The goal of this project is to determine if a cholinesterase inhibitor is more effective than placebo in delaying cognitive and brain functional decline in people at risk for Alzheimer's disease.

Studies to date show that pictures of the brain using PET (positron emission tomography) scan measures predict memory decline in people with genetic risks for developing AD. They have also been shown to predict memory decline in people with mild memory complaints. These findings are consistent with other evidence that the changes of Alzheimer's Disease (AD) begin years before the doctor can confirm a diagnosis.

In this study, PET and genetic risk studies will be performed in people with mild memory complaints. A total of 138 participants (age 40 to 90 years) who are at risk for further memory decline will be enrolled. They will be randomized (like the flip of a coin) to one of two treatment groups, donepezil (a medication to treat mild AD) or placebo, and followed 18 months for evidence of future decline. Participants will receive magnetic resonance imaging (MRI) scans, PET scans, genetic risk assessment for Alzheimer's Disease, and neuropsychological assessments. Repeat brain imaging studies will be performed at the end of the 18-month treatment trial.

These procedures will allow researchers to explore how baseline brain function and genetic risk for AD onset influences brain metabolic rate and memory decline, and treatment outcome. Participants receiving donepezil are expected to show less evidence of decline than those receiving placebo. This project will expand a growing research program in early detection and prevention of AD, designed (1) to identify persons without memory complaints who are most likely to benefit from early intervention and (2) to provide an objective way to monitor the activity in the brain.

Inclusion Criteria:

• Agreement to participate in a 18 month clinical trial
• NIMH diagnostic criteria for age-associated memory impairment (AAMI)
• Age 40 to 90 years
• MMSE score between 24 and 30 (unless < 8 years of educational achievement)
• No significant cerebrovascular disease - modified Ischemic Score of < 4
• The following medications are allowed if stable for > 1 month: antidepressants (without anticholinergic effects) if not currently depressed and no history of major depression for 2 years; estrogen replacement therapy; thyroid replacement therapy as long as patient is euthyroid
• On entering the study, there must be a family member or potential caregiver available in case the patient develops cognitive impairment that interferes with independent study participation.
• Memory and verbal fluency cut-off scores increasing the probability of incipient dementia (Buschke-Fuld - 34; verbal fluency - 46 for letters, 7 for categories; Benton Visual Retention - 5)
• Adequate visual and auditory acuity to allow neuropsychological testing
• Screening laboratory tests and ECG without significant abnormalities that might interfere with the study

Exclusion Criteria:

• Diagnosis of possible or probable AD or any other dementia (e.g., vascular, Lewy body, frontotemporal)
• Evidence of neurologic or other physical illness that could produce cognitive deterioration, including Parkinson's disease; volunteers with a history of TIAs, carotid bruits, or lacunes on MRI scan will be excluded
• History of myocardial infarction within the previous year or unstable cardiac disease
• Uncontrolled hypertension, history of significant liver disease, clinically significant pulmonary disease, diabetes, or cancer
• Such current major psychiatric disorders as mania, according to DSMIV criteria, within the previous two years
• Current diagnosis or history of alcoholism or drug dependence
• Evidence of untreated depression
• Use of any of the following drugs: centrally active beta-blockers, narcotics, clonidine, anti-Parkinsonian medications, antipsychotics, benzodiazepines, systemic corticosteroids, medications with significant cholinergic or anticholinergic effects, anti-convulsants, or warfarin; vitamins other than the standard multivitamin supplement, ginkgo biloba, and any nutraceuticals will not be allowed; once enrolled in the study, occasional chloral hydrate use will be allowed, but discouraged, for insomnia
• Use of any investigational drugs within the previous month or longer, depending on drug half-life
• Contraindication for MRI scan (e.g., metal in body, claustrophobia)