a), said first active ingredient ( a) 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. Additionally, a method for treating or preventing Alzheimer's disease in a mammal that has been examined for Alzheimer's disease by a medical practitioner and diagnosed in need of therapy for said Alzheimer's disease by co-administration of the designated active ingredients is provided. as (a) and (b) below, comprising 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. Additionally, a group is provided for achieving 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 salt and 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. Additionally, a first pharmaceutical composition is provided for use with a second pharmaceutical composition to achieve a modifying effect of Alzheimer's disease in a mammal suffering from Alzheimer's disease, said modifying effect of Alzheimer's disease being 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 an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable carrier or diluent.

Additionally, a method is provided for stabilizing the symptoms of Alzheimer's disease in a mammal that requires stabilization comprising administering to said mammal a stabilizing amount of the pharmaceutical composition described above. Additionally, the method is provided in which said stabilization is assessed using the Alzheimer's disease assessment scale-cognitive scale (ADAS-Cog). Additionally, the method in which said stabilization is assessed by the cooperative study of Alzheimer's disease -global clinical impression of the scale of the scale of change (ADCS-CGIC) is provided. Even 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 salt thereof; and a pharmaceutically acceptable carrier or diluent. Additionally, the above pharmaceutical composition comprising between about 0.2 mg and about 20 mg of an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt thereof between about 5 mg and about 80 mg of a statin or a pharmaceutically acceptable salt thereof is provided. . In addition to providing the above pharmaceutical composition comprising a fixed combination selected from the group consisting of: a statin, 5 mg active and an inhibitor of acetylcholine esterase, 10 mg active; a statin, 10 mg active and an inhibitor of acetylcholine esterase, 10 mg active; a statin, 20 mg active and an inhibitor of acetylcholine esterase, 10 mg active; calcium atorvastatin, 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 inhibitor of acetylcholine esterase, 5 mg active; an active 10 mg statin and an acetylcholine esterase inhibitor, 5 mg active; a statin, 20 mg active and an inhibitor of acetylcholine esterase, 5 mg active; an active 40 mg statin and an acetylcholine esterase inhibitor, 5 mg active, and a statin, 80 mg active and an inhibitor of acetylcholine esterase, 5 mg active; Additionally 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. Additionally, a method is provided for treating a mammal that has been diagnosed as suffering from Alzheimer's disease or the risk of Alzheimer's disease, which would benefit from the therapy by the combined administration of both (a) and (b) below, and by therefore the administration of both (a) and (b) has been prescribed, which comprises administering to said mammal thus diagnosed and prescribed, an amount of a first active ingredient (a), said first active ingredient (a) being a inhibitor of acetylcholine esterase 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. Additionally, a method for treating or preventing Alzheimer's disease is provided in a mammal that is examined for Alzheimer's disease by an optional physician and has been diagnosed in need of therapy for said Alzheimer's disease by co-administration of the active ingredients designated as (a) and (b) below, comprising 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. Additionally, a kit is provided to achieve 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. Additionally, a first pharmaceutical composition is provided for use with a second pharmaceutical composition to achieve a modifying effect of Alzheimer's disease in a mammal suffering from Alzheimer's disease, said modifying effect of Alzheimer's disease being 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 statin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, and wherein said second pharmaceutical composition comprises an amount of an acetylcholine esterase inhibitor or a pharmaceutically acceptable carrier or diluent. Additionally, a method for stabilizing the symptoms of Alzheimer's disease in a mammal that requires stabilization comprises administering to said mammal a stabilizing amount of the pharmaceutical composition described above. Additionally, the above method is provided in which said stabilization is assessed by the Alzheimer's disease evaluation scale - cognitive subscale (ADAS-Cog). Additionally, the method is provided in which said stabilization is assessed by the cooperative study of Alzheimer's disease - global clinical impression of scale of change (ADCS-CGIC). Even 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 carrier or diluent. Additionally, the above pharmaceutical composition comprising the Hemicalcium salt of atorvastatin is provided. In addition, the composition comprising donepezil HCI is provided. Additionally, the above pharmaceutical composition comprising between about 0.2 mg and about 20 mg of donepezil or a pharmaceutically acceptable salt thereof and between about 5 mg and about 80 mg of atorvastatin or a pharmaceutically acceptable salt thereof is provided. Additionally, the above pharmaceutical composition comprising a fixed combination selected from the group consisting of: calcium atorvastatin, active 5 mg and donepezil, active 10 mg is provided.; calcium atorvastatin, 10 mg active and donepezil, 10 mg active; calcium atorvastatin, 20 mg active and donepezil, 10 mg active; calcium atorvastatin, active 40 mg and donepezil, 10 mg active; calcium atorvastatin, active 80 mg and donepezil, 10 mg active; calcium atorvastatin, 5 mg active and donepezil, 5 mg active; calcium atorvastatin, active 10 mg and donepezil, active 5 mg; calcium atorvastatin, active 20 mg and donepezil, 5 mg active; calcium atorvastatin, active 40 mg and donepezil, 5 mg active; and calcium atorvastatin, active 80 mg and donepezil, active 5 mg; 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 donepezil compound 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. Additionally 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 donepezil compound 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. Additionally, the above method comprising the hemicalcium salt of atorvastatin is provided. Additionally, the method comprising donepezil HCI is provided. Additionally, a method is provided for treating a mammal that has been diagnosed as suffering from Alzheimer's disease or the risk of Alzheimer's disease, which would benefit from the therapy by the combined administration of both (a) and (b) below, and by therefore the administration of both (a) and (b) has been prescribed, which comprises the administration to said mammal thus diagnosed and prescribed, of 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 composition pharmaceutically with a pharmaceutically acceptable carrier or diluent. Additionally, the above method is provided in which the active ingredient (b) is the hemicalcium salt of atorvastatin. Additionally, the method is provided in which the active ingredient (a) is donepezil HCI. Additionally, a method for treating Alzheimer's disease in a mammal that has been examined for Alzheimer's disease by an attending physician is provided and has been diagnosed in need of therapy for said Alzheimer's disease by co-administration of the active ingredients designated as ( a) and (b) below, comprising 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. Additionally, the above method is provided in which the active ingredient (b) is the hemicalcium salt of atorvastatin. Additionally, the method is provided in which the active ingredient (a) is donepezil HCI. Additionally, a kit is provided to achieve a therapeutic effect in a mammal comprising a therapeutically effective amount of donepezil 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 diluent carrier in a second unit dosage form; and container means for containing said first and second dosage forms. Additionally, a first pharmaceutical composition is provided for use with a second pharmaceutical composition to achieve an Alzheimer's disease modifying effect in a mammal suffering from Alzheimer's disease, said modifying effect of Alzheimer's disease being 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 an amount of donepezil or a pharmaceutically acceptable diluent carrier. Additionally, a method for stabilizing the symptoms of Alzheimer's disease in a mammal that requires stabilization comprising administering to said mammal a stabilizing amount of the pharmaceutical composition described above is provided. In addition, the above method is provided in which said stabilization is assessed using the Alzheimer's disease-cognitive subscale (ADAS-Cog) evaluation scale. Additionally, the above method is provided in which said stabilization is assessed by the cooperative study of Alzheimer's disease-global clinical impression of scale of change (ADCS-CGIC). One embodiment of the present invention is an improved method for stabilizing the symptoms of Alzheimer's disease in a mammal in need of stabilization comprising the administration of atorvastatin plus the donepezil acetylcholine esterase inhibitor, which is improved upon the donepezil treatment alone. , as measured by cognition and global function, in particular as assessed by the Alzheimer's disease scale-cognitive subscale (ADAS-Cog) and the cognitive study of Alzheimer's disease-global clinical impression of scale of change (ADCS-CGIC), respectively. As used in this description, "stabilizer" means no further decline in the measurements referenced above (ADAS-Cog and ADCS-CGIC) over time. A further embodiment of the invention is a combination statin pharmaceutical formulation, for example, atorvastatin plus an acetylcholine esterase inhibitor (eg, donepezil) which has an Alzheimer's disease modifying effect. A further embodiment of this invention is a pharmaceutical formulation of a combination of a statin, for example, atorvastatin, plus an inhibitor of acetylcholine esterase, for example, donepezii, which significantly slows down progression and reduces the deterioration of Alzheimer's disease. "Combination treatment" as used in this disclosure means administering a statin, for example, atorvastatin and an acetylcholine esterase inhibitor, for example, donepezii together in a single pharmaceutical composition with a pharmaceutically acceptable carrier or diluent. "Modifying effect of Alzheimer's disease" or "stabilization" as used in this description means no further decline in the symptoms of AD in a mammal suffering from AD. A "stabilizing amount of Alzheimer's disease" as used in this description means the dosage required to achieve such stabilization of AD symptoms in such a mammal. Other clinical measurements of AD as well as the disease-modifying effects of an AD treatment regimen include the following: conduct, as measured by the neuropsychiatric inventory (NPI); General cognitive state, measured by the miniexamen of mental state (MMSE); the severity of global dementia measured by the clinical evaluation of dementia - number of squares (CDR - SB); and daily functioning as assessed by functional assessment of Alzheimer's disease and scale of change (ADFACS). Additionally, the measurement of brain volume and metabolism by MRI and MRS provides indication of the disease modifying effects of an AD treatment regimen. MRI measurements include whole brain, ventricular and hippocampal volumes. MRS measurements include N-acetylaspartate (NAA) and myoinosite! (MY). Evidence of disease modification is demonstrated by differences between treatment groups in these measurements. Additionally, measuring the peripheral biomarkers of AD, specifically plasma levels of the β-amyloid peptide (β1-40, β1-42), cerebrosterol (24S-hydroxycholesterol), and S 100b provide indication of the disease-modifying effects of a treatment regimen of AD. The evidence of disease modification is demonstrated by differences between treatment groups in these measurements. As used in this description, 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 present invention that when administered to a patient ameliorates a symptom of AD. The term "pharmaceutically acceptable salt" refers to the relatively non-toxic inorganic and organic acid or base addition salts of the compounds of the present invention. These salts can be prepared in situ during the isolation and final purification of the compound 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 salts hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, Naphthylate, Masylate, Glucoheptonate, Lactobionate, and Laurylsulfonate, and the like. These may include cations based on 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 cations, 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. Pharm. Sci., 1977; 66: 1-19, which is incorporated herein by reference). The free base form can be regenerated by contacting the salt form with a base. Although 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 for administration to a patient for the treatment, control, or prevention of Alzheimer's disease. The terms "treatment", "treating", "controlling", "preventing" and the like, refer to reversing, alleviating or inhibiting the progress of the disease or condition to which such term is applied, or one or more symptoms thereof. disease or condition As used in this description, these terms also encompass, depending on the condition of the patient, the prevention of the onset of a disease or condition or symptoms associated with a disease or condition, including the reduction of the severity of a disease or condition. or symptoms associated with it before the affliction with said disease or condition. Such prevention or reduction before affliction refers to the administration of the compound of the invention to a subject that is not at the time of administration afflicted with the disease or condition. "Prevention" also covers the prevention of the recurrence of a disease or condition or symptoms associated with it. According with the last, the composition of the present invention can be administered to a patient alone or as part of a composition containing other components such as excipients, diluents, and vehicles, 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 in the form of a buccal or nasal spray. Compositions suitable for parenteral injection may comprise sterile aqueous or non-aqueous sterile solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures of the same vegetable oils (such as olive oil), and esters injectable organics such as ethyl oleate. The 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 preservatives, humectants, emulsifiers, and dispersants. The 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 carried out by the use of agents that delay 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 mixed with at least one conventional inert excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, such as, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as, for example, glycerin; (d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, such as paraffin; (f) absorption accelerators, such as, for example, quaternary ammonium compounds; (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, such as, for example, kaolin and bentonite; and (i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium laurel sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms can also comprise pH regulating agents. Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols, 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 may 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 that can be used are polymeric substances and waxes. The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the aforementioned 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, such as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate , benzyl alcohol, benzyl benzoate, propylene glycol, 3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, peanut oil, corn germ oil, olive oil, resinous oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and sorbitan fatty acid esters or mixtures of these substances, and the like. In addition to such inert solvents, the composition may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavors, and perfuming agents. The suspensions, in addition to the active compounds, may contain suspending agents, such 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 similar. Compositions for rectal administration are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or vehicles such as cocoa butter, polyethylene glycol, or a suppository wax, which are solid at ordinary temperatures but liquid at temperature body and therefore, they 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 inhalers. The active component is mixed under sterile conditions with a physiologically acceptable carrier and any preservative, pH regulator, or propellant that may be required. Ophthalmic formulationsOintments, powders, and solutions for the eye are also contemplated as being within the scope of the present 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 2.5 mg to about 160 mg and preferably about 10 mg to approximately 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; lovastatin, generally about 2.5 mg to about 160 mg and preferably about 10 mg to about 80 mg; and atorvastatin, in general about 2.5 mg to about 160 mg, and preferably about 10 mg to about 80 mg. However, the specific dosage used may vary. For example, the dosage may depend on numerous 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 optimal dosages for a particular patient is well known to those skilled in the art. Methods of preparing various compositions with a certain amount of active ingredient are known or will be apparent in light of this description, to those skilled in the art. For examples of methods of preparing pharmaceutical compositions, see Reminqton's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th edition (1975). Since the present invention has an aspect that relates to the treatment of diseases / conditions described in this description with a combination of active ingredients that can be administered separately, the invention also relates to the combination of separate pharmaceutical compositions in the form of a kit. . The kit comprises two separate pharmaceutical compositions: a compound of the present invention, a prodrug thereof or a salt of said prodrug or compound and a second compound as described above. The equipment comprises means for containing the separate compositions such as a container, a divided bottle or a divided thin sheet container. Typically, the equipment comprises instructions for the administration of the separate components. The form of equipment is particularly advantageous when the separate components are preferably administered in different dosage forms (eg, oral and parenteral), administered at different dosage intervals, or when the prescribing physician wishes to assess the individual components of the dosage form. the combination. An example of such equipment is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively rigid material covered with a foil laminate. a preferably transparent plastic material. During the packaging process, alveoli are formed in the plastic sheet. The alveoli have the size and shape of the tablets or capsules to be packaged. Next, the tablets or capsules are placed in the alveoli and the sheet of relatively rigid material is sealed against the plastic sheet on the face of the sheet which is opposite to the direction in which the alveoli are formed. As a result, the tablets or capsules are sealed in the alveoli between the plastic sheet and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by applying a manual pressure on the socket, whereby an opening is formed in the sheet at the alveolus site. The tablet or capsule can then be removed by said opening. It may be desirable to provide a reminder about the equipment, for example, in the form of numbers next to the tablets or capsules in which the numbers correspond to the days of the regimen in which the tablets or capsules so specified should be ingested. Another example of such a reminder is a calendar printed on the cardboard, for example, as follows "first week", Monday, Tuesday, ... etc ... second week, Monday, Tuesday, ... "etc. Other variations of reminders will be readily apparent. to be a tablet or capsule alone or several pills or capsules to be taken on a given day.Also, a daily dose of compounds of this invention may consist of a tablet or capsule while a daily dose of the second compound may consist of several tablets or capsules and vice versa.The reminder should reflect this.In another specific embodiment of the invention, a dispenser designed to dispense daily doses one at a time in the order of its intended use is provided.Preferably, the dispenser is equipped with a reminder, so It also facilitates the fulfillment of the regime.An example of such a reminder is a mechanical counter that indicates the number of daily doses that have been dispensed.Another example of such a reminder is a battery-powered microchip memory coupled to a liquid crystal reader, an audible reminder signal, which, for example, reads aloud the arrow in which the last daily dose has been taken and / or reminds one when to take the next dose.

