GENE MUTATION AND ENVIRONMENTAL RISK FACTORS IN ALZHEIMER'S DISEASE

阿尔茨海默病的基因突变和环境风险因素

• 批准号: 5204870
• 负责人: RICHARD MAYEUX
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5204870
• 关键词: Alzheimer's disease; United States; age difference; amyloid proteins; blood chemistry; chromosome 21; data collection; disease /disorder proneness /risk; ethnic group; family genetics; gender difference; gene mutation; genetic disorder; genetic polymorphism; genetic promoter element; head /neck injury; human old age (65+); human subject; human very old age (85+); interview; longitudinal human study; nervous system disorder epidemiology; neuropsychological tests; nucleic acid sequence; tissue /cell culture; trisomy

Deposition of amyloid in the cerebral cortex of humans may be one of several key early events in the pathogenesis of Alzheimer's disease (AD), but the etiology of this process remains unknown. Evidence for a mutation in the gene for the amyloid precursor protein (APP) exists indicating a genetic mechanism may cause AD in some families. AD could also be caused by the release of beta A4 amyloid in the brain following severe head injury. Thus, as might be expected, the etiology of AD (and extensive beta amyloid deposition in the cerebrum) is multifactorial and likely the result of factors both genetic and not genetic. We intend to exploit and extend these concepts by proposing that the cause (or causes) of AD may be the result of an interaction between genetic and environmental factors. The hypothesis tested in this LEAD award is twofold: familial AD is a complex genetic disorder in which reduced penetrance results from either the exposure to, or the lack of exposure to, environmental factors and nonfamilial AD results from environmental factors or previously unexplored genetic mechanisms such as mitotic nondisjunction leading to low level mosaicism for trisomy 21. In Project 1, we will identify and measure the relationship between specific environmental and genetic risk factors in AD, and identify mutations in the coding region and upstream promoter sequences of the APP gene or the occurrence of low level mosaicism for trisomy 21 in patients and controls from 3 ethnic groups (Black, Hispanic and White) in a heterogeneous community in northern Manhattan. In Project 2, similar interviews, clinical and laboratory examinations will be done in all living first-degree relatives of all patients with familial AD and a sample of those with "sporadic" AD (identified in Project 1) in order to establish age-specific risk of AD, and associations of AD with environmental risk factors and with mutations in the coding region and upstream promoter sequences of the APP gene. In Project 3, a prospective case-base study we will determine the cumulative incidence of AD in those exposed and unexposed to the risk factors identified in Project 1, compare rates across ethnic groups; determine for each risk factor the attributable risk and relative risks and establish risk profiles. Our results will provide methods to predict the risk of AD in 3 distinct ethnic groups represented in our community according to the presence or absence of certain risk factors of genetic susceptibility.

淀粉样蛋白在人类大脑皮层中的沉积可能是之一 阿尔茨海默氏病（AD）的发病机理中的几个关键早期事件， 但是这个过程的病因仍然未知。 突变的证据 在淀粉样前体蛋白（APP）的基因中存在表明 遗传机制可能导致某些家庭的AD。 广告也可能引起 通过释放βA4淀粉样蛋白在大脑之后的严重头部 受伤。 因此，可以预期，AD的病因（和广泛的Beta） 大脑中的淀粉样蛋白沉积）是多因素的，可能是结果 遗传和遗传因素的因素。 我们打算利用和扩展 这些概念通过提出AD的原因（或原因）可能是 遗传因素与环境因素之间相互作用的结果。 这 在该铅奖中检验的假设是双重的：家族广告是一个复杂的 遗传疾病降低了外渗部由 暴露于环境因素或缺乏暴露于环境因素和 非家族广告来自环境因素或以前未开发的 遗传机制，例如有丝分裂的非分离导致低水平 三体第21三体镶嵌。在项目1中，我们将识别并测量 AD中特定环境和遗传危险因素之间的关系， 并确定编码区域和上游启动子序列中的突变 App基因或在21中的三体性镶嵌物的出现 来自3个族裔（黑人，西班牙裔和白人）的患者和对照 曼哈顿北部的一个异质社区。 在项目2中，类似 访谈，临床和实验室检查将在所有生活中进行 所有家庭AD患者的一级亲戚和样本 为了建立“零星”广告（项目1中确定）的人 广告的特定年龄风险以及广告与环境风险的关联 因素和编码区域和上游启动子的突变 应用基因的序列。 在项目3中，一项前瞻性案例研究我们 将确定暴露的人的AD累积发生率和 未接触项目1中确定的风险因素，比较 种族群体；确定每个风险因素的归因风险和 相对风险并建立风险概况。 我们的结果将提供 预测3个不同种族的AD风险的方法 根据存在或缺乏某些风险在我们的社区中 遗传敏感性的因素。