GENETICS OF LATE AND EARLY ONSET ALZHEIMER'S DISEASE

这个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）的假设是 遗传，并确定遗传位点的负载和早发性 家族性AD（EOAD）。 EOAD与匿名DNA探针有关 在21号染色体上， 描述遗传位点将集中在染色体21具体 EOAD中的表达差异。 临床遗传学鉴定 EOAD和LOAD的系列开发计划 介绍了 同胞对筛选和标准似然分析是 提出了 消减杂交（使用可从 杜克阿尔茨海默病研究中心快速尸检 方案）、候选基因分析、染色体作图 技术和其他分子遗传学策略来定义 用于EOAD的21号染色体基因座和用于EOAD的推定基因， 负载描述。 国际环境与发展学院的建议分为六个部分 综合项目，包括两个初级调查员项目， 三个试点项目。 铅项目（玫瑰）包括 家族发展和筛选与LOAD的联系，以及 旨在检测21号染色体特异性基因的实验 EOAD和对照脑区中的表达差异。 初级 研究者项目1（CNOK）描述了详细的计划， 持续和扩展的临床确认和开发 LOAD和EOAD系列。 初级研究员项目2 （ALBERTS）描述了大脑区域特异性减影 LOAD中的杂交实验。 试点项目1（BREITNER） 开展双胞胎研究，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 将采用同胞配对方法对晚发性家庭进行研究， 其中几个受影响个体的DNA 无法获得，但其基因型可以从家庭数据推断。 试点项目3（BARTLETT）使用强大的新方法， 基因组分析，以开发更紧密的EOAD侧翼标记 并确定消减杂交的基因组限度 战略布局

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.