GENETIC MAPPING OF LATE-ONSET ALZHEIMER'S DISEASE GENES

阿尔茨海默病(AD)是老年人痴呆症的最常见原因。这种使人衰弱的神经退行性疾病的病因尚不清楚。大量证据表明，阿尔茨海默病有遗传基础。这些证据包括鉴定出突变导致早发性家族性AD （FAD）的三个基因：淀粉样蛋白前体蛋白（APP）基因，以及染色体14和1上的早老素1 （PSEN1）和早老素2 （PSEN2）。迟发性AD （LO）是一种更为复杂的多因素疾病，只有APOE被确定为危险因素。APOE也影响LO AD的发病年龄，最近的证据也表明APOE对PSEN1和PSEN2突变诱导的AD的发病年龄有影响。这一证据为遗传基础的发病年龄跨越了广泛的阿尔茨海默病发病范围，加上

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.