GENETIC EPIDEMIOLOGY ALZHEIMER DISEASE IN TWINS

阿尔茨海默病(AD)似乎是由遗传因素共同作用的结果 和环境决定因素，但这些病因学的性质 这些因素目前还不清楚。为了阐明阿尔茨海默病的原因及其影响，我们 建议对10,000对双胞胎进行一项关于这种疾病的纵向研究 美国国家科学院老年双胞胎退伍军人登记表。大约375人 270对双胞胎的病例将在5年内初步确定 对书记官处进行电话筛查，随后进行正式诊断 筛查阳性受试者的评估和年度随访 同卵双胞胎。 我们将通过比较年龄和年龄来评估遗传因素对AD的影响。 单合子(MZ)和双合子(DZ)对的特异性符合率， 以及一对互不相关的个体。我们将描述 MZ和DZ同卵双胞胎发病后首发症状的分布 双胞胎。我们将估计MZ或MZ人群中AD的未审查终身风险 受影响个体的DZ双胞胎；如果(一些研究表明)AD是一种 孟德尔显性特征具有完全但依赖于年龄的外显性， 这些风险应该分别接近100%和50%。我们还将 调查因遗传异质性而导致的发病变异性 决定因素，以及因不同环境影响而产生的变异性， 通过对比AD发病时间的配对内和配对间变化 MZ对，并通过应用依赖于特定年龄的方法 MZ和DZ对中的一致性数据。我们将研究以下方面的影响 通过对比发病变异性研究发病时间的遗传背景 在和谐的DZ对和MZ对之间。我们将调查是否有可能 阿尔茨海默病基因载量在不同民族之间的差异 中国几个民族发病率和患病率的比较 注册表。 即使在MZ双胞胎中，AD发作时的年龄也可能有很大的差异。这 事实表明，非遗传因素可能会影响发病，我们会 因此，通过以下方式检查AD的其他主机或环境风险因素 比较不协调的MZ配对的风险因素暴露， 另外一个很强的风险因素也是一样的。我们将进一步研究 这些危险因素与MZ配对发病差异的关系， 并测试风险因素是否通过加速疾病的发病而起作用 在易感人群中。最后，我们将检查以上是否 遗传和/或环境因素可能会影响过程中的变化 以及疾病的进展，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 通过检查证据来支持或驳斥这种基因，从而易患上阿尔茨海默病 通过研究AD(和)的年龄相关性表达来影响 因此，它的易感基因，如果存在的话)，并通过研究 非遗传寄主或环境因素可能对 疾病表现。即使对AD的易感性最终被证明是 在基因决定的情况下，这项研究具有 确定两个重要的预防战略，延误 疾病的发病和临床病程的改善，可能会使 可能大幅降低随行人员的发病率。

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.