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 to treat, prevent or control 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 the typical formulations of the compositions provided by the invention.

As used in this description, "compound" means an acetylcholine esterase inhibitor or a statin, including donepezil and atorvastatin, respectively.

FORMULATION 1 The above ingredients are mixed and dissolved in the saline solution for IV administration to a patient.

FORMULATION 2 Ingredient Amount Compound 1 5 to 80 mg Compound 2 5 to 80 mg Microcrystalline cellulose 400 mg Stearic acid 5 mg Silicon dioxide 0 mg Sugar, confectionery 50 mg The above ingredients are mixed until uniform and compressed to form a tablet that is suitable for oral administration to a patient.

FORMULATION 3 Ingredient Amount Compound 1 5 to 80 mg Compound 2 5 to 80 mg Dry starch 250 mg Magnesium stearate 10 mg The above ingredients are combined and ground to provide material suitable for filling hard gelatin capsules administered to a patient.

FORMULATION 4 The above ingredients are combined by melting and then poured into molds. Although the embodiments of the invention have been illustrated and described, these embodiments are not intended to illustrate and describe all possible forms of the invention. Rather, the words used in the description are words of description rather than limitation, and it is understood that various changes can be made without departing from the spirit and scope of the invention.

Alzheimer's Disease Rating Scale - Cognitive Subscale (ADAS - Cog) The ADAS - Cog is a 11-item scale designed to assess the severity of cognitive impairments in AD patients. Articles include word retention, naming of objects and fingers, command follow-up, constructive praxis, ideational praxis, guidance, word recognition, spoken language ability, spoken language comprehension, difficulty finding words in spontaneous speech, and memory of the test instructions. Total scores vary between 0-70, 70 indicates worse cognition. For this study, two additional articles have been added to the ADAS - Cog. These are reminders of delayed words and concentration / distraction. When these two additional articles are combined with the ADAS - Cog of 11 original articles, the instrument will be called ADAS - Cog modified.

Cooperative study of Alzheimer's disease - global clinical impression of the scale of change (ADCS - CGICV ADCS - CGIC is the ADCS version of a change impression based on the doctor's interview and caregiver information (CIBIC - Plus). It is a global assessment of the change in patient function derived from comprehensive interviews of the subject and caregiver by an independent physician.

Classification of clinical dementia - sum of squares (CDR - SB) The CDR - SB is a measure of the severity of dementia in six domains that value cognition and function: memory, orientation, judgment and problem solving, community affairs, home, and hobbies, and personal care.

Neuropsychiatric Inventory (NPI) The Neuropsychiatric Inventory (NPI) is a 12-item scale of behavioral alterations that normally occur in subjects with dementia: delusions, hallucinations, agitation / aggression, depression / dysphoria, anxiety, joy / euphoria, apathy / indifference , disinhibition, irritability / instability, aberrant motor activity, sleep, and appetite and feeding disorders. A. 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 exhaustion of the caregiver (0 - 5) is also determined for each behavior.

Functional assessment of Alzheimer's disease and scale of change (ADFACS). The ADFACS is a functional assessment instrument of 16 articles based on instrumental and basic activities of the scales of daily life (ADL) commonly used in clinical research. Includes 6 basic ADL (neat, food, clothing, personal hygiene and grooming, bathroom and walk) and 10 ADL instrumental (ability to use phone, household chores, use of household appliances, video management, shopping, food preparation, ability to be inside and outside the home, hobbies and leisure activities, personal mail handling, and understanding of situations or explanations). The evaluation of each article is based on an interview with the subject's caregiver. Each of the basic ADL items is scored on a scale of 0 (no deterioration) to 4 (very severe impairment), providing a total score of the basic ADLs of 0 - 24. Each of the articles of the instrumental ADLs is scored on a scale of 0 (no impairment) to 3 (severe impairment) providing a total score of instrumental ADLs from 0 - 30. Therefore ADFACS of 16 global items has a total score range of 0 - 54.

Mini mental status test (MMSE); The MMSE is a short essay, widely used to assess the global cognitive state. The MMSE measures selected aspects of cognition such as memory orientation, attention, language and praxis on a scale of 0 - 30. The internal scores indicate a greater cognitive deterioration.

Alzheimer's disease assessment scale - Modified cognitive subscale (ADAS - modified Cog); The modified ADAS - Cog is the same instrument as the ADAS - Cog of 11 articles described above with the addition of 2 articles - recall of words delayed and concentration / distraction.

Classification of clinical dementia - Sum of squares (CDR-SB). The CDR-SB is a measure of the severity of dementia in 6 domains that value cognition and function: memory, orientation, judgment and problem solving, community issues, home, hobbies. The evaluation of each domain will be agreed by the assessment team of the subject (excluding the doctor performing the ADCS - CGIC) after considering the results of all the tests carried out during a clinical visit. The discussion of the CDR - SB consensus should include the interview and evaluation notes of the ADCS - CGIC interviewer, but the ADCS - CGIC interviewer does not participate in the CDR - SB discussion. The evaluations of each of the domains are added to provide a global clinical measurement, the sum of the boxes.

Neuropsychiatric Inventory (NPI) The Neuropsychiatric Inventory (NPI) is a 12-item scale of behavioral alterations that normally occur in subjects with dementia: delusions, hallucinations, agitation / aggression, depression / dysphoria, anxiety, joy / euphoria, apathy / indifference , disinhibition, irritability / instability, aberrant motor activity, sleep, and appetite and feeding 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 exhaustion of the caregiver (0 - 5) is also determined for each behavior.

Functional assessment of Alzheimer's disease and scale of change (ADFACS). The ADFACS is a functional assessment instrument of 16 articles based on instrumental and basic activities of the scales of daily life (ADL) commonly used in clinical research. Includes 6 basic ADL (neat, food, clothing, personal hygiene and grooming, bathroom and walk) and 10 ADL instrumental (use of telephone, household chores, use of household appliances, money management, shopping, food preparation, ability to be inside and outside the home, hobbies and leisure activities, personal mail handling, and understanding of situations or explanations). The evaluation of each article is based on an interview with the subject's caregiver. Each of the basic ADL items is scored on a scale of 0 (no deterioration) to 4 (very serious deterioration), providing a total score of the basic ADLs of 0 - 24. Each of the instrumental items of the ADLs it is scored on a scale of 0 (no impairment) to 3 (severe impairment) providing a total score of instrumental ADLs of 0 - 30. Therefore ADFACS of 16 global items has a total score range of 0 - 54.

Disease modification Phase-out: The randomized withdrawal design (Leber 1996, 1997) has been proposed as a study design to assess drug-induced changes in the progression of AD (Leber P. Observations and suggestions on antidementia drug development.) Alzheimer Disease and Asociated Disorders, 10 (1): S31-S35; 1996). The international working group on the harmonization of guidelines (in AD) approved 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 Progression Sub-Group, Alzheimer Dis Dissover Disord, 1 1 (section 3): 50-3, 1997.) In the randomized design of withdrawal, after treatment with a disease modifying agent potential for a sufficient duration, the active treatment is withdrawn (a subgroup is subject to remaining with active treatment, and a subgroup is withdrawn). If the treatment, (for example, in the case of atorvastatin) has only a symptomatic effect, then the behavior of subjects diverted to placebo would be expected to decrease to the level of behavior of the group of subjects receiving placebo from the beginning. This has been at least one clinical trial published in AD that uses 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 triais Dementia Geriatr Cogn Disord, 9 (1): 36-43, 1998).

MRI / MRS Substudy: Neurological Imaging: Magnetic Resonance Imaging (MRIV) Magnetic Resonance Spectroscopy (MRS) As a cognitive decline progresses AD, corresponding changes occur in brain volume, leading to progressive atrophy. Histopathological and radiological studies have shown that there are significant differences between the size and certain brain structures as well as the speed of atrophy between patients with AD and normal controls.As the severity of the disease progresses, these changes can be controlled by the use of MRI to measure structural volume as an in vivo measurement of total atrophy (Kesslak, JP, Nalcioglu O, Cotman C W. Quantification of magnetic resonant scans for hippocampal and for hippocampal atrophy in Alzheimer's disease., Neurology, 41: 57; These differences are marked more in areas associated with memory and other cognitive functions. Studies have highlighted the usefulness of medial temporal lobe structures, and particularly hippocampus, as well as total and ventricular brain volume to control the progression of the disease (Friedhoff L T, Cullen E I, Geohagen NS, Buxbaum JD. Treatment with controlled - lovastatin decreases serum concentrations of human beta - amyloid (? ß) peptide. Int J Neuropsychopharmacol., 4 (2): 127-30; June 2001). Specifically, atrophy of the hippocampus has been shown 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 approximately 90% each. In addition, the degree of hippocampal atrophy has been shown to correlate with the severity of memory loss (Laasko MP, Soininen H, Partanen K et al MRI of hippocampus in Alzheimer's disease: sensivity, specificity and analysis of the incorrectly classified subjects, Neurobiol Aging, 19: 23-31, 1998). As treatments for AD are developed, the question remains as to whether such therapies are only symptomatic, or they also modify the disease. With the use of the MRI scanner and specific software, magnetic resonance spectroscopy (MRS) can measure biochemical metabolites in a brain region of interest. In AD, studies have shown particular changes in two metabolites: N-acetyl (NAA) apparatus and myoinositol (MI). NAA, produced mainly by neurons, is a marker of neuronal mitochondrial metabolism and thus of neuronal integrity, it has been shown to decrease in various regions of the brain in AD patients (Klunk, Panchalingam K, Moosy J, McClure R, Pettigrew J. N-acetyl-L-aspartate and other aminoacid metabolites in Alzheimer's disease brain: a preliminary / nuclear proton resonant magnetic study Neurology, 42: 1578-1585; 1992). Reciprocally, MI, generated in astrocytes and a gliosis marker, has been shown to increase in this population. Taken together, studies have shown high sensitivity and specificity to identify patients with mild to moderate AD (Shonk TK, Motas R, Gifford P, Michaelis T, Mandingo JC, Izumi J, Ross B D. Probable Alzheimer's disease: diagnosis with proton MR spectroscopy, Radiology, 195: 65-72, 1995). In this way, such measurements could serve as a control of disease progression and response to therapy. The measurements of interest of MRI are global brain atrophy and regional brain atrophy (hippocampal atrophy) as defined by the rate of change in regional or global volumes,? volume / time. The measurements of interest for MRS are the change in aspartate from N-acetyl to creatine (NAA / Cr) and normalized NAA levels in the frontal cortex and occipital cortex, as well as Ml / Cr and MI / NAA and normalized MI levels. "Peripheral biomarkers", as used in this description, refers to proteins, peptides and lipids that are found in the blood and are involved in the pathophysiology of Alzheimer's disease. Peripheral biomarkers, specifically plasma levels of β-amyloid peptide (β1-40, β1-42), cerebrosterol (24S-hydroxycholesterol), and S100b are evidence of the modifying effects of the combined statin disease, for example , atorvastatin plus an inhibitor of acetylcholine esterase (eg donepezil). Apolipoprotein B (Apo B), Apolipoprotein E (ApoE) (Davignon J, Gregg RE, Sing CE.

Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis, 8: 1 - 21; 1988), total serum cholesterol, LDL - C serum, serum VLDL - C, triglyceride cerebrosterol and HDL - C) and the inhibition of RBC acetylcholine esterase (RBC AChE - I) are additional biomarkers of the modification or progress of the illness. Plasma biomarkers of interest include β-amyloid peptide (β1-40, β1-42), S100b, and 24-hydroxycholesterol (cerebrosterol) in plasma. Plasma ß-levels are elevated in several familial forms of AD and in first-degree relatives of AD patients before the onset of the disease (Golde TE, Eckam CB, Younkin SG.) Biochemical detection of Abeta soforms: implications for pathogenesis, diagnosis, and treatment of Alzheimer's disease Biochim Biophys Acta., 26; 1502 (1): 172-87; July 26, 2000). These findings imply an association of high levels of ßß in plasma and with risk of AD. A retrospective study in an aged population (mean age> 80 years) revealed that subjects with higher levels of ßß in plasma who had an increased risk for a diagnosis of AD during the following 3 years (Mayeux R, Tang MX, Jacobs DM, Manly J, Bell K, Merchant C, Small SA, Stern Y, Wisniewski HM, Metha PD Plasma amyloid beta-peptide 1-42 and incipient Alzheimer's disease Ann neurol., 46 (3): 412-6; September 1999). A recent study indicates that the level of ßß in plasma can be reduced in human subjects by treatment with a HMG-CoA reductase inhibitor (Friedhoff LT, Cullen EI, Geoghagen NS, Buxbaum JD. Treatment with controlled - read lovastatin decreases serum concentrations of human beta - amyloid (? ß) peptide Int J Neuropsychopharmacol., 4 (2): 127-30, June 2001). The cerebrosterol (24 S-hydroxycholesterol) is produced mainly in the brain (Bjorkhem I, Lutjohann D, Diczfalusy U, Stalhe L, Ahlborg G, and Wahren J. Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a brain 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, Eggersten G, Diczfalusy U, Bjorkhem, moves through of the blood - brain barrier (61 Lutjohann D, Breuer O, Ahlborg G and others) Cholesterol homeostasis in human brain: evidence for an age - dependent flux of 24S - hydroxycholesterol from the brain into the circulation Proc Nati Acad Sci USA, 93 : 9799 - 9804; 1996) and is found at high plasma concentrations in patients with early onset AD (Lutjohann D, Papassotiropoulos A, Bjorkhem I and others.) Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer's and vascular demented patients.J Lipids Res, 41: 195 198; 2000). Locatelli et al. (Locatelli S, Lutjohann D, Schmidt HH, Otto C, Beisiegel U, von Bergmann K. Reduction of plasma 24S-hydroxycholesterol (cerebrosterol) levéis using high-dosage simvastatin in patients with hypercholesterolemia: evidence that simvastatin affects cholesterol metabolism in the human brain, Arch Neurol., 59 (2): 213 - 6, February 2002) showed 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 W S. The roles of activated astrocytes and of the neurotrophic cytokine S 100B in the pathogenesis of Alzheimer's disease, Neuriobiol Aging, 22 ( 6): 915 - 22. Review, November - December 2001). Astrocytes activated have high S 100b levels that result from brain injury and inflammation. The levels of S 100b in CSF of patients with mild to moderate AD is high in relation to control subjects matched according to age (Peskind ER, Griffin WS, Akama KT, Raskind MA, Van EIdik LJ, Cerebrospinal fuid S 100 B is elevated in the earlier stages of Alzheimer's disease, Neurochem Int., 39 (5 - 6): 409-413, November-December 2001). An increase of S 100b in brain can also result in elevated levels of S 100b in the blood. As used in this description, the following terms have the meanings shown.

AChE Acetylcholine esterase AD Alzheimer's disease ADAS-Cog disease evaluation scale Alzheimer-cognitive subscale Cooperative study of Alzheimer's disease- ADCS-CGIG global clinical impression of change Functional assessment of Alzheimer's disease and ADFACS scale of ADL change Activities of daily living Diagnostic criteria for ADRDA-NINCDS disease Alzheimer's for dementia of multiple cognitive deficits of Alzheimer's type AE Adverse case APP Amyloid precursor protein FDA Administration for foods and drugs Alanine amino transferase (ALAT) = Glutamate ALT pyruvate transaminase (GTP) ANCOVA Analysis of covariance ANOVA Analysis of variance ApoE Apolipoprotein E AST Aspartate aminotransferase (ASAT) = Glutamate oxaloacetate transaminase (GOT) BP Blood pressure BPM Beats per minute BUN Nitrogen of blood urea CAD Coronary artery disease CDR- SB Evaluation of clinical dementia - sum of squares CFR Code of federal regulations Cl Confidence interval CIBIC-Plus Impression based on the change physician interview plus caregiver information CGIC Global change clinical impression CPK Creatine phosphokinase CRF Form of case report CRO Clinical research organization CRP Protein C- reactive CSF Cerebrospinal fluid CT Cranial CT scan CVA Stroke DSM-IV Diagnostic and statistical manual of mental disorders of the American Psychiatric Association, fourth edition- revised in 1987 DNA Deoxyribonucleic acid ECG Electrocardiogram ECT Electroconvulsive therapy EDTA Ethylene diamine tetraacetate EEG Electroencephalogram ELISA Assay enzyme-linked immunosorbent GCP Good clinical practice HAM-D Hamilton HDL depression scale. High specific weight lipoprotein HIS Hachinski ischemia scale HIV Human immunodeficiency virus HMG-CoA Hydroxymethylglutaryl Coenzyme A ICH International harmonization conference IEC Independent ethics committee IPI International product information IRB Institutional review board LDL Low weight lipoprotein specific LOCF Last observation carried out MAN OVA Multivariate analysis of variance MDD Major depressive disorder MI Myoinositol MITT Modified attempt to treat MMSE population Miniexamen of mental state MRI Magnetic resonance imaging MRS Magnetic Resonance Spectroscopy NAA N-Acetyl Aspartate NAA / Cr N-Acetyl Aspartate to Creatine NPH Normal Pressure Hydrocephalus NPI Neuropsychiatric Inventory NSAID Non-Spheroidal Anti-Inflammatory Drug Pl Package Insertion PRN Pro re nata = when the occasion arises QD Daily RBC Red blood cell count RBC AChE-l Inhibition of acetylcholinesterase red blood cell count ROI Range of interest RPR Rapid recovery of plasma RR Risk ratio SAE Severe adverse event SOP Conventional operating procedure TSH Thyroid stimulating hormone TFT Assay of thyroid function ULN Limit higher than normal Diagnostic criteria of DMS - IV for dementia of the alzheimer type (Alzheimer's disease) Dementia Dementia is characterized by the development of multiple cognitive deficits (including memory impairment) that are due to the direct physiological effects of a general medical condition, to the persistent effects of a substance, or to multiple etiologies, (for example, the effects combined cerebrovascular disease and Alzheimer's disease).

Diagnostic characteristics The essential characteristic of a dementia is the development of multiple cognitive deficits that include memory impairment and at least one of the following cognitive alterations: aphasia, apraxia, agnosia, or an alteration in executive functioning. Cognitive deficits must be serious enough to cause deterioration in occupational or social functioning and must represent a decrease from a previously higher level of functioning. A diagnosis of dementia should not be made if cognitive deficits occur exclusively during the course of a delirium. Nevertheless, a dementia and a delirium can both be diagnosed if dementia is present at times when delirium is not present. Dementia may be etiologically related to a general medical condition, to the persistent effects of substance use (including exposure to toxins), or to a combination of these factors. Memory impairment is required to diagnose dementia and is a prominent early symptom (Criterion A1). In individuals with dementia, their ability to learn new material is deteriorated, or they forget the previously learned material. Most individuals with dementia have both forms of memory impairment, although it is sometimes difficult to demonstrate the loss of previously learned material at the beginning of the course of the disorder. They can lose valuables such as wallets, keys, forget the cooking of food in the fire, and get lost in unknown neighborhoods. In advanced stages of dementia, the deterioration of memory is so severe that the person forgets his occupation, teaching, birthdays, family members and sometimes even the name. Memory can be formally rehearsed by asking the person to register, retain, remember, and recognize information. The ability to learn new information can be assessed by asking the individual to learn a list of words. The individual is asked to repeat the words (record), remember the information after a wait of several minutes (retention, recall), and to recognize the words from a list of multiple (recognition). Individuals with difficulty in learning new information are helped by clues or suggestions (eg, multiple choice issues) because they did not learn the material initially. On the contrary, the individuals with a deficit mainly of recovery can be helped by clues and suggestions because their deterioration is in the ability to access their memory. Remote memory can be rehearsed by asking the individual to remember personal information or past material that the individual found interesting (eg, politics, sports, entertainment). It is also useful to determine (from the individual and the informants) the impact of memory alterations on the functioning of an individual (for example, ability to work, buy, cook, pay bills, return home without getting lost). The deterioration of language function (aphasia) can be manifested by the difficulty in producing the names of individuals and objects (Criterion A2a). The conversation of individuals with aphasia becomes vague or empty, with long circumlocutory phrases and excessive use of indefinite terms of reference such as "thing" and "it". The understanding of spoken and written language and repetition of language may also be compromised. In advanced stages of dementia, individuals may be mute or have an impaired conversation pattern characterized by echolalia (ie, repetition of what is heard) or palilalia (ie, repetition of sounds or words repeatedly). The language is rehearsed by asking the individual to name objects in the room (for example, tie, dress, desk, lamp) or parts of the body (for example, nose, chin, shoulder), to follow commands (he points to the door and then the table "), or to repeat phrases (" without using the words yes, and, but "). Individuals with dementia may exhibit apraxia (ie, impaired ability to perform motor activities despite remaining intact motor abilities, sensory function, and understanding of the tasks required) (Criterion A2b). It will be impaired in its ability to mimic the use of objects (for example, combing hair) or to perform known motor acts (for example, saying goodbye with mime). Apraxia can contribute to deficits in cooking, dressing, and drawing. Alterations of motor practices can be tested by asking the individual to perform motor functions (for example, showing how to brush your teeth, copy intersecting pentagons, assemble blocks, place sticks in specific designs). Individuals with dementia may show agnosia (ie failure to recognize or identify objects despite remaining sensory function intact) (Criterion A2c). For example, the individual may have normal visual acuity but lacks the ability to recognize objects such as chairs or pencils. Eventually they may be unable to recognize members of the family and even their own reflection in the mirror. Similarly, they may have normal tactile sensation, but the inability to identify objects placed in their hands just by touch (for example, a coin or keys). Alterations in executive functioning are a common manifestation of dementia (Criterion A2d) and may be related especially to frontal lobe disorders or associated subcortical routes. Executive functioning implies the ability to think abstractly and plan, initiate, sequence, control, and stop complex behavior. The deterioration in abstract thinking can be manifested by the difficulty in the individual to copy with novel tasks and avoid situations that require the processing of new and complex information. The capacity for abstraction can be formally assessed by asking the person to find similarities or differences between related words. Executive dysfunction is also evident in a reduced ability to displace mental assemblies, to generate novel verbal or nonverbal information, and to execute serial motor activities. Trials to evaluate executive function include asking the individual to count to 0, recite the alphabet, subtract in series from 7, say as many animals as possible in 1 minute, or draw a continuous line consisting of alternating letters m and n. It is also useful to assess (from the individual and informants) the impact of alterations in the executive functioning of the individual's daily life (for example, ability to work, planned activities, budget). The articles in both criterion A1 (impairment in memory) and criterion A2 (aphasia, apraxia, agnosia, or alteration in executive function) must be sufficiently serious to produce significant impairment in social or occupational functioning (for example, to school, work, shopping, dressing, bathing, managing finances, and other activities of daily living) and must represent a deterioration of the previous level of functioning (Criterion B). The nature and degree of deterioration are variable and often depend on the particular social environment of the individual. The same level of cognitive impairment can significantly alter an individual's ability to perform a complex job, but not a job that is less demanding. Conventional published rating scales that measure physical maintenance (eg, personal hygiene), intellectual functioning, and the ability to use utensils or tools (eg, telephone, washing machine) can be used to measure the severity of deterioration. Dementia is not diagnosed if these symptoms occur exclusively during the course of a delirium. However, a delirium can be superimposed on a preexisting dementia, in which case both diagnoses must be provided.

