GENETIC MAPPING OF LATE-ONSET ALZHEIMER'S DISEASE GENES

阿尔茨海默病(AD)是导致老年人痴呆的最常见原因。这种衰弱的神经退行性疾病的原因尚不清楚。大量证据表明，阿尔茨海默病有遗传基础。这一证据包括鉴定了三个突变导致早发性家族性AD(FAD)的基因：淀粉样前体蛋白(APP)基因，以及分别位于14号和1号染色体上的早老素1(PSEN1)和早老素2(PSEN2)。迟发性阿尔茨海默病(LO)是一种更复杂、多因素的疾病，只有APOE被确认为危险因素。APOE还影响LO AD的发病年龄，最近的证据还表明，APOE对PSEN1和PSEN2突变导致的AD发病年龄也有影响。这一证据证明了广泛阿尔茨海默病发病年龄的遗传基础，再加上 支持存在更多这样的基因的信息表明，阐明起病年龄或AD的遗传学基础将有助于理解AD的一般病因。该项目的长期目标是通过识别导致疾病的基因来确定阿尔茨海默病的潜在原因。当前项目的目标是重点研究发病年龄的遗传基础。具体目的是(1)在UW ADRC数据集中识别包含LO-FAD起病年龄基因座的染色体区域；(2)在NIMH LO-FAD数据集中识别包含LO-FAD起病年龄基因座的染色体区域；以及(3)更准确地解析在分析中检测到的感兴趣区域的大小 这两个数据集都包括更准确地定位这样的QTL，确定是否可以检测到连锁不平衡，以及评估感兴趣区域中的候选基因。识别影响AD发病年龄的基因将有助于理解AD的病因，导致更好的诊断方法，并潜在地改进治疗和预防措施。

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.