GENETIC EPIDEMIOLOGY ALZHEIMER DISEASE IN TWINS

双胞胎阿尔茨海默病的遗传流行病学

• 批准号: 3120250
• 负责人: John C S Breitner
• 金额: $ 81.51万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-04 至 1994-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3120250
• 关键词: aging; disease /disorder proneness /risk; gene expression; genotype; human ecology; human population genetics; interview; longitudinal human study; molecular pathology; nervous system disorder epidemiology; patient /disease registry; prognosis; twin /multiplet

Alzheimer disease (AD) appears to result from a combination of genetic and environmental determinants, but the nature of these etiologic factors is obscure. To elucidate the causes of AD and their effects, we propose a longitudinal study of this disease in 10,000 twin pairs of the National Academy of Sciences Registry of aging twin veterans. Some 375 cases in 270 twin pairs will be ascertained over 5 years by initial telephone screening of the Registry, with subsequent formal diagnostic assessment and annual follow-up of screen-positive subjects and their co-twins. We will assess influence of genetic factors in AD by comparing age- specific concordance rates in monozygotic (MZ) and dizygotic (DZ) pairs, as well as pairs of unrelated individuals. We will characterize the distributions of onsets in MZ and DZ co-twins after onset in the first twin. We will estimate the uncensored lifetime risks of AD among MZ or DZ twins of affected individuals; if (as some studies suggest) AD is a Mendelian dominant trait with complete but age-dependent penetrance, these risks should approach 100% and 50% respectively. We will also investigate variability of onset due to heterogeneity of genetic determinants, and variability due to varying environmental influences, by contrasting within-pair and among-pair variation of AD onset times in MZ pairs, and by application of methods relying on age-specific concordance data in both MZ and DZ pairs. We will examine effects of genetic background on timing of onset by contrasting onset variability among concordant DZ vs. MZ pairs. We will investigate possible variations in genetic loading for AD among different ethnic groups by comparing incidence and prevalence among several ethnic groups in the Registry. Even in MZ twin pairs, age at onset of AD can vary substantially. This fact suggests that non-genetic factors may influence onset, and we will therefore examine other host or environmental risk factors for AD by comparing risk factor exposures in discordant MZ pairs whose genotype, an otherwise strong risk factor, is identical. We will further examine the relationship of such risk factors to onset differences in MZ pairs, and test whether risk factors operate by accelerating onset of disease in susceptible individuals. Finally, we will examine whether the above genetic and/or environmental factors may influence variations in course and progression of disease, as they may act on onset. This study will complement the current molecular search for genes that predispose to AD by examining evidence to support or refute such genetic influences, by investigating the age-dependent expression of AD (and hence its predisposing genes, if such exist), and by studying the possible influence of non-genetic host or environmental factors on disease expression. Even if susceptibility to AD proves ultimately to be genetically determined, this study holds potential for the identification of two important strategies for prevention, delay of disease onset and amelioration of clinical course, which may make possible substantial reduction in attendant morbidity.

阿尔茨海默病（AD）似乎是由遗传因素和 和环境决定因素，但这些病因的性质 因素是模糊的。 为了阐明AD的病因及其影响，我们 我建议对10，000对双胞胎进行这种疾病的纵向研究， 国家科学院老年双胞胎退伍军人登记处。 约375人 270对双胞胎中的病例将在5年内通过初步确定 登记处电话筛查，随后进行正式诊断 筛查阳性受试者的评估和年度随访及其 双胞胎姐妹 我们将通过比较年龄- 单卵（MZ）和双卵（DZ）对的特异性一致率， 以及成对的不相关的个体。 我们将描述 MZ和DZ双胞胎中首次发病后的发病分布 双胞胎姐姐 我们将估计MZ或MZ中AD的未删失终生风险， 受影响个体的DZ双胞胎;如果（正如一些研究所表明的那样）AD是一种 孟德尔显性性状，具有完全但年龄依赖性的显性遗传， 这些风险应分别接近100%和50%。 我们还将 研究由于遗传异质性引起发病变异性 决定因素，以及由于不同环境影响而产生的可变性， 通过对比AD发病时间的配对内和配对间变化， MZ对，并通过应用依赖于年龄特异性 MZ和DZ对的一致性数据。 我们将研究 通过对比发作变异性确定发作时间的遗传背景 在一致的DZ与MZ对之间。 我们将调查可能的 不同种族人群中AD遗传负荷的变化， 比较美国几个种族群体的发病率和患病率， 注册表 即使在MZ双胞胎对中，AD发病时的年龄也可能有很大差异。 这 事实表明，非遗传因素可能会影响发病，我们将 因此，通过以下方式检查AD的其他宿主或环境风险因素： 比较不一致MZ对的风险因素暴露， 一个很强的风险因素，是相同的。 我们将进一步研究 这些风险因素与MZ对中发作差异的关系， 并测试风险因素是否通过加速疾病的发生而起作用 在易感人群中。 最后，我们将研究上述 遗传和/或环境因素可能会影响过程中的变化 和疾病进展，因为它们可能在发病时起作用。 这项研究将补充目前对基因的分子搜索， 易患AD通过检查证据来支持或反驳这种遗传 通过研究AD的年龄依赖性表达（以及 因此，它的易感基因，如果存在的话），并通过研究 非遗传宿主或环境因素对 疾病表达。 即使对AD的易感性最终被证明 基因决定，这项研究具有潜力， 确定两项重要的预防战略， 疾病发作和临床病程的改善，这可能使 可能大幅降低伴随发病率。