GENETIC MAPPING OF LATE-ONSET ALZHEIMER'S DISEASE GENES

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Alzheimer's disease (AD) is the most common cause of dementia in the elderly. The causes of this debilitating neurodegenerative disease are unknown. A large body of evidence indicates that AD has a genetic basis. This evidence includes the identification of three genes in which mutations cause early-onset familial AD (FAD): the amyloid precursor protein (APP) gene, and presenilin 1 (PSEN1) and presenilin 2 (PSEN2) on chromosomes 14 and 1, respectively. Late onset (LO) AD is a more complex, multifactorial disease, with only APOE identified is a risk factor. APOE also affects age-at-onset of LO AD, with recent evidence also showing that there are effects of APOE on age-at-onset of AD induced by mutations in PSEN1 and PSEN2. This evidence for genetic basis of age-at-onset across a wide range of onset of AD, coupled with information supporting the existence of additional such genes, indicates that elucidation of the genetic basis of age-at-onset orf AD would contribute to understanding of the general etiology of AD. The long-range goal of this project is to identify the underlying causes of AD by identifying genes that contribute to the disease. The goal of the current project is to focus on the genetic basis of age-at-onset. The specific aims are (1) To identify chromosomal regions containing LO-FAD age-at-onset loci in the UW ADRC data set; (2) To identify chromosomal regions containing LO-FAD age-at-onset loci in the NIMH LO-FAD dataset; and (3) To more accurately resolve the size of the regions of interest detected in the analysis of both of these data sets including more accuractly localizing such QTLs, determining whether linkage disequlibrium can be detected, and evaluating candidate genes in the regions of interest. Identifcation of genes affecting AD age-at-onset will facilitate an understanding of the etiology of AD, lead to better diagnostic methods, and potentally also to improved therapeutic and preventative measures.