GENETIC STUDIES OF FAMILIAL ALZHEIMER'S DISEASE

阿尔茨海默病(AD)是老年人痴呆症最常见的原因 老年人。在美国，大约有300-400万人受到 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 如果不是所有的阿尔茨海默病病例都是由遗传因素引起的 一代又一代。多发性骨髓瘤家系的遗传分析 老年前期AD病例提示常染色体显性基因是 对这种疾病的至少部分发生负有责任。在这些 家庭，受影响的人的后代似乎有50%的风险 遗传家族性阿尔茨海默病(FAD)基因与阿尔茨海默病长距离的 这项研究项目的目标是通过以下方式确定AD的潜在原因 确定导致这种疾病遗传形式的基因。 实现这一目标的第一步是定位染色体区域。 通过建立FAD基因与FAD基因的连锁关系 已知的遗传标记和FAD基因。FAD基因的鉴定将 促进确定AD的病因，可能导致更好的 诊断方法，并潜在地为设计 治疗和预防措施。 目前已经确定了三个遗传位点，它们是AD的遗传因素： 淀粉样前体蛋白(APP)基因，14号染色体AD基因和一个 19号染色体载脂蛋白E基因/区域的易感基因 这项研究项目的主要努力是进一步描述这些 并确定与AD遗传有关的其他基因座 如下：1)将确定更多的家庭，其中 AD基因的遗传可以研究；2)基因组筛选方法将 用于定位早发性常染色体显性AD的致病基因 在伏尔加德国家庭中；3)导致迟发的其他基因- 还将通过基因组扫描方法寻找起病的家族性AD；4) 载脂蛋白E、性别和脂蛋白的作用将作为风险进行调查 晚发性AD的因素；5)19号染色体的ApoE/CI/CII区域将 识别与载脂蛋白E不平衡的区域；6) FAD家庭将接受APP突变筛查，以提供更多 进一步的临床和神经病理特征的信息。

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.