Alzheimer's type dementia Diagnostic characteristics Cognitive deficits (Criterion A) and the required impairment (Criterion B) are described above. The onset of Alzheimer's type dementia is gradual and implies the continuation of cognitive decline (Criterion C). Due to the difficulty of obtaining direct pathological evidence of the presence of Alzheimer's disease, diagnosis can only be made when other etiologies for dementia have been excluded. Specifically, cognitive deficits are not due to other conditions of the central nervous system that produce progressive deficits in memory or cognition (eg, cerebrovascular disease, Parkinson's disease, Huntington's disease), systemic conditions known to cause dementia ( example, hypothyroidism, vitamin B 2 deficiency, HIV infection), or the persistent effects of a substance (eg alcohol) (Criterion D). If there is an additional etiology (for example, head trauma that worsens an Alzheimer's type dementia) both types of dementia must be coded (see dementia due to multiple etiologies, page 154). Type Alzheimer's dementia should not be diagnosed if symptoms occur exclusively during delirium (Criterion E). However, delirium can be superimposed on a pre-existing dementia of Alzheimer's type, in which case the subtype should be indicated with delirium. Finally, cognitive deficits are not better justified by another disorder of axis I (for example, major depressive disorder or schizophrenia) (Criterion F).

Diagnostic criteria for Alzheimer-type dementia A. The development of multiple cognitive deficits manifested by both (1) memory impairment (altered ability to learn new information or recall previously learned information) (2) one (or more) of the following cognitive alterations: (a) aphasia (language impairment) (b) apraxia (altered ability to perform motor activities despite remaining intact motor function) (c) agnosia (failure to recognize or identify objects despite remaining intact sensory function) (d) alteration of executive function (ie, planning, organization, sequencing, abstraction) B. Cognitive deficits in criteria A1 and A2 can produce significant impairment in social or occupational functioning and represent significant impairment with respect to the previous level of operation. C. The course is characterized by the gradual onset and continuation of cognitive decline. D. The cognitive deficits in criteria A1 and A2 are not due to any of the following: (1) other conditions of the central nervous system that produce progressive deficits of memory and cognition (eg, cerebrovascular disease, Parkinson's disease, Hutington, subdural hematoma, normal-pressure hydrocephalus, brain tumor) (2) systemic conditions known to produce dementia, (eg, hypothyroidism, vitamin B12 or folic acid deficiency, niacin deficiency, hypercalcemia, neurosyphilis, HIV infection ) (3) Substances induced by substances. E. Deficits do not occur exclusively during the course of a delirium. F. The alteration is not better justified by another disorder of axis I (for example, major depressive disorder, schizophrenia). Types (including code DSM - IV) Alzheimer's type dementia, late onset (appearance after 65 years) 290.30 with delirium 290.20 with hallucinations 290.21 with depressive mood 290.00 without complications Alzheimer's type dementia, early onset (appearance at age 65) years or less) 290.11 with delirium 290.12 with hallucinations 290.13 with depressive mood 290.10 without complications Clinical diagnosis of Alzheimer's disease criteria NINCDS - ADRDA A. Criteria for dementia syndrome Dementia is the deterioration of memory and other cognitive functions compared to the previous level of patient functioning as determined by a history of deterioration in behavior and by abnormalities detected from clinical examination and trials. neuropsychological A diagnosis of dementia can not be made when consciousness is impaired by delirium, drowsiness, stupor, or coma or when other clinical abnormalities prevent proper assessment of mental status. Dementia is a behavioral diagnosis and can not be determined by computed tomography, electroencephalography, or other laboratory instructions, although specific causes of dementia can be identified by these means.

B. Criteria for Alzheimer's disease Alzheimer's disease is a progressive, insane disorder, usually of middle or late age. The clinical criteria for diagnosing PROBABLE, POSSIBLE and DEFINITIVE Alzheimer's disease are indicated in Table 1. A clinical diagnosis of probable Alzheimer's disease can be made with confidence if there is a typical insidious onset of dementia with progression and if not There are other systemic or brain diseases that could justify memory deficits and other progressive cognitive deficits. Among the disorders that should be excluded are manic depressive disorder, Parkinson's disease, multi-infarct dementia, and drug intoxication; less common disorders that can cause dementia include thyroid disease, pernicious anemia, lysical brain disease and other chronic nervous system infections, subdural hematoma, occult hydrocephalus, Huntington's disease, Creutzfeldt-Jakob disease, and brain tumors . A diagnosis of definitive Alzheimer's disease requires histopathological confirmation. A clinical diagnosis of possible Alzheimer's disease can be made in the presence of other significant diseases, particularly if, after clinical judgment, Alzheimer's disease is considered the most likely cause of progressive dementia. The clinical diagnosis of possible Alzheimer's disease more than likely can be used if the presentation or course is somewhat aberrant. The information needed to apply these criteria is obtained through conventional methods of examination: medical history; neurological exams; psychiatric, and clinical; neuropsychological tests; and laboratory studies.

TABLE 1 Criteria for clinical diagnosis of Alzheimer's disease.

I. The criteria for the clinical diagnosis of PROBABLE Alzheimer's disease include: established state of dementia through clinical examination and documented by a mental mini-trial, Blessed dementia scale or similar examination, and confirmed by neuropsychological tests; deficits in two or more areas of cognition; progressive worsening of memory and other cognitive functions; without alterations of conscience; appearance between the ages of 40 and 90, most often after 65 years; and absence of systemic disorders or other brain diseases that themselves could justify the progressive deficits in memory and cognition. II. The diagnosis of PROBABLE Alzheimer's disease is supported by: progressive deterioration of specific cognitive functions such as language (aphasia), motor skills (apraxia), and perception (agnosia); deteriorated activities of daily life and altered behavior patterns; family history of similar disorders, particularly if it is confirmed neuropathologically; and laboratory results; Normal lumbar puncture as assessed by conventional techniques, normal pattern or non-specific changes in EEG, such as slow wave activity increase, and evidence of cerebral atrophy on CT with documented progression by serial observation. III. Other clinical characteristics consistent with the diagnosis of PROBABLE Alzheimer's disease, after excluding causes of dementia other than Alzheimer's disease, include: plateaus in the course of disease progression; associated symptoms of depression, insomnia, incontinence, hallucinations, illusions, hallucinations, verbal, emotional or physical outbursts, catastrophic, sexual disorders and weight loss; other neurological abnormalities in some patients, especially with more advanced disease and including motor signals, such as increased muscle tone, myoclonus, or seizure disorder in advanced disease; and normal CT for age. IV. Features that make the diagnosis of PROBABLE Alzheimer's disease uncertain or improbable include: Sudden apoplectic apparition; focal neurological findings such as hemiparesis, sensory loss, visual field deficits, and early incoordination in the course of the disease; and seizures or alterations in walking at the onset or very early in the course of the disease. V. Clinical diagnosis of Alzheimer's disease POSSIBLE: it can be performed at the base of the dementia syndrome, in the absence of other neurological disorders; psychiatric, or systemic enough to cause dementia, and in the presence of variations in the appearance, presentation, or clinical course; it can be performed in the presence of a second systemic or cerebral disorder sufficient to produce dementia, which is not considered to be the cause of dementia; and should be used in research studies when an individual, progressively severe cognitive progressive deficit is identified in the absence of another identifiable cause. SAW. The criteria for the diagnosis of DEFINITIVE Alzheimer's disease are: the clinical criteria for probable Alzheimer's disease and histopathological evidence obtained from a biopsy or autopsy. VII. The classification of Alzheimer's disease for research purposes must specify characteristics that can differentiate subtypes of the disorder, such as: Family appearance; Appearance before the age of 65; Presence of trisomy of 21; and coexistence of back relevant conditions such as Parkinson's disease.

Experimental The utility of the compositions of the present invention as medical agents in the treatment of Alzheimer's disease in mammals (eg, humans) or at risk of developing AD is demonstrated by the activity of the compositions of this invention in the clinical protocol described later. This is a multi - center, double - blind, randomized study of a parallel group with phases. Approximately 600 male and female human subjects with mild to moderate Alzheimer's disease are studied. The treatment groups are divided into approximately 300 subjects in the treatment arm of atorvastatin 80 mg plus donepezil 10 mg and approximately 300 subjects in the placebo treatment arm plus donepezil 10 mg. During a double-blind treatment period of 72 weeks (18 months), all subjects received donepezil 10 mg (300 subjects per arm, 600 subjects total). These subjects are randomly assigned by a 1: 1 ratio to receive the addition of atorvastatin 80 mg or Matching placebo. At the end of 18 months, the arms of the treatment are separated. Subjects who receive placebo plus an inhibitor of Acetylcholine esterase (donepezil 10 mg) continues with this drug regimen. A quarter of the subjects receiving atorvastatin 80 mg more acetylcholine esterase inhibitor (donepezil 10 mg) continue with this drug regimen. The other three quarters of the subjects are changed from atorvastatin 80 mg to receive placebo plus an acetylcholine inhibitor esterase (donepezil 10 mg). The groups continue in this course for 8 weeks. Approximately 200 subjects are further evaluated by MRI / MRS. This is a parallel group study, multi - center, double - blind, randomized with three phases. All subjects are required to take a 10 mg dose of donepezil or acetylcholine esterase inhibitor subject during > 3 months before the selection.

Selection Treatment phase of withdrawal phase Day-14 to day-1 double-blind double-blind 72 weeks 8 weeks * A similar procedure can be followed using any statin and any acetylcholine esterase inhibitor.

Study visits Selection visit 1 (days -14 to -1) The selection can be made between days -14 to -1 to the administration of the drug. Before entering the study, the following selection procedures are carried out: • obtain consent (s) informing in writing • record medical history • verify compliance with entry criteria • complete physical examination • record height and weight • complete neurological examination • vital signs • laboratory evaluations, urinalysis, chemistry, hematology, serology, serum sample archived and complete lipid profile • 12-lead electrocardiogram (ECG) • MRI / CT scan (only if a previous MRI / CT scan is not possible to confirm the diagnosis of disease of mild to moderate Alzheimer's within 12 months is selected). • review all simultaneous medications • miniexamen of mental state (MMSE) • scale of Alzheimer's disease assessment - cognitive subscale (ADAS - Cog) • Hachinski modified by Rosen (subjects must have less than or equal to 4 in the selection for inclusion) • assign the only 8-digit number to the subject, which should not be assigned to another subject • plan the next visit (Visit 2 / initial level) Procedures during the study drug treatment period Visit 2 initial level / Visit 2 of random distribution (Day 0) • verify conformation with entry criteria • complete physical examination • record weight • complete neurological examination • vital signs • laboratory evaluations, urine analysis, chemistry, hematology, plasma biomarker sampling, anonymous genotype sampling, donepezil and RBC AChE levels. • Miniexamen of mental state (MMSE) • scale of assessment of Alzheimer's disease -sub-cognitive scale (ADAS-Cog) • cooperative study of Alzheimer's disease -global scale impression of change (ADCS - CGIC) • Neuropsychiatric inventory ( NPI) • Classification of clinical dementia - Sum of squares (CDR - SB) • Functional assessment of Alzheimer's disease and scale of change (ADFACS) • Caretaker burden questionnaire • Use questionnaire of source of patient health care • Assign The lowest random number available. This number should not be reassigned to another subject. • disperse the study medication for visit 2 • plan next visit (Visit 3 / week 6) • record simultaneous medications • record adverse events Visit 3 / week 6 (day 42) • lab, chemistry and hematology evaluations • plan next visit (Visit 4 / month 3) • register simultaneous medications • record adverse events Visit 4 / month 3 (day 84) • assess modified physical examination • record weight • vital signs • laboratory evaluations, chemistry, hematology, complete lipid profile, and sampling of plasma biomarkers • miniexamen of mental state (MMSE) • scale of assessment of Alzheimer's disease -sub-cognitive scale (ADAS-Cog) • cooperative study of Alzheimer's disease -global scale clinical impression of change (ADCS - CGIC) • record study medication taken since visit 2 • assess compliance with the medication regimen Study • Collect all medication containers • Dispense study medication for visit 4 • Plan next visit (visit 5 / month 6) • Record all medications simultaneously • Record adverse events Visit 5 / Month 6 (Day 168) • Signs vital • record weight • laboratory evaluations, urinalysis, chemistry, hematology, complete lipid profile and plasma biomarker sampling • 12-lead electrocardiograms (ECG) • miniexamen of mental state (MMSE) • scale of assessment of Alzheimer's disease - cognitive subscale (ADAS - Cog) • cooperative study of Alzheimer's disease - global impression of scale of change ( ADCS - CGIC) • Neuropsychiatric inventory (NPI) • Functional assessment of Alzheimer's disease and scale of change (ADFACS) • Caretaker burden questionnaire • Use questionnaire from the patient's health care source • Register study medication taken from the visit 4 • assess compliance with the study medication regimen • collect all medication containers • disperse study medication for visit 5 • plan next visit (Visit 6 / month 9) • record all medications simultaneously • record episodes adverse Visit 6 / month 9 (day 252) • evaluation of the modified physical examination • record weight • vital signs • miniexamen of mental status (MMSE) • scale of assessment of Alzheimer's disease cognitive subscale (ADAS - Cog) • cooperative study of Alzheimer's disease global clinical impression of scale of change (ADCS - CGIC) • record study medication taken since visit 5 • assess compliance with study medication regimen • collect all medication containers • dispense study medication for visit 6 • plan next visit (Visit 7 / month 12) • record all medications simultaneously • record adverse events Visit 7 / month 12 (day 336) · complete physical examination • complete neurological examination • record weight • vital signs • laboratory assessment, urinalysis, chemistry, hematology, complete lipid profile, and plasma biomarker sampling • Miniexamen of mental state (MMSE) • scale of assessment of Alzheimer's disease -sub-cognitive scale (ADAS-Cog) • cooperative study of Alzheimer's disease -global scale impression of change (ADCS - CGIC) • neuropsychiatric inventory ( NPI) • classification of clinical dementia - sum of squares (CDR - SB) • Functional assessment of Alzheimer's disease and scale of change (ADFACS) • caregiver burden questionnaire Questionnaire on use of source of patient health care • Register all the study medication taken since the visit 6 • assess compliance with the study medication regimen • collect all medication containers • dispense study medication from visit 7 • plan next visit (visit 8 / month 15) • record all medications simultaneously • record episodes Adverse events Visit 8 / month 15 (day 420) • vital signs • register weight • miniexamen of mental state (MMSE) • scale of assessment of Alzheimer's disease - cognitive subscale (ADAS - Cog) • cooperative study of Alzheimer's disease - global impression of change scale (ADCS - CGIC) • record all study medication taken since the visit • assess compliance with the study medication regimen • collect all medication containers • dispense the study medication to the visit 8 • plan next visit (visit 9 / month 18) • register all medications simultaneously • register adverse events • Visit 9 / month 18 (day 504) - first withdrawal maneuver visit / participation of the MRI substudy ends / early termination visit for the double-blind part. • complete physical examination • complete neurological examination • vital signs • record weight • laboratory evaluations, urinalysis, chemistry, hematology, complete lipid profile, serum sample archived and plasma biomarker sampling, levels of donepezii and RBC AChE - 1 • 12-lead electrocardiogram (ECG) • miniexamen of mental state (MMSE) • scale of assessment of Alzheimer's disease -sub-cognitive scale (ADAS-Cog) -coagulative study of Aizheimer's disease - global impression of scale of change (ADCS) - CGIC) • neuropsychiatric inventory (NPI) • clinical dementia score - sum of squares (CDR - SB) • functional assessment of Alzheimer's disease and scale of change (ADFACS) • caregiver burden questionnaire • source utilization questionnaire of patient health care. · Record all study medication taken since the visit 8 • assess compliance with the study medication regimen • collect all medication containers • dispense study medication for visit 9 (withdrawal maneuver medication) • plan the next visit (visit 10 / month 20) • register all simultaneous medications • record adverse events Visit 10 / month 20 (day 560) final visit / early termination visit for withdrawal maneuver treatment arm • complete physical examination • record weight • vital signs • laboratory evaluations, urinalysis , chemistry, hematology, complete lipid profile and plasma biomarker sampling • 12-lead electrocardiogram (ECG) • miniexamen of mental state (MMSE) • scale of assessment of Alzheimer's disease -sub-cognitive scale (ADAS-Cog) • cooperative study of Alzheimer's disease -global scale clinical impression of change ( ADCS - CGIC) • classification of clinical dementia - sum of squares (CDR -SB) • record of study medication taken since visit 9 • assessment of compliance with the study medication regimen • collect all medication containers • record all the simultaneous medications • record adverse episodes Laboratory determination: Subjects are fasting 12 hours before the test, and they should not do any strenuous exercise and no change in diet the day before the test. If the subject is not fasting, the clinic visit should be rescheduled as soon as possible. The subject's posture should be normalized for lipid blood extractions. Subjects must be in the seated position (no more than 5 minutes). A tourniquet (no more than 2 minutes) should be used, but it can be released before the blood is drawn. The following laboratory tests must be carried out.

· Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell count, and platelet count, differential (if WBC is abnormal) including neutrophils, lymphocytes, monocytes, eosinophils, and basophils.

· Clinical chemistry: albumin, glucose, alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), creatinine, uric acid, chloride, potassium, total protein, sodium, phosphorus, calcium, globulin, lactate dehydrogenase, reactive protein C, alanine transaminase (ALT), aspartate transaminase (AST), and CPK. If ALT or AST are > 3 x the normal upper limit (ULN), the subject must return within 1 week for a repeat test. If the value remains > 3 x ULN, the subject should be removed from the study, and the following ALT / AST measurements should continue until the abnormality has been resolved. If CPK > 5x ULN, then CPK - MB should be performed. If CPK is > 10 x ULN then the subject must exclude, and the following CPK measurements must be continued until the abnormality has been resolved.

• Lipid profile: total cholesterol, LDL-C, HDL-C, VLDL-C, triglycerides, and apolipoproteins (ApoE and Apo B); Direct measurements of LDL-C will be made independently of the level of triglycerides. Security measures, blind. Samples will be collected in the selection, months 3, 6, 12, 18 and 20 for analysis.

• Thyroid profile: thyroid stimulating hormone (TSH) and serum thyroxine (T4) (in the selection only) · Serology: hepatitis C and RPR (positive tests to be confirmed with a specific selection test only).

• Vitamins: vitamin B 2 and folate levels in RBC (selection only) • Glycemic control: HbA-iC level (selection only) • Urinalysis: dipstick test of recent voided sample to assess pH, leukocytes, nitrite, urobilinogen, specific gravity, protein, glucose, ketones, and blood. The urinalysis will be performed in the selection, initial level, months 6, 12, 18 and 20. The laboratory evaluations are made in the selection, initial level, week 6, months 3, 6, 12, 18 and 20 (except that is indicated otherwise). In the value of the clinically noteworthy abnormal laboratory test indicated after the selection (other than ALT / AST / CPK, for which instructions have been given above), the test must be approved by the medical study control and repeated immediately and Follow until you have returned to the normal range and / or you find an adequate explanation of the abnormality. 12-lead electrocardiogram The electrocardiogram (ECG) is a complete, 12-lead record. The ECG is performed in the selection, months 6, 18 and 20.

Vital signs, body weight and height The vital signs are obtained in the selection, initial level, months 3, 6, 9, 12, 15, 18 and 20. These will include the body temperature (oral), respiratory rate, pulsations, and pressures systolic and diastolic blood gases determined in the sitting position. The records will be made after the subject has sat for 5 minutes. Body weight (kg) is measured without shoes. The height is recorded in cm in the selection. The weight is recorded in the selection, initial level, and months 3, 6, 9, 12, 15, 18 and 20.

Complete physical examination A complete physical examination is performed in the selection, initial level, months 12, 18 and 20. The general physical state will be assessed by evaluation of the head, eyes, ears, nose, throat, neck, heart, chest, lungs , abdomen, extremities, peripheral pulses, skin and other physical conditions of interest (breasts, genitourinary and rectal are optional). Any other assessment necessary to establish the initial status or evaluate the symptoms or AE should also be made. An AE form must be completed for all changes identified after the selection as clinically noteworthy. Height without shoes will be recorded in the selection only. The weight is recorded at each visit.

Assessment of physical condition Brief routine physical examination: the general physical condition is assessed by a brief physical examination in months 3 and 9. The subject and caregiver should be consulted in relation to changes in physical condition from the previous examination done in the selection. The weight is recorded at each visit.

Neurological examination A complete neurological examination is performed at the visits, selection clinics, initial level, months 12 and 18. This examination includes evaluation of the cranial nerves (including visual fields), motor, sensory, brainstem, cerebellar and autonomic functions .

CT or MRI in the selection If it is not done in the past 12 months, a CT or MRI scan must be completed. For subjects not participating in the MRI / MRS substudy, MRI is required only if the CT results are equivocal to meet the diagnostic criteria.

Psychometric tests A certified estimator is required for the administration of the Alzheimer's disease evaluation scale - cognitive subscale (ADAS - Cog); cooperative study of Alzheimer's disease - global scale change clinical impression (ADCS - CGIC), and neuropsychiatric inventory scale (NPI) The same certified evaluator should perform all psychometric exams at approximately the same time of day. All changes in the evaluators for a given assessment should be noted in the subject's source documents. The psychometric test must be produced after the laboratory test, and only after the subjects have had the opportunity to eat.

Miniexamen of the mental state (MMSE) The MMSE is a short essay, widely used to assess the global cognitive state. The MMSE measures selected aspects of cognition such as memory, orientation, attention, language, and praxis on a scale of O - 30. Lower scores indicate greater cognitive impairment. The MMSE is done in the selection, in the initial state and months 3, 6, 9, 12, 15, 18, and 20.

Alzheimer's Disease Evaluation Scale - Cognitive Scale (ADAS - Cog) The ADAS - Cog is a scale of 11 articles designed to assess the severity of cognitive impairments in AD patients. Articles, include, memory of words, appointment of objects and fingers, follow-up of commands, constructive praxis, ideational praxis, orientation, word recognition, spoken language ability, understanding of spoken language, difficulty in finding words in a spontaneous conversation , and I remember the trial instructions. The total scores vary between 0-70, with 70 indicating a worse cognition. For this study, two additional articles have been added to the ADAS - Cog. These are delayed memory of words and concentration / distraction. When these two additional items are combined with the original ADAS - Cog of 11 items, the instrument will be called ADAS - Cog modified. It will be necessary to ensure that the subject is able to complete the modified ADAS - Cog for inclusion in the study. The modified ADAS - Cog is performed in the selection, initial state and months 3, 6, 9, 12, 15, 18 and 20.

Cooperative study of Alzheimer's disease - global clinical scale change impression (ADCS - CGIC) The ADCS - CGIC is the ADCS version of a change impression based on a physician interview plus caregiver information (CIBIC - Plus). It is a global assessment of the change in patient function derived through compressive interviews of the subject and caregiver by an independent physician. In the initial state only, clinical information about the subject from any source should be used to generate the initial status notes such as other members of the assessment team, medical history, physical examination, and evaluation scale and trial results. from the selection visits and initial state. The subject and the caregiver are always interviewed separately; the subject will interview first. Videos of subject and caregiver interviews are also required in the initial state. After the visit in the initial state, the doctor must refer to his initial status notes and to the videotaped interviews but the review of other procedures / study results or the discussion about the subject with other members of the member of the valuation team. The doctor evaluates the subject on a 7-point scale to assess the degree of change from the initial state: 1 - marked improvement, 2 - moderate improvement, 3 - minimal improvement, 4 - no change, 5 - minimal worsening, 6 - moderate worsening, and 7 - noticeable worsening. Only these initial status notes and videotaped interviews will be available to the physician during the management of each interview and evaluation after the initial status (Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg G, Schmitt FA, Grundman M, Thomas RG, Ferris SH and the cooperative study of Alzheimer's disease, Validity and reliability of the Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change, Alzheimer's Dis. Assoc. Disorder, 2: S22 - S32; 1997). The doctor should only make decisions about the change without consulting other staff. At the beginning of each interview, the doctor should warn the interviewer about refraining from mentioning any side effects that they may experience. The valuation of change from the initial stage is done in months 3, 6, 9, 12, 15 and 18. The valuation of the change in month 20 (at the end of the phase of withdrawal of the study) is not performed in relation to the initial state, but in relation to month 18.

Clinical dementia evaluation - sum of squares (CDR - SB) The CDR - SB is a measure of the severity of dementia in six domains that assesses cognition and function: memory, orientation, judgment, and problem solving, community affairs , home and hobbies, and personal care. The evaluation of each domain will be agreed by the assessment team of the subject (excluding the doctor who performs the ADCS - CGIC) after considering the results of all the trials conducted during a clinical visit. The CDR consensus discussion should include the interview and assessment notes of the ADCS - CGIC interviewer, but the ADCS - CGIC interviewer does not participate in the CDR discussion. The evaluations in each of the domains are added to provide a global clinical measure, the sum of the boxes. The CDR -SB is performed in the initial state, months 12, 18 and 20.

Neuropsychiatric Inventory (NPI) The Neuropsychiatric Inventory (NPI) is a 12-item scale of behavioral alterations that commonly occur in subjects with dementia: delusions, hallucinations, agitation / aggression, depression / dysphoria, anxiety, joy / euphoria, apathy / indifference, disinhibition, irritability / instability, aberrant motor activity, sleep, and appetite and feeding 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. High scores indicate more psychopathology. In addition, the degree of exhaustion of the caregiver (0 - 5) is also determined for each behavior. The NPI is performed in the initial state, months 6, 12, and 18.

Functional assessment of Alzheimer's disease and scale of change (ADFACS). The ADFACS is a functional assessment instrument of 16 articles based on the instrumental and basic activities of the scales of daily life (ADL) commonly used in clinical research. Includes 6 basic ADL (toilet, food, clothing, personal hygiene and grooming, bathroom and walk) and 10 ADL instrumental (ability to use phone, household chores, use of household appliances, money management, shopping, food preparation, ability to be inside and outside the home, hobbies and leisure activities, personal mail handling, and understanding of situations or explanations). The evaluation of each article is based on an interview with the subject's caregiver. Each of the basic ADL items is scored on a scale of 0 (no impairment) to 4 (very serious impairment), providing a total score of the basic ADLs of 0 - 24. Each of the instrumental ADL items it is scored on a scale of 0 (no impairment) to 3 (severe impairment) providing a total score of instrumental ADLs from 0 - 30. Therefore ADFACS of 16 global items has a total score range of 0 - 54. ADFACS is done in the initial state, months 6, 12 and 18.

