Title:  Methods for determining risk of Alzheimer's disease

United States Patent:  6,440,387

Issued:  August 27, 2002

Inventors:  Yankner; Bruce A. (West Newton, MA); Nadeau; Philip (Boston, MA)

Assignee:  Children's Medical Center Corporation (Boston, MA)

Appl. No.:  239387

Filed:  January 28, 1999

Blood cholesterol levels are correlated with production of amyloid .beta. protein (A.beta.), and are predictors of populations at risk of developing AD. Methods for lowering blood cholesterol levels can be used to decrease production of A.beta., thereby decreasing the risk of developing AD. The same methods and compositions can also be used for treating individuals diagnosed with AD. Methods include administration of compounds which increase uptake of cholesterol by the liver, such as the administration of HMG CoA reductase inhibitors, administration of compounds which block endogenous cholesterol production, such as administration of HMG CoA reductase inhibitors, administration of compositions which prevent uptake of dietary cholesterol, and administration of combinations of any of these which are effective to lower blood cholesterol levels. Methods have also been developed to predict populations at risk, based on the role of cholesterol in production of A.beta.. For example, individuals with Apo E4 and high cholesterol, defined as a blood cholesterol level of greater than 200 mg/dl, post menopausal women with high cholesterol levels--especially those who are not taking estrogen, or individuals which high blood cholesterol levels who are not obese are all at risk of developing AD if blood cholesterol levels are not decreased.

DETAILED DESCRIPTION OF THE INVENTION

I. Methods for Predicting Populations at Risk for AD

Individuals at increased risk for A.beta. accumulation and Alzheimer's disease are those who carry a copy of the apolipoprotein E4 gene (Strittmatter et al., (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 1977-1981), those with trisomy 21 (Down's syndrome) (Mann and Esiri, (1989) J. Neurol. Sci. 89, 169-179)), and individuals who carry a mutation in one of the genes that encode the amyloid precursor protein, presenilin-1 or presenilin-2 (reviewed in Yankner, 1996). In addition, individuals with a family history of Alzheimer's disease have been documented to be at increased risk of Alzheimer's disease (Farrer et al., (1989) Ann. Neurol. 25, 485-492; van Duijn et al., (1991) Int. J. Epidemiol. 20 (suppl 2). S13-S20), and could therefore benefit from prophylactic treatment with an HMG CoA reductase inhibitor.

Methods have also been developed to predict populations at risk, based on the role of cholesterol in production of A.beta.. Several risk factors for developing AD have been identified. These include:

(1) individuals with Apo E4 and high cholesterol, defined as a blood cholesterol level of greater than 200 mg/dl,

(2) post menopausal women with high cholesterol, especially those who are not taking estrogen,

(3) young individuals with high blood cholesterol levels who are not obese (age 48-65 yrs),

(4) individuals with high blood cholesterol levels who have a family history of AD,

(5) individuals with high blood cholesterol levels who have a family history of AD, and

(6) all adult individuals with Down's syndrome.

These individuals are all at risk of developing AD if blood cholesterol levels are not decreased. In the preferred embodiment, individuals with these risk factors are treated to lower blood cholesterol levels prior to developing any mental impairment attributable to AD using accepted neuropsychiatric and diagnostic criteria for probable Alzheimer's disease (McKhahn et al. (1984) Neurology 34:939-944).

Individuals can be screened using standard blood tests for cholesterol, ApoE4, and/or total lipoprotein levels, as well as by taking a medical and family history. In addition, over the counter immunoassay tests can be used by individuals who may be at risk, so that they can seek further medical advise. These immunoassay kits can be qualitative and/or quantitative for elevated cholesterol, total lipoproteins, and Apo E4.

II. Methods of Treatment to Decrease Production of A.beta..

Methods for lowering blood cholesterol levels can be used to decrease production of A.beta., thereby decreasing the risk of developing AD. The same methods can also be used to treat patients who have already been diagnosed with AD. Methods include administration of compounds which increase uptake of cholesterol by the liver, such as the administration of HMG CoA reductase inhibitors, administration of compounds which. block endogenous cholesterol production, such as administration of HMG CoA reductase inhibitors, administration of compositions which prevent uptake of dietary cholesterol, and administration of combinations of any of these which are effective to lower blood cholesterol levels.

The examples indicate that several different HMG CoA reductase inhibitors reduce the production of A.beta.. HMG CoA reductase inhibitors may act to lower cholesterol at several different levels. For example, HMG CoA reductase inhibitors have been shown to lower blood cholesterol levels by upregulating lipoprotein clearance receptors in the liver (Brown and Goldstein, (1986) Science 232, 3447). In addition, HMG CoA reductase inhibitors will directly inhibit cholesterol synthesis in neurons. Since every HMG CoA reductase inhibitor tested reduces A.beta. production, it is anticipated that new members of this class of drugs will also inhibit A.beta. production. Furthermore, since increased dietary cholesterol increases A.beta. in the brain, drugs which act through other mechanisms to reduce cholesterol will also inhibit A.beta. production.

Representative CoA reductase inhibitors include the statins, including lovastatin, simvastatin, compactin, fluvastatin, atorvastatin, cerivastatin, and pravastin. These are typically administered orally.

Compounds which inhibit cholesterol biosynthetic enzymes, including 2,3-oxidosqualene cyclase. squalene synthase, and 7-dehydrocholesterol reductase, can also be used.

Representative compositions which decrease uptake of dietary cholesterol include the bile acid binding resins (cholestryramine and colestipol) and the fibrates (clofibrate). Probucol, nicotinic acid, garlic and garlic derivatives, and psyllium are also used to lower blood cholesterol levels. Probucol and the fibrates increase the metabolism of cholesterol-containing lipoproteins. The cholesterol-lowering mechanism of nicotinic acid is not understood.

Although the preferential route of administration of HMG CoA reductase inhibitors would be oral, the drugs could also by administered by intravenous, subcutaneous or intramuscular routes. In some cases, direct administration into the cerebrospinal fluid may be efficacious.

Claim 1 of 6 Claims

We claim:

1. A method for predicting if a person is at risk of developing Alzheimer's Disease but has not yet developing the clinical signs of Alzheimer's Disease comprising determining if the person has elevated blood levels of cholesterol, wherein the level is 200 mg/dl or greater.
 

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