GENETIC STUDIES OF FAMILIAL ALZHEIMER'S DISEASE

阿尔茨海默病（AD）是老年痴呆症的最常见原因， 老人 在美国，大约有3-4百万人受到 这种疾病每年给美国经济造成超过400亿美元的损失。 这种使人衰弱的神经退行性疾病的原因目前是 未知 然而，大量证据表明，至少有一些 如果不是所有的AD病例都是由于遗传因素， 一代接一代 多发性骨髓瘤家系的遗传分析 早老性AD的病例表明，常染色体显性基因是 导致了至少某些疾病的发生。 在这些 家庭，受影响的人的后代似乎有50%的风险， 遗传家族性AD（FAD）基因并发展为AD。 远程 本研究项目的目标是通过以下方法确定AD的根本原因： 找出导致这种疾病的基因 实现这一目标的第一步是定位染色体区域 通过在一个含有FAD基因的基因组之间建立连锁关系， 已知的遗传标记和FAD基因。 FAD基因的鉴定将 有助于确定AD的病因，可能导致更好的 诊断方法，并可能为设计 治疗和预防措施。 已经鉴定了三个遗传基因座，它们是AD的遗传因素： 淀粉样前体蛋白（APP）基因，染色体14 AD基因座，和 19号染色体上ApoE基因/区域的易感性位点。 的 本研究项目的主要努力是进一步表征这些 基因座，并确定参与AD遗传的其他基因座， 以下：1）将确定额外的运动，其中 可以研究AD基因的遗传; 2）基因组筛选方法将 用于定位早发性常染色体显性AD的基因 在伏尔加德国家庭; 3）额外的基因负责晚- 还将通过基因组扫描方法寻找发病的家族性AD; 4） 将研究ApoE、性别和脂蛋白的作用作为风险 5）19号染色体的ApoE/CI/CII区域将与晚发性AD的发病相关。 表征以鉴定与ApoE不平衡的区域; 6） 将对FAD家族进行APP突变筛查， 进一步临床和神经病理学表征的信息。

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. In the US, approximately 3-4 million individuals are affected by this disease costing the US economy over $40 billion dollars per year. The cause of this debilitating neurodegenerative disease is presently unknown. However, a large body of evidence indicates that at least some if not all AD cases are due to genetic factors which can be passed from one generation to the next. Genetic analysis of families with multiple cases of presenile AD suggests that autosomal dominant genes are responsible for at least some occurrences of the disease. In these families, off-spring of affected persons appear to be at 50% risk of inheriting a familial AD (FAD) gene and developing AD. The long range goal of this research project is to identify the underlying cause of AD by identifying the genes responsible for the genetic form of this disease. The first step in attaining this goal is to locate the chromosomal regions containing FAD genes by establishing a linkage relationship between a known genetic marker and the FAD genes. Identification of FAD genes will facilitate establishing the etiology of AD, possibly lead to better diagnostic methods, and potentially provide a rationale for designing therapeutic and preventative measures. Three genetic loci have been identified which are heritable factors in AD: the amyloid precursor protein (APP) gene, a chromosome 14 AD locus, and a susceptibility locus at the ApoE gene/region on chromosome 19. The primary efforts of this research project are to further characterize these loci and to identify additional loci involved in AD inheritance as follows: 1) Additional kindreds will be identified in which the inheritance of AD genes can be studied; 2) Genomic screening methods will be used to map the gene responsible for early-onset autosomal dominant AD in the Volga German families; 3) Additional genes responsible for late- onset familial AD will also be sought by genomic scanning methods; 4) The role of ApoE, gender, and lipoproteins will be investigated as risk factors for late-onset AD; 5) The ApoE/CI/CII region of chromosome 19 will be characterized to identify the region in disequilibrium with ApoE; 6) FAD families will be screened for APP mutations to provide additional information for further clinical and neuropathologic characterization.