The temporal origin of Alzheimer's disease (AD) and markers of progression of this disease process are relatively obscure. Despite outstanding advances in the understanding of the underlying biology of AD, the clinical diagnosis is still made by consensus following progressive cognitive deterioration and confirmed only at autopsy. The protocol will serve two functions. First, we will evaluate and longitudinally follow a cohort of first-degree relatives of AD subjects who are currently normal but are at increased risk of developing AD sometime in the future. This cohort will be compared to a group of normal controls along multiple behavioral, cognitive, motor function, genetic and biologic parameters over a period of years. While differential rates of conversion to AD might eventually be expected based on family history and other fixed variables (i.e., APO E status), this study is not powered to simply be a study of conversion to AD. Rather, it is a study of biomarker change over time in a distinct cohort of people with increased risk of developing AD. Conversion to a clinical diagnosis of AD is only one of the variables; others will include cognitive testing, neuroimaging, genetic markers, assessment of functional capacities and cerebrospinal fluid (CSF) measures that may ultimately function as disease surrogates. As part of this at risk cohort, we will recruit and longitudinally follow a series of pre-symptomatic and symptomatic subjects with known genetic mutations (presenilin 1, presenilin 2, or APP). Second, we will follow a large cohort of dementia subjects themselves for whom the diagnosis is either AD or some other related dementia. The purpose of this second part of the follow-up study is to identify and track those biologic changes that occur with progressive illness and, furthermore, to relate those changes to the known cognitive and emotional disturbances which characterize AD.

By longitudinally following separate cohorts of normal controls without a family history of AD, normal controls with a family history of AD, subjects with mild cognitive impairments and diagnosed dementia subjects, we hope to track the spectrum of AD from its clinical and biologic origins. As a result, this study is both a diagnostic screening protocol and a natural history protocol. It will address a series of important clinical and biological questions among a wide range of normal and diseased individuals and should serve as a basis for the development of biologic markers in AD that could be used for diagnostic and therapeutic purposes in the future. A long-term goal of this protocol to identify markers and eventually individual people who are at increased risk of developing AD before the typical cognitive changes of AD become manifest. In pursuit of that goal, we will also carefully monitor and evaluate the clinical medications taken by our subjects to see if they influence the course of AD.