Neurological imaging: brain morphology and metabolism In this MRI / MRS sub-study, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) will be used as secondary efficacy variables to assess the effects of treatment on the measurements of disease progression in the brain. The MRI is performed in the initial state and in the visit 9 / month 18 to assess the volumetric changes of the brain (global and regional atrophy). MRS will be performed on the same visits to assess endogenous brain metabolites, including N-acetyl aspartate (NAA) and myoinositol (MI). The analyzes of interest for MRI are global cerebral atrophy and regional cerebral atrophy (hippocampal atrophy) as defined by the rate of change in regional or global volumes,? volume / time. The analysis of interest for MRS is the change in N-acetyl aspartate with respect to creatine (NAA / Cr) and normalized NAA levels in the frontal cortex and occipital cortex, as well as Ml / Cr and MI / NAA and normalized MI levels . Given the logistical complexity of obtaining neurological imaging, these are performed in a subgroup of approximately 200 subjects.

Peripheral biomarkers The proteins, peptides and lipids found in blood are measured and are involved in the pathophysiology of Alzheimer's disease in the study population.

Plasma biomarkers Plasma biomarkers of interest include ß-amyloid peptide (ß1-40, AB1-42), S100b and 24-hydroxycholesterol (cerebrosterol) in plasma. Plasma biomarkers are collected in the initial state, months 3, 6, 12, 18 and 20 for analysis. The plasma fraction of 10 ml of whole blood will be collected in EDTA for each subject. The samples are rapidly frozen at -70 ° C and stored on site.

Serum biomarkers The subject's lipid profile is assessed by measuring: total cholesterol, LDL-C, HDL-C, VLDL-C, triglycerides, and apolipoproteins (ApoE and Apo B). The assay of serum samples for lipids and lipoproteins is carried out. Serum biomarkers are collected in the initial state, months 3, 6, 12, 18 and 20 for analysis. The selection sample is considered initial status since the selection is within two weeks of the initial status visit.

Plasma level of donepezil and inhibition of acetylcholinesterase in RBC (RBC AChE - I): Seven milliliters (7 ml) of whole blood are collected in the initial state and month 18 (see appendix I) for the measurement of RBC AChE - I in subjects. The concentrations of donepezil in plasma are correlated with the activity of acetylcholine esterase measured in red blood cells.

Analysis of donepezil concentrations in plasma: Using a high performance liquid chromatography method, the donepezil concentration is quantified. Before the analysis of the study samples, the sensitivity, specificity and reproducibility of the assay is documented.

Analysis of cholinesterase inhibition in RBC: Using a radioenzymatic method, the activity of acetylcholinesterase in red blood cells is quantified. Before use in this study, the sensitivity, specificity and reproducibility of the assay is documented.

Caretaker burden and health economics Caregiver assessments - caregiver burden questionnaire - initial level The caregiver's assessments include the measurement of the load of the subject's caregiver using the caregiver's load questionnaire. In the initial state the questionnaire consists of two main sections, caregiver time (3 questions) and subject accommodation (ie, life situation, 1 question). The caregiver's time section consists of questions applicable to the 4 weeks from the initial status visit. The subject's accommodation section assesses the current life situation.

Definition of efficiency endpoints Efficacy pri Primary efficacy measurements and measurement instants are as follows Alzheimer's disease assessment scale - cognitive subscale (ADAS - Cog). The ADAS - Cog on a scale of 11 articles designed to assess the severity of cognitive impairments in subjects with AD. Articles include word recall, appointment of objects and fingers, follow-up of commands, constructive praxis, ideational praxis, orientation, word recognition, spoken language capacity, compression of spoken language, difficulty of finding words in a spontaneous conversation, and recall of test instructions . The total scores vary between 0 - 70, with 70 indicating worse cognition. The ADAS - Cog is performed in the selection, initial state and months 3, 6, 9, 12, 15, 18 and 20.

Cooperative study of Alzheimer's disease - global clinical impression of scale of change (ADCS - CGIC). The ADCS - CGIC is the ADCS version of the impression of change based on the doctor 's interview plus caregiver information (CIBIC - plus). It is a global classification of change in the function of the subject derived from the compressive interviews of the subject and caregiver by an independent physician. Only in the initial state, clinical information about the subject from any other source should be used to generate initial status notes such as other members of the assessment team, medical history, physical examination, and classification scale and outcome of the trial from the visits of the selection and the initial state. Video tapes of subject and caregiver interviews are also required in the initial state. After the initial status visit, the physician must refer to his / her initial status notes and videotaped interviews but prevent the review of other procedures / study results or discussion about the subject with other members of the assessment team. The doctor evaluates the subject on a 7-point scale to determine the degree of change from the initial state: 1 - marked improvement, 2 - moderate improvement, 3 - minimal improvement, 4 - no change, 5 - minimal worsening, 6 - worsening moderate, and 7 noticeable worsening. Only these notes in the initial state and videotaped interviews will be available to the physician during the management of each interview and classification after the initial status (Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg G, Schmitt FA , Grundman M, Thomas RG, Ferris SH and the cooperative study of Alzheimer's disease, Validity and reliability of Alzheimer's Disease Cooperative Study - Clinical Global Printing of Change, Alzheimer's Dis. Assoc. Disorder, 2: S22 - S32; 1997). The doctor should only make decisions about the change without consulting other personnel. At the beginning of each interview, the doctor should warn the interviewee about abstaining from mentioning any side effects that they may experience. The valuation of the change from the initial stage is done in months 3, 6, 9, 12, 15, and 18. The valuation of the change in month 20 (at the end of the phase of withdrawal of the study) is not performed in relation to to the initial state, but in relation to month 18. Secondary efficacy variable (s) - psychometric exams Secondary clinical efficacy measurements and instants are as follows: Miniexamen of mental state (MMSE); The MMSE is a short essay, widely used to assess the global cognitive state. MMSE measurements selected aspects of cognition such as memory, orientation, attention, language, and praxis on a scale of 0 - 30. Lower scores indicate a greater cognitive decline. The MMSE is performed in the selection, the initial state, and in months 3, 6, 9, 12, 15, 18 and 20.

Alzheimer's disease assessment scale - modified co-routine subscale (ADAS - modified Cog); The modified ADAS - Cog is the same instrument as the ADAS - Cog of 11 articles described above with the addition of two articles - delayed memory recall and concentration / distraction. The modified ADAS - Cog is performed in the selection, the initial state, and in months 3, 6, 9, 12, 15, 18 and 20.

Clinical Clemency Evaluation - Sum of squares (CDR - SB) The CDR - SB is a measure of the severity of dementia in six domains that value cognition and function: memory, orientation, judgment and problem solving, community affairs, and home and hobbies. The evaluation of each domain will be agreed upon by the subject's assessment team (excluding the physician performing the ADCS-CGIC) after consideration of the results of all the trials conducted during a clinical visit. The CDR - SB consensus discussion should include the interview and assessment notes of the ADCS - CGIC interviewer, but the ADCS - CGIC interviewer does not participate in the CDR - SB discussion. The evaluations of each of the domains are added to provide a global clinical measurement, the sum of the boxes. The CDR - SB is performed in the initial state, in months 12, 18, and 20.

Neuropsychiatric Inventory (NPI) The Neuropsychiatric Inventory (NPI) is a 12-item scale of behavioral alterations that normally occur in subjects with dementia: delusions, hallucinations, agitation / aggression, depression / dysphoria, anxiety, joy / euphoria, apathy / indifference , disinhibition, irritability / instability, aberrant motor activity, sleep, and appetite and feeding 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 exhaustion of the caregiver (0-5) is also determined for each behavior. The NPI is performed in the initial state, in months 6, 12, and 18.

Functional assessment of Alzheimer's disease and scale of change (ADFACS). The ADFACS is a functional assessment instrument of 16 articles based on instrumental and basic activities of the daily life scales (ADL) commonly used in clinical research. Includes 6 basic ADL (neat, food, clothing, personal hygiene and grooming, bathroom and walk) and 10 ADL instrumental (ability to use phone, household chores, use of household appliances, money management, shopping, food preparation, ability to be inside and outside the home, hobbies and leisure activities, personal mail handling, and understanding of situations or explanations). The evaluation of each article is based on an interview with the subject's caregiver. Each of the basic ADL items is scored on a scale of 0 (no deterioration) to 4 (very severe impairment), providing a total basic ADL score of 0-24. Each of the instrumental ADL items is scored on a scale of 0 (no impairment) to 3 (severe impairment) providing a total instrumental ADL score of 0 - 30.

Therefore ADFACS of 16 global articles has a total score range of 0 - 54. ADFACS is performed in the initial state, in months 6, 12, and 18.

Disease modification: Withdrawal phase: At the end of month 18, subjects randomly assigned to receive an acetylcholine esterase inhibitor, for example, (donepezil) plus, for example, atorvastatin will continue to receive an acetylcholine esterase inhibitor, eg, (donepezil) plus atorvastatin until the end of the trial or they will be withdrawn from active atorvastatin therapy and will complete the study taking only donepezil therapy. This randomly predetermined second stage will be decided before the start of the study. Approximately 75% of subjects in active atorvastatin therapy will be redistributed randomly to withdraw them from active atorvastatin therapy. In this way, the subjects will be randomly distributed in the initial state so that in month 18, they are either: a. continue with the matching placebo plus an acetylcholine esterase inhibitor, for example (donepezil 10 mg) or b. continue with atorvastatin 80 mg plus an inhibitor of acetylcholine esterase, for example (donepezil 0 mg) or a. they withdraw from the treatment with atorvastatin 80 mg in this way the subjects receive 8 weeks of matching placebo plus an inhibitor of acetylcholine esterase, for example (donepezil 10 mg). Two study designs have been proposed (Leber 1996, 1997) that would indirectly evaluate changes in the disease procedure'57 '58).

MRI / MRS substudy; Neurological Imaging: Magnetic Resonance Imaging (MRI) / Magnetic Resonance Spectroscopy (MRS) In this MRI / MRS sub-study, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) will be used as Secondary efficacy variables to assess the effects of treatment on measures of disease progression in the brain. MRI is performed in the initial state and in month 18 to assess cerebral volumetric changes (global and regional atrophy). MRS is performed on the same visits to assess endogenous brain metabolites, including L-aspartate N-acetyl (NAA) and myoinositol (MI). The measurements of interest from MRI are global cerebral atrophy and regional cerebral atrophy (hippocampal atrophy) as defined by the rate of change in regional or global volumes,? volume / time. The measurements of interest for MRS are the change in N-acetyl aspartate with respect to creatine (NAA / Cr) and normalized NAA levels in the frontal cortex and occipital cortex, as well as Ml / Cr and MI / NAA and normalized MI levels. . Given the logistical complexity of obtaining neurological imaging studies, these are done in a subgroup of 200 subjects.

Apolipoproteins (Apo E and ApoB). Assay of serum samples for plasma lipids and biomarkers Plasma biomarkers of interest include β-amyloid peptide (β1-40, β1-42), S100b and 24-hydroxycholesterol (cerebrosterol) in plasma. Plasma biomarkers are collected in the initial state, months 3, 6, 12, 18 and 20 for analysis. S 100b is a molecule of intercellular signaling, involved in the regulation of calcium levels. Mrak R E, Griffin W. S. The role of activated astrocytes and of the neurotrophic cytokine S 100B in the pathogenesis of Alzheimer's disease. Neurobiol Aging, 22 (6): 915-22. Review; November - December 2001. Activated astrocytes have elevated S 100b levels that are produced by brain injury and inflammation. The S 100b level in CSF of mild to moderate AD patients is elevated in relation to matched control subjects according to age. Peskind E R, Griffin W S, Afama K T, Raskind M A, Van Eldik L J. Cerebrospinal fluid S 100b is elevated in the earlier stages of Alzheimer's disease. Neurochem Int., 39 (5-6): 409-413; November - December 2001. An increase in S 100b in the brain can also cause high levels of S 100b in the blood. In this way, the level of S 100b in plasma and the impact of medication on S 100b levels are evaluated.

Inclusion / exclusion criteria Inclusion criteria: > Written informed consent must be obtained from the subject, the carer and legal guardian of the subject (if applicable), before the start of any selection activity. If the subject is not able to provide written informed consent, verbal assent must be obtained from the subject in the presence of authorized representative and witnesses. The documentation of the verbal assent and the identity of those present should be done both in the source document and in the consent form. > Subjects and caregivers must be sufficiently skilled in their local language and be able to complete the assessments of the study in the selection and initial state. > Outpatients male and female, of any race, with ages between 50 and 90 inclusive. > Women who have experienced the appearance of spontaneous or surgical menopause before the beginning of the study and have been amenorrheic for at least 6 months. Spontaneous menopause is defined as the natural cessation of ovarian function. Surgical menopause is defined as bilateral oophorectomy with an intact uterus. > Diagnostic evidence of probable Alzheimer's disease consistent with the NINCDS / ADRDA and DMS IV criteria made by the local doctor at the time of selection. This evidence must be fully documented in the source document of the subject before the initial situation. The investigator should consider the severity of mild to moderate AD and the subject be otherwise in good health. > CT or MRI in the last 12 months consistent with a diagnosis of probable Alzheimer's disease and without any other clinically significant comorbid pathology. A copy of the report will be required and must be attached to the CRF. If there is a significant clinical change suggesting stroke or other possible neurological disease with appearance between the time of the last CT or MRI and the evaluation of the selection, the sweep may be repeated with the approval of the sponsors.

