GENETIC STUDIES OF FAMILIAL ALZHEIMER'S DISEASE

阿尔茨海默病(AD)是老年人痴呆症的最常见原因。在美国，大约有3-4百万人受到这种疾病的影响，每年给美国经济造成的损失超过500亿美元。这种使人衰弱的神经退行性疾病的病因目前尚不清楚。然而，大量证据表明，至少有一些（如果不是全部的话）AD病例是由遗传因素引起的。对多例早发性阿尔茨海默病家族的遗传分析表明，至少有三种常染色体显性基因导致了该疾病的某些发生。在这些家庭中，患者的后代有50%的风险遗传家族性AD （FAD）基因并发展为AD。迟发性FAD （LOFAD）似乎与其他基因有关，是一种更为复杂的疾病。使用连锁分析和其他复杂的统计遗传方法，该项目的长期目标是通过识别负责这种疾病遗传形式的基因来确定阿尔茨海默病的潜在原因。目前已经确定了4个基因位点是AD的遗传因素：淀粉样蛋白前体蛋白（APP）基因、14号染色体上的早老素1 （PS1）、1号染色体上的早老素2 （PS2）和19号染色体上ApoE基因/区域的易感位点。本项目的具体目标如下：1)鉴定和取样新的FAD种类。2)鉴定含有LOFAD位点的染色体区域。3)鉴定具有特定PS2突变的伏尔加德国家族中含有改变AD发病年龄基因的染色体区域。4)在其他协变量存在的情况下，表征ApoE基因型与FAD的关系。FAD基因和修饰因子的鉴定将有助于确定AD的病因，导致更好的诊断方法，并可能为设计治疗和预防措施提供依据。

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. In the U.S., approximately 3-4 million persons are affected by this disease, costing the U.S. economy more than $50 billion per year. The cause(s) of this debilitating neurodegenerative disease is(are) presently unknown. However, a large body of evidence indicates that at least some, if not all, AD cases are due to genetic factors. Genetic analyses of families with multiple cases of early-onset AD has shown that three autosomal dominant genes are responsible for at least some occurrences of the disease. In these families, offspring of affected persons are at 50% risk of inheriting a familial AD (FAD) gene and developing AD. Late-onset FAD (LOFAD) seems to involved other genes and is a more complex disease. Using linkage analysis and other sophisticated statistical genetic methods, the long-range goal of this project is to identify the underlying causes of AD by identify the genes responsible for the genetic forms of this disease. Four genetic loci have been identified which are heritable factors in AD: the amyloid precursor protein (APP) gene, presenilin 1 (PS1) on chromosome 14, presenilin 2 (PS2) on chromosome 1, and a susceptibility locus at the ApoE gene/region on chromosome 19. The following Specific Aims of this project address characterizing existing AD genes and mapping new AD loci: 1) Identify and sample new FAD kindreds. 2) Identify the chromosomal regions containing LOFAD loci. 3) Identify chromosomal regions containing genes that modify age of onset of AD in Volga German families with a specific PS2 mutation. 4) Characterize the relationship between ApoE genotypes and FAD in the presence of other covariates. Identification of FAD genes and modifying factors will facilitate establishing the etiology of AD, lead to better diagnostic methods, and potentially provide a rationale for designing therapeutic and preventive measures.