TRISOMY 21 MOSAICISM, APP GENE MUTATIONS AND DEMENTIA IN DOWN'S SYNDROME ADULTS

这项研究将调查老年痴呆症的遗传危险因素， 唐氏综合征（Down Syndrome，DS）患者及其亲属。 的大脑 事实上，所有患有唐氏综合征的成年人都表现出高密度的 斑块和神经纤维缠结的病理特征 阿尔茨海默病（AD）的变化，与DS的个人在增加 临床痴呆的风险。 DS和AD的共同遗传易感性 女性DS分娩患病率增加的研究结果支持了这一观点 或其亲属有AD， AD在DS患者亲属中的频率，以及与 早发性家族性AD的21号染色体 β-淀粉样蛋白基因 前体蛋白（APP）已定位于21号染色体， DS成人中AD病理学的发生归因于 β-淀粉样蛋白表达增加。 然而，并非所有患有DS的人 和AD病理要素。 21三体嵌合体可能与 β-淀粉样蛋白表达减少和AD发病年龄晚。 在 此外，APP基因的突变已被证明与 在几个早发性AD家族中发现AD。 我们将确定这些或 APP基因中的相关突变与表达增加有关 唐氏综合征患者或有 早发性阿尔茨海默病 本研究的受试者将来自一项正在进行的更大规模的研究， 唐氏综合征和阿尔茨海默病的家族聚集性。 我们将研究 第一批150名DS患者及其父母。 数据来自大 这项研究将提供有关AD发生率和相关 DS先证者一级和二级亲属的疾病， DS先证者的医疗状况和功能技能水平， DS先证者中发生具有临床意义的消退的情况与 被诊断为痴呆 我们将确定DS核型（三体，易位，嵌合）， 估计21三体嵌合体的年龄特异性患病率。 我们将 确定痴呆症的风险和痴呆症发作的年龄是否 与马赛克的水平相关。 我们会筛选所有 与DS及其亲本在编码区和启动子中的突变 APP基因的序列，并估计APP突变的患病率。 我们 将确定是否增加的风险，临床痴呆症的成年人， DS与APP突变相关，通过比较DS病例有和没有 突变在痴呆症的终生累积发病率方面。 我们 将确定DS先证者亲属中AD风险增加是否 与APP突变相关，通过比较DS病例， APP基因突变与AD的累积发病率之间的关系， 他们的一级和二级亲属。

This study will investigate genetic risk factors for dementia in individuals with Down syndrome (DS) and their relatives. The brains of virtually all adults with Down syndrome show high densities of senile plaques and neurofibrillary tangles characteristic of the pathological changes of Alzheimer disease (AD), and individuals with DS are at increased risk for clinical dementia. A shared genetic susceptibility to DS and AD is supported by the findings of increased prevalence of DS births to women who themselves have AD or whose relatives have AD, by findings of increased frequency of AD in relatives of individuals with DS, and by linkage of early-onset familial AD to chromosome 21. The gene for beta-amyloid precursor protein (APP) has been localized to chromosome 21 and the early occurrence of AD pathology in adults with DS has been attributed to increased expression of beta-amyloid. However, not all individuals with DS and AD pathology dement. Mosaicism for trisomy 21 may be associated with reduced expression of beta-amyloid and later age of onset of AD. In addition, mutations in the gene for APP have been shown to cosegregate with AD in several families with early onset AD. We will determine if these or related mutations in the APP gene are associated with increased expression of clinical dementia in individuals with Down syndrome or with a history of early-onset AD in their families. Subjects for this study will be drawn from a larger ongoing study of the familial aggregation of Down syndrome and Alzheimer disease. We will study the first 150 individuals with DS and their parents. Data from the larger study will provide information on the occurrence of AD and related disorders in first- and second-degree relatives of DS probands, on the medical status and functional skills level of DS probands and on the occurrence of clinically significant regression in DS probands consistent with a diagnosis of dementia. We will determine DS karyotype (trisomy, translocation, mosaicism) and estimate the age-specific prevalence of mosaicism for trisomy 21. We will determine whether the risk for dementia and age of onset of dementia is correlated with the level of mosaicism. We will screen all individuals with DS and their parents for mutations in the coding region and promoter sequences of the APP gene and estimate the prevalence of APP mutations. We will determine whether increased risk for clinical dementia in adults with DS is associated with APP mutations by comparing DS cases with and without mutations in terms of the lifetime cumulative incidence of dementia. We will determine whether increased risk for AD in relatives of DS probands is associated with APP mutations by comparing DS cases with and without mutations in the APP gene in terms of the cumulative incidence of AD in their first- and second-degree relatives.