MRI / MRS Substudy: Subjects participating in the MRI substudy should be able to experience a specific MRI of the study in the initial state and in the 9 / month 18 visit (or early termination if there is at least 9 months after the initial state), independently of the programming of any previous neurological imaging study. The MRI in the initial state also serves as the MRI of selection to support the diagnosis of probable AD (including in those subjects for whom there has been a clinical change suggesting the possibility of comorbid pathology and for which a repetition of the exploration of neuroimaging). > The miniexamen mental state score (MMSE) of the Subject must be in the range of 13 - 25 (inclusive) in the selection. > The subjects must have been taking a stable dose of 10 mg of donepezil during > 3 months before the selection. > That the subjects do not take any medication antihyperlipidemic Hachinski's ischemia modified by Rosen from subjects (Rosen WG, Terry RD, Fuld PA, Karzman R, Peck A. Pathological Verification of Ischemic Score in Differentiation of Dementias, Ann Neurol., 7: 486-488; 1980) scale < 4. [Exceptions can be made case by case together with the sponsor for the selected subjects who do not meet the Hachinski scoring criteria, but who, in the researcher's clinical opinion, do not have multi-infarct dementia or dementia associated with the disease cerebrovascular disease (for example, without focal neurological signs or symptoms and no history of AVC)]. > The laboratory findings of the subjects must be within of normal limits, or if they are abnormal, judged clinically insignificant in the selection. (Any abnormality must be documented by the investigator as "not clinically significant," that is, not likely to produce cognitive decline or medical instability.) > The subjects should have LDL-C levels = 100 mg / dl and < 190 mg / dL, and do not require treatment for dyslipidemia with any lipid-lowering drug in the opinion of the investigator. > Subjects with a history or evidence of arterial disease coronary should be approved by medical control. Subjects with diabetes with a stable diet regimen and / or oral hypoglycemic agents and / or insulin are eligible provided they are regularly monitored to ensure the adequacy of diabetes control and are approved by medical control. Subjects with known diabetes should have an HbA-iC level < 10% and a fasting serum glucose value < 170 mg / dl. Subjects who meet the above criteria should also have LDL-C > 100 mg / dl and < 130 mg / dl. > The subjects must be able to ingest oral medication (tablets). The tablets should not be crushed. > The vital signs of the subject should be considered normal for age. The 12-lead ECG in subject selection should demonstrate predominantly sinus rhythm. Unimportant abnormalities (including sinus bradycardia <v50 beats per minute) documented as clinically insignificant by the investigator will be allowed. Subjects with clinically significant but stable ECG abnormalities can enter the trial only with documented permission (eg, telephone, in writing) from the sponsor. > Subjects with right bundle branch block (complete or partial) and pacemakers can be included in the study, if they are considered clinically stable. Subjects must have the same trusted caregiver or family member who agrees to accompany the subject in all planned visits, provide information about the subject as required by this protocol, and ensure compliance with medication planning. The caregiver must be a reliable and constant informant and must have contact at least 5 days a week with the subject and for a minute of 10 hours on alert a week. The investigator should judge this contact as adequate to ensure accurate reporting of the subject's behavior and ability to perform activities of daily living. > The subjects will be without sensory difficulties (for example, hearing or altered vision) or motor difficulties that impede their participation in all aspects of the study. [A walking stick is allowed) or walker.] > Subjects in assisted living situations where, in the The researcher's opinion and with approval of the medical control, he / she has the opportunity to perform and be evaluated for all activities of daily life as specified in the ADFACS. This life situation is expected to be maintained during the course of the study. > The cognitive potential assumptions of no Prescription / prescription (eg gingko, high dose of vitamin E, lecithin, estrogen, NSAID) are not excluded but should be disapproved. If a putative cognitive enhancer is allowed, the dosage should have been stable for at least 3 months before randomization and should not change during the course of the study.

Exclusion criteria: > Subjects who have received treatment with any cholinesterase inhibitor other than the acetylcholine esterase inhibitor assay within 3 months of selection. > Subjects that may not be able to meet the protocol or perform the result medications. > Subjects with any condition active or clinically significant that affects the absorption, distribution or metabolism of the study drugs (for example, inflammatory bowel disease, gastric or duodenal ulcers, severe lactose intolerance). > Subjects that currently or within the past five have met the DSM IV criteria for abuse or dependence on drugs or alcohol. Subjects with significant allergies to or intolerance significant of donepezii or piperidine derivatives or known hypersensitivity or intolerance to HMG - CoA reductase inhibitors. > The subjects are on any other reducing agent of lipids. > Subjects who have not tolerated 10 mg per day of treatment of donepezii in the three months before the selection. > Participation in any other study that involves research products or marketed simultaneously or in the 30 days or 5 half-lives before the selection, whichever is longer. > Subjects likely to require treatment during the study period with drugs not allowed by the study protocol. > Subjects who have donated blood or blood products for 30 days before the screening, or who plan to donate blood while participating in the study or within four weeks after the completion of the study. Subjects with a current DS - IV diagnosis of major depressive disorder (MDD), MDD in partial remission, or any current primary psychiatric diagnosis other than Alzheimer 's disease (such as for DSM - IV). > Subjects with complicated dementia are excluded by another organic disease or Alzheimer's disease with delirium (DSM 290.30 or 290.11). Psychiatric symptoms (for example, depression, anxiety, hallucinations) are common in AD, but subjects with pronounced severe symptoms such as those that guarantee an alternative simultaneous diagnosis should be excluded. > The subjects that, in the opinion of the researcher, represent currently a significant risk of suicide. > The subjects that, in the opinion of the researcher, would require treatment with electroconvulsive therapy (ECT). > Subjects with unstable psychiatric symptoms that, in the The investigator's option is likely to require major adjustments or modifications in psychotropic medication. > Subjects with a history or presence of disorders of seizures or encephalitis. > Subjects with CT scan or MRI consistent with the diagnosis of stroke, intracranial effusion, mass lesion, or normal-pressure hydrocephalus (NPH).

MRI / MRS Substudy All potential subjects for the MRI / MRS substudy will be assessed for contraindications to the MR examination. Any subject with contraindications for MR examination (eg, pacemaker, neurostimulation, aneurysm staples, etc.) will be excluded from the substudy. The assessment will occur during both the initial state and in the sweep in month 18. Subjects with dementia due to causes other than Alzheimer disease. These include toxic, alcoholic or vascular etiologies, and medical disorders such as HIV, Parkinson's disease, Lewy body dementia, Huntington's disease, Pick's disease, Creutzfeld-Jacob's disease and neurosyphilis. > Subjects with a history of cognitive deficits immediately after cephalic trauma. Subjects with severe cephalic trauma with loss of consciousness require the investigator to make a judgment. (Note: a remote history of cephalic trauma without cognitive sequelae is not excluded). > Subjects who are hospitalized or reside in a full of specialized assistance or subjects that are expected to enter a nursing home during the course of study. > Subjects with a history of deep vein thrombosis, pulmonary embolism or any other thromboembolic disorder. > The subjects who have taken simultaneous medications Prohibited before the selection. > Subjects who currently experience any condition clinically significant or instable medical that includes: dermatological disease, hematological disease, lung disease, cardiovascular disease, kidney disease, liver disease, gastrointestinal disease, genitourinary disease, endocrine disease, neurological disease (other than Alzheimer's disease). > Subjects who have suffered serious infections or a important surgical operation within three months before the selection (for example, septicemia, coronary angioplasty, coronary artery bypass graft, chain replacement). > Subjects with a history of malignant neoplasm treated within 5 years prior to participation in the study (other than basal or squamous cell carcinoma of the skin) or where there is current evidence of recurrent or mastastic disease. > Subjects with a vitamin B-t2 deficiency. Nevertheless, Subjects with a stable dose of medication for at least 3 months before screening, and who have normal serum B12 levels in the selection, will be acceptable. The stable dose should be maintained throughout the study. > Subjects with hypothyroidism and uncontrolled hyperthyroidism.

Subjects with a stable dose of medication for at least 3 months before selection with normal TSH and free T4 in the selection are considered euthyroid and will be acceptable. The stable dose should be maintained throughout the study. > Subjects with impaired hepatic function, as shown but it is not limited to AST (SGOT) or ALT (SGPT) > 3.0 times the upper limit of normal in the selection. > Subjects with a BUN value > 30 mg / dl in the selection. > Subjects with serum creatinine > 3.0 mg / dl or any proteinuria greater than "signs" present in urinalysis in the selection. > Subjects with CPK values (creatine phosphokinase) > 5 times the upper limit of normal range in the selection. > Subjects with lipid reduction therapy within the last 6 months. > Subjects with a serum triglyceride level > 500 mg / dl. > Subjects with uncontrolled hypertension (diastolic BP in been sitting > 95 mm Hg and systolic > 160 mm Hg), as determined by the Investigator, regardless of whether or not to take a simultaneous antihypertensive medication. Any other condition, which in the opinion of the researcher may increase the risk to the subject or decrease the reliability of the data required to meet the objectives of the study.

The following medications / therapies are prohibited during the study: • All antilipidemic medications [eg, niacin, probucol, fibrates and derivatives, bile acid sequestrant resins, xenical, HMG-CoA reductase inhibitors, psyllium derivatives including metamucil (> 2 teaspoons a day) or fish oil.] • Known drugs that are associated with rhabdomyolysis in combination with HMG-CoA reductase inhibitors (eg, cyclosporine, erythromycin, etc.) If these drugs are temporarily needed during the study, the study medication should be properly discontinued • Azole antifungals • Any immunosuppressive agent (eg, cyclosporine, mycophenolate mofetil) • Known drugs that have significant adverse effects on lipid levels such as all retinoids including isotretinoin.

• If antacids are to be used, do not take at the same time as the study drug. It is allowed to take it at least two hours before or two hours after the study drug. The following medications are NOT ALLOWED as simultaneous medications during the study.

ANALGESICOS Tramado I Ultram ANTICOLINERGICOS COMMERCIAL NAME GENERIC NAME Benztropine Cogentin ® Amantadine Simmetrel Cyproheptadine Periactina Dicyclomine Bentil Diphenhydramine Benadryl, Sominex, 2, Diphenoxylate with atropine Lomotil benilin Hydroxyzine Vistaril, Atarax Meclizine Antivert, bonina Orphenadrine Citrate Oxybutynin Ditropan Prochlorperazine Compazine Norflex Promethazine Phenergan Trihexyphenidyl Artano Trimetobezamida Tigan ANTICONVULSIVOS NOMBRE GENERICO NOMBRE COMERCIAL ® Carbamazepine Tegretol Clonazepan Klonopin Clozabazam Etosuximide Zarontln LIST OF PROHIBITED MEDICATIONS Felbamate Felbatol Levitiracetam Kepra Lamotrigine Lamictal Phenobarbital Phenytoin Dilantin Primidone Misolina Topimarate Topamax Valproate Depakene, Depakote Vigabatrin Sabril ANTIDEPRESSANTS GENERIC NAME COMMERCIAL NAME ® Amitriptyline Elavil Amoxapine Asendin Bupropion Welbutrin, Zyban Clomipramine Anafranil Desipramine Norpramin, pertofrane Doxepin Sinequan Imipramine Tofranil Isocarboxazide Marplan Lithium Maprotiline Ludiomil Mirtazapine Remeron Nefazodone Serzona Nortriptyline Aventil, Pamelor Fenelzine Nardil Protriptiline Vivactil Tranilcipromine Parnate Trimipramine Surmonil LIST OF PROHIBITED MEDICATIONS ANTIPYSCOTICS Chlorpromazine Thozarine Flufenazine Prolixin, permitil Thioridazine Mellaril Loxapine Loxitane Clozapine Clozaril Molindone Moban ANTIFUNGIC AGENTS GENERIC NAME COMMERCIAL NAME ® Ancobon Flucytosine Amphotericin B Intravenous Fungizone, Anfotec. AmBisome, Abelcet Ketoconazole Nizoral Fluconazole Diflucan Griseofulvin Fulvicin U / F, Grifulvin V, Grisactin Nistatin Nistatin, Micostatin, Nilsat Intraconazole Sporanox ANTIPARKINSONIAN AGENTS NOMBRE GENERICO NOMBRE COMERCIAL ® Biperiden Akineton Bromocriptine Parlodel Levodopa Larodopa, Sinemet Pergolide Permax Ropinerol Requip Selegliline Deprenil, Eldepril Tolcapona Tasmar LIST OF PROHIBITED MEDICATIONS ANSIOLITICS GENERIC NAME COMMERCIAL NAME ® Alprazolam Xanax Clorazepate Tranxeno Chlordiazepoxide Librium Diazepam Valium Estrazolam ProSom Flurazepam Dalmane Meprobamate Equanil, Equagesic, Miltown Oxazepam Serax Temazepam Restroril Triazolam Halcion COLINOMIMETIC AGENTS NAME GENERIC NAME COMMERCIAL ® Beta ñeco I Duvoid, urecoline Galantamine Remlnil Fisostigmine Pyridostigmine Pyridostigmine Mestinon Rivastigmine Exelon Tetrahydroaminoacidine (tacrine) Cognex * Except acetylcholine esterase inhibitor compound of the subject's trial.

