Donepezil and Brain Activity Patterns in Those at Risk For Alzheimer's Disease

Efficacy of Donepezil in Normalizing Brain Activation Patterns in People Genetically at Risk for Alzheimer's Disease

The purpose of the study is to examine patterns of brain activity in people who are at risk for memory problems (e.g., Alzheimer's disease or dementia)before and after the medication donepezil. Although genetic testing will be done, the results will not be shared with study participants. Once the genetic testing is completed subjects may continue to the second phase of the study. During this time they will be asked to take the medication donepezil (which is approved by the FDA for the treatment of Alzheimer's disease). Donepezil is not FDA approved for healthy volunteers and is therefore considered investigational in this study.

HYPOTHESIS Cognitively intact individuals with normal brain morphology at genetic risk for developing Alzheimer's' Disease (AD) show alterations in brain activation patterns during tasks that require memory compared to similar individuals with lower risk for developing AD. Donepezil, a cholinesterase inhibitor, can normalize such brain activation patterns in subjects at risk for AD. SPECIFIC AIMS To replicate a recent study1, and compare brain activation in subjects genetically at risk for AD (carriers of the є4 allele of the apolipoprotein E gene (APOE)) with subjects at lower risk for AD (lacking the є4 allele) during tasks that require memory, via functional magnetic resonance imaging (fMRI). To determine if administration of a drug currently indicated in the treatment of AD, donepezil, can reverse fMRI brain activation patterns of at risk subjects to patterns similar to those of subjects at lower genetic risk for AD.

Inclusion Criteria: Subjects may report experiencing subjective memory dysfunction, however they must be found by clinical evaluation to have no memory dysfunction Neuropsychological test battery in the normal range Ages 40-85 Exclusion Criteria: Dementia (Mini-Mental State Exam less than 25/30) Left-handedness Current medication that could influence cognition Medical, psychiatric, and neurologic conditions, including cerebrovascular disease or uncontrolled hypertension Claustrophobia Surgical clips or implants Pacemakers or other implanted electronic devices History of sheet metal work

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