GENETICS OF LATE AND EARLY ONSET ALZHEIMER'S DISEASE

此领导奖提案是一个综合项目，旨在 测试晚发性阿尔茨海默病(LOAD)是 遗传和鉴定遗传基因座的负荷和早发 家族性AD(Eoad)。Eoad与匿名DNA探针有关 在21号染色体上，所以旨在识别和识别 描述将重点放在21号染色体上的遗传位点 Eoad中的表达差异。一种临床遗传确证 而Eoad和Load的家庭发展计划是 描述。SIB对筛选和标准似然分析 呈上了。减法杂交(使用可从 杜克阿尔茨海默病研究中心快速尸检 协议)、候选基因分析、染色体作图 技术和其他分子遗传策略来定义 EoAD的21号染色体基因座和一个可能的基因(S) 对负载进行了描述。主要提案分为六个部分 综合项目，包括两个初级调查员项目和 三项试点。牵头项目(ROSES)包括 家庭发展和筛查与负荷的联系，以及 旨在测试21号染色体特异性基因的实验 Eoad和对照脑区的表达差异。朱尼尔 调查员项目1(Clark)描述了 持续和扩展的临床确认和发展 载荷族和载荷族。初级调查员项目2 (艾伯茨)描述了大脑区域特定的减法 杂交种的加载实验。试点项目1(布莱特纳) 开发双胞胎研究，可以提供更多的家庭 对基因作图感兴趣。试点项目2(道森)开发 兄弟姐妹配对方法将应用于#年晚发家庭 其中几个受影响个人的DNA是 无法获得，但可以从家族数据中推断出谁的基因。 试点项目3(Bartlett)使用强大的新方法 基因组分析为Eoad开发更接近的侧翼标记 并确定了消减杂交的基因组极限 战略。

This LEAD Award proposal is an integrated project designed to test the hypothesis that late onset Alzheimer's Disease (LOAD) is genetic and to identify the genetic loci for LOAD and early onset familial AD (EOAD). EOAD is linked to anonymous DNA probes on chromosome 21 so that experiments designed to identify and describe the genetic locus will focus on chromosome 21 specific expression differences in EOAD. A clinical genetic ascertainment and family development program for EOAD and LOAD is described. Sib-pair screening and standard likelihood analyses are presented. Subtraction hybridization (using tissue available from the Duke Alzheimer's Disease Research Center Rapid Autopsy Protocol), candidate gene analyses, chromosome mapping techniques, and other molecular genetic strategies to define the chromosome 21 gene locus for EOAD and a putative gene(s) for LOAD are described. The LEAD proposal is organized into six integrated projects including two junior investigator projects and three pilot projects. The LEAD project (ROSES) includes the family development and screening for linkage to LOAD, as well as experiments designed to test chromosome 21 specific gene expression differences in EOAD and control brain regions. Junior investigator Project 1 (CLARK) describes the detailed plan for continued and expanded clinical ascertainment and development of LOAD and EOAD families. Junior investigator Project 2 (ALBERTS) describes brain region specific subtraction hybridization experiments in LOAD. Pilot Project 1 (BREITNER) develops twin studies that can provide additional families of interest for gene mapping. Pilot Project 2 (DAWSON) develops the sib-pair methodology to be applied to late onset families in which the DNA of several of the affected individuals are unavailable but whose genotype can be inferred from family data. Pilot Project 3 (BARTLETT) uses powerful new methods of genomic analyses to develop closer, flanking markers for EOAD and to define the genomic limits for subtraction hybridization strategies.