**** CYTOCHROME INHIBITORS P450 - 3A4 GENERIC NAME COMMERCIAL NAME ® Amiodarone Cordarone, Pacerone Cannabinoids Cimetidine Tagamet Clarithromycin Biaxin LIST OF PROHIDED MEDICATIONS Clotrimazole Lotrimin, Mycelex Ciclosporin Gengraf, Neoral, Sandinmune Danazol Danocrine Erythromycin Ery - Tab Fluconazole Diflucan Indinavir Crixivan Itraconazole Sporanox Cetoconazole Nizole ral Miconazole Nelfinavir Viracept Nicardipine Norfloxacin Omeprazole Prilosec Propoxyphene Darvon, Darvon Pulvule Quinidine Quinidex Extentab, Quinaglute - Dura -Tab Ritonavir Kaletra, Norvir Saquinavir Fortovase, Invarise Troleandomycin Tao Zafirlukast Zileuton ERYTHROMYCINMA NAME GENERIC NAME COMMERCIAL ® Erythromycin base E - Micin, Ery - Tab, ERYC, Erythromycin, delayed erythromycin release, PCE Dispertab Erythromycin ethylsuccinate Pediazole Acetyl sulfisoxazole LIST OF PROHIBITED MEDICATIONS IMMUNOSUPPRESSIVE AGENTS GENERIC NAME COMMERCIAL NAME ® Atom lymphocyte immunoglobulin Rho immunoglobulin (D) HypRho-D, MICRhoGAM, Rohm Azathiopan sodium Imuran Basiliximab Simulect Muromonab - CD3 Ortoclone OKT3 Cyclosporine Gengraf, Neoral, Sandinmune Mycophenolate Mofetil Celicept Daclizumab Zenapax Glatiramer Acetate Copaxone Tacrolimus Prograf Sirolimus Rapamune PHARMACOS REGULATORS OF LIPID NAME GENERIC NAME COMMERCIAL ® Niacin / nicotinic acid Niacor, nicobid, nicolar, Slo - Niacin Probucol Lorelco Clofibrate Atromid - 5 Cholibar cholesterrin, Questran, Questran (light), Prevalita, the CHOLEST Colesevelam WelChol Colestipol Colestid hydrochloride Gemfibrozil Lopid Fish oils (omega -3 fatty acids only prescription) Fluvastatin Lescol Lovastatin Mevacor Pravastatin Pravacol Simvastatin Zocor Cerivastatin Baychol Orlistat Xenical LIST OF PROHIBITED MEDICATIONS Fenofibrate Tricor Sodium Dextrothyroxine Choloxin Rosuvastatin Crestor STIMULANTS NAME GENERIC NAME COMMERCIAL ® Amphetamine Dexedrine Methylphenidate Ritalin Pemoline Cilert OTHER AGENTS GENERIC NAME COMMERCIAL NAME ® Cyclobenzaprine Flexeril Ergoloid mesylate Hidergine Isotretinoin Accutane Isoxsuprine Vasodilan Memantine Ebixa Metocarbamol Robaxin Mibefradil dihydrochloride Posicor Mitoxantrone Novantrone Nimodipine Nimotop Oxybutynin Ditropan Papaverine Pavabid Medications allowed with restrictions Supposed cognitive potentiators The so-called cognitive potentiators of no prescription / prescription (for example, gingko, vitamin E in high doses, lecithin, estrogen, NSAID) are not excluded but should be disapproved. If a putative cognitive enhancer is allowed, the dose should have been stable for at least 3 months before randomization and should not change during the course of the study.

Clinical laboratory parameters 1. Complete clinical laboratory Hematology RBC Hemoglobin Hematocrit WBC Platelet count Differential (if WBC is normal) Neutrophils Lymphocytes Monocytes Eosinophils Basophils Chemistry SGOT (AST) SGPT (ALT) Alkaline phosphatase LDH CPK (CPK - MB if CPK rises above 5 times the upper limit) Blood urea nitrogen Chloride Creatinine Uric acid Total protein Albumin Sodium Potassium Glucose Globulin Phosphorus Calcium HbA1c (at visit 1 only) Total bilirubin C-reactive protein TSH level (in visit 1 only) Free T4 (in visit 1 only) B12 (in visit 1 only) RBC folate (in visit 1 only) Hepatitis C serology (at visit 1 only) RPR (at visit 1 only) Lipid profile Total cholesterol LDL - C VLDL - C Triglycerides HDL - C Apo B Apo E Sampling plasma ß - amyloid (A ß 1 - 40, A ß 1 - 42) S - 100b 24 S-hydroxycholesterol (cerebrosterol) RBC AChE - 1 Urine test Determination by dipstick test of leukocytes Nitrite Urobilinogen Protein PH Blood Specific weight Glucose ketone TABLE 1 Table 1 below summarizes the experimental method described in detail above. APPENDIX L - Study flow plan / yaws of observations Protocol A2581078 Procedure / Visit 1 of Visit 2 in Week 6 Month 3 Month 6 Month 9 Month 12 Month 15 Month 18 Month 20 Assessment of state selection Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 study Days - 14 to initial / Day 42 + 7 Day 84 ± Day 168 + 7 Day 252 ± 7 Day 336 ± 7 Day 420 ± 7 End Visi -1 ± 7 end 7 Early End / random visit Double - Day 0? Blind day Termination 504 + 7? Early Day 560 ± 7 X Consents informed Medical history X Physical exam X ''? ' X '?' X1 Assessment of x ¿X physical state Exam X X X X neurological Procedure / Visit 1 of Visit 2 in Week 6 Month 3 Month 6 Month 9 Month 12 Month 15 Month 18 Month 20 Assessment of Selection State Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 Study Days -14 a Initial / Day 42 ± 7 Day 84 ± 7 Day 168 ± 7 Day 252 ± 7 Day 336 ± Day 420 ± 7 Final Termination / visit -1 ± 7 Distribution 7 Early Random Double - Termination Day 0? Blind Early day 504 ± 7? Day 560 ± 7 Vital Signs X X X X X X X X X Reviews of Xa X X X X X X X Laboratory (chemistry / hematol ogy) Urinalysis X X X X X X Lipid profile in X X X X X X serum Biomarkers X X X X X X in Plasma6 Sampling of X genotype Anonymous7 Sampling of X X Archived serum Procedure / Visit 1 of Visit 2 in Week 6 Month 3 Month 6 Month 9 Month 12 Month 15 Month 18 Month 20 Assessment of Selection State Visit 3 Visit 4 day Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 Study Days - 14 a Initial / Day 42 ± 7 84 ± 7 Day 168 +7 Day 252 ± 7 Day 336 +7 Day 420 ± 7 End Visit -1 ± 7 Final Early Distribution / Random Double visit - From Day 0? Blind day Termination 504 ± 7? Early Day 560 ± 7 Levels of X X donepezil and RBC AChE -1 ECG X X X Subjects from ?? X4"MRI / MRS substudy Only MRI / CT X scan (only in the selection) * Medications X X X X X X X X X X Simultaneous Adverse episodes X X X X X X X X Procedure / Visit 1 of Visit 2 in Week 6 Month 3 Month 6 Month 9 Month 12 Month 15 Month 18 Month 20 Assessment of Selection State Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 Study Days - 14 a Initial Day 42 + 7 Day 84 ± 7 Day 168 ± 7 Day 252 ± 7 Day 336 ± 7 Day 420 ± 7 End Visit -1 ± 7 Final Early Distribution / Random visit Double - Day 0? Blind day Termination 504 ± 7? Early Day 560 ± 7 Miniexamen of X X X X X X X X X X Mental state (MMSE) Scale of X X X X X X X X X X evaluation of Alzheimer's disease-Cognitive scale (ADAS COG) Study XJ X X X X X X X X Cooperative of Alheimer's disease-Clinical Global impression of (ADCS-CGIC) Procedure / Visit 1 of Visit 2 in Week 6 Month 3 Month 6 Month 9 Month 12 Month 15 Month 18 Month 20 Assessment of Selection State Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 Study Days -14 a Initial / Day 42 ± 7 Day 84 ± 7 Day 168 ± 7 Day 252 ± 7 Day 336 ± 7 Day 420 ± 7 End Visit -1 ± 7 Final Early Distribution / Double Random visit - From Day 0? blind day Termination 504 ± 7? Early Day 560 ± 7 Inventory X X X X neuropsychiatric (NPI) Evaluation of X X X X clinical dementia-sum of squares (CDR-SB) Hachinski X modified by Rosen Procedure / Visit 1 of Visit 2 in Week 6 Month 3 Month 6 Month 9 Month 12 Month 15 Month 18 Month 20 Assessment of Selection State Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 Study Days -14 a Initial / Day 42 ± 7 Day 84 ± 7 Day 168 ± 7 Day 252 ± 7 Day 336 ± 7 Day 420 ± 7 End Visit -1 ± 7 Final Early Distribution / Double Random visit - From Day 0? blind day Termination 504 ± 7? Early Day 560 + 7 X X X X functional assessment of Alzheimer's disease and scale of change (ADFACS). X X X X questionnaire caregiver burden Questionnaire X X X X Use of health care source Patient Dispenses of X X X X X X X donepezil Procedure / Visit 1 of Visit 2 in Week 6 Month 3 Month 6 Month 9 Month 12 Month 15 Month 18 Month 20 Assessment of Selection state Visit 3. Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 study Days -14 a Initial / Day 42 ± 7 Day 84 ± 7 Day 168 ± 7 Day 252 ± 7 Day 336 ± 7 Day 420 ± 7 End Visit -1 ± 7 Final Early Distribution / Random visit Double - Day 0? Blind day Termination 504 ± 7? Early Day 560 ± 7 Scattering X X X X X X X3 Double Blind Study Medication Checking X X X X X X X Drug compliance Complete physical examination dispensation of withdrawal maneuver medication 2 Modified physical examination * MRI / CT scan beforehand should diagnose probable AD within 12 months before the screening visit 3Initial survey of initial status and videotape for subject and caregiver Visits with peripheral biomarkers include ß - amyloid (A B1-40, A ß 1 -42), S 100 by cerebrosterol MRI / MRS mode on month 18 / early termination visit 7 Includes ApoE only if the subject is interrupted at month 9 or 9 later 8Serology only in the initial MRI / MRS search, initial status must be -10 days from the start 8Serología only in the selection of the study medication and during month 18 + / - 10 days of the planned visit

Claims

NOVELTY OF THE INVENTION CLAIMS

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 according to claim 1, further characterized in that it comprises: a fixed combination selected from the group consisting of: a statin, 5 mg active and an inhibitor of acetylcholine esterase, 10 mg active; a statin, 10 mg active and an inhibitor of acetylcholine esterase, 10 mg active; a statin, 20 mg active and an inhibitor of acetylcholine esterase, 10 mg active; calcium atorvastatin, 40 mg active and an acetylcholine esterase inhibitor, 10 mg active; a statin, 80 mg active and an inhibitor of acetylcholine esterase, 10 mg active; a statin, 5 mg active and an inhibitor of acetylcholine esterase, 5 mg active; a statin, 10 mg active and an inhibitor of acetylcholine esterase, 5 mg active; a statin, 20 mg active and an inhibitor of acetylcholine esterase, 5 mg active; a statin, 40 mg active and an inhibitor of acetylcholine esterase, 5 mg active; and a statin, 80 mg active and an inhibitor of acetylcholine esterase, 5 mg active.

3. - The pharmaceutical composition according to claim 1 or claim 2, further characterized in that it comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition according to claim 3, further characterized in that it comprises 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 composition to achieve a modifying effect of Alzheimer's disease in a mammal suffering from Alzheimer's disease, said modifying effect of Alzheimer's disease being greater than the sum of the effects achieved by administration of 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 an amount of Donepezil or a pharmaceutically acceptable carrier or diluent.

7. The use of the pharmaceutical composition defined in any one of claims 1-6, respectively, for the manufacture of a medicament for treating Aizheimer's disease.

8. The use of the pharmaceutical composition defined in any one of claims 1-6, respectively, for the manufacture of a medicament for stabilizing the symptoms of Aizheimer's disease in a mammal that requires stabilization.

9. The use as claimed in claim 8, wherein said stabilization is assessed by the disease evaluation scale of Aizheimer - cognitive subscale (ADAS - Cog), or through the cooperative study of Aizheimer's disease - global clinical impression of scale of change (ADCS - CGIC).

10. - A method of treatment or prevention of a mammal that has been diagnosed with Aizheimer's disease or the risk of Aizheimer's disease, which can benefit from the therapy through the combined administration of both (a) and ( b) subsequent, and therefore the administration of both (a) and (b) has been prescribed, which comprises the administration to said mammal in this way 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 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 simple pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.