GENETIC EPIDEMIOLOGY OF ALZHEIMER'S DISEASE IN TWINS

描述：（改编自研究者摘要）美国国家科学院 科学/国家研究理事会孪生登记处（“登记处”）包含 大约有4,300对白色男性双胞胎，年龄在72-83岁之间， 2000.这一竞争性延期申请建议在书记官处进行研究， 结合迄今为止的工作，将产生240对双胞胎，其中一个或两个 老年痴呆症（AD）患者。这个基于人口的小组将使 继续调查四个广泛的目标：1）估计的规模 遗传因素对AD发病年龄和发展的影响 单合子（MZ）和 双合子（DZ）对; 2）表征环境的贡献， AD发病的变异性。例如，MZ对内的发病变异性 定义了环境影响可以改变 评估特定基因在AD发病中的作用 使用同胞传递/不平衡检验方法， 研究候选基因之间的关联， 巨球蛋白（A2 M）和AD;和4）确定环境因素， 与AD发病风险相关的研究。 这项研究将利用AD遗传学的最新发展， 特别是载脂蛋白E（APOE）基因型和候选人的影响， A2 M基因对AD易感性和发病时间的影响。这些发现可能是 用于改进研究广泛（但 异质性）遗传和环境影响。一个人不仅可以 对AD的遗传度进行了总体估计， 分析以估计归因于APOE基因型的表型方差 或其它标记系统，如这些被识别的。然而，直到所有的 当识别出易患AD的基因时，双胞胎方法具有几个 与其他方法相比， 环境对AD的贡献 几个MZ双胞胎对已被描述为AD发病差异很大。 因此，环境因素可能会改变发病率，从而改变人口 风险，一些遗传定义的AD形式。本研究将分析 环境对发病变异性的贡献，并将表征 遗传匹配个体之间的发病差异。以来 全面的环境因素资料已收集在所有 参加双胞胎登记处的成员，这项研究还将聘请 双胞胎控制方法，以寻求可能的特定环境因素， 对这种变化负责。基于人口的双胞胎设计仍然是 这类调查的理想方法。

DESCRIPTION: (Adapted from the Investigator's Abstract) The National Academy of Sciences/National Research Council Twin Registry ("the Registry") contains approximately 4,300 living pairs of white male twins who will be aged 72-83 in 2000. This competing renewal application proposes studies in the Registry that, combined with work to date, will yield 240 twin pairs in which one or both members have Alzheimer's disease (AD). This population-based panel will enable the continued investigation of four broad aims: 1) Estimate the magnitude of genetic influences on the development and age of onset of AD by contrasting concordance rates and the similarity of onsets within monozygotic (MZ) and dizygotic (DZ) pairs; 2) Characterize the environmental contribution of variability of onset of AD. For example, variability of onset within MZ pairs defines the maximum degree to which the environmental influences can modify the onset of AD; 3) Evaluate the role of specific genes on the development and age of onset of AD using the Sibling Transmission/Disequilibrium Test approach to investigate the association between candidate genes such as alpha-2 macroglobulin (A2M) and AD; and 4) Identify environmental factors that are associated with the risk of developing AD, using the co-twin control method. The research will capitalize upon recent developments in the genetics of AD, specifically the influence of apolipoprotein E (APOE) genotype and candidate gene A2M on both liability to AD and its timing of onset. Such findings can be used to refine the classical twin paradigm of investigating broad (but heterogeneous) genetic and environmental influences. Thus, one can not only estimate the heritability of AD in general, but also undertake partitioned analyses to estimate the phenotypic variance attributable to genotypes at APOE or other marker systems, as these are identified. However, until all of the genes that predispose to AD are identified, the twin method has several advantages over other approaches in identifying the extent of the genetic and environmental contribution to AD. Several MZ twin pairs have been described with widely divergent onsets of AD. Environmental factors may therefore alter the onset, and hence the populations risk, of some genetically defined forms of AD. This study will analyze the environmental contribution to variability of onset, and will characterize the divergence in onset within sets of genetically matched individuals. Since comprehensive information on environmental factors has been collected on all participating members of the twin registry, this study will also employ the co-twin control method to seek the specific environmental factors that may be responsible for this variation. A population-based twin design remains the ideal approach to these sorts of investigations.