Genetic Epidemiology of Alzheimer's Disease in Down Syndrome

该项目的总体目标是确定遗传变异对唐氏综合征（DS）成人发病年龄和阿尔茨海默病（AD）风险的影响。连锁和关联研究为AD风险的显着遗传影响提供了证据，但大多数这些遗传因素的作用尚未在DS成人中进行研究。患有DS的成人过度表达β淀粉样前体蛋白（APP），具有AD神经病理学的早期发作和痴呆的高风险。然而，AD发病的年龄范围很广，并非所有DS成人都会发展为AD，这表明其他风险决定因素的重要性。在以前的工作中，我们做了几个关键的观察，支持遗传和环境因素可以有助于发病年龄和AD的DS的风险的假设。我们现在建议确定可能影响认知功能，AD风险，AD发病年龄和AB肽水平差异的遗传变异的贡献，在我们当前项目的一个大型DS成人队列中。我们将利用自本研究开始以来已经完成的深度表型分析和重复评估。该队列已完成多达6次随访评估，我们有大量AD病例的样本，其发病和进展已得到充分记录。我们存储了366名DS男性和女性的DNA、神经心理学和功能状态测试分数、病史、AP肽水平和痴呆状态，并将招募和随访一名 与子项目1和2一起增加150名非痴呆参与者。因此，我们处于一个独特的位置，将遗传变异与一系列AD相关表型联系起来。我们将对DS成人中AD的一系列候选基因进行分析。我们将使用Illumina GoldenGate定制阵列精细定位候选基因。分析将首先关注在之前的全基因组连锁或关联研究、荟萃分析中已识别的变体，以及与AD发病机制有关的变体，包括在生物学上对筛选具有重要意义的区域，以及21号染色体上的候选基因，这些基因在DS成人中是三重的。我们将进行等位基因和基因型关联研究，以确定对以下因素影响最大的多态性：（1）AD风险;（2）AD发病年龄;（3）痴呆和非痴呆成人中AB肽的水平和变化率;（4）认知功能。然后，我们将使用与AD具有稳健显著关联的SNP来确认独立复制数据集中的关联，首先在具有DS的成年人的大型良好表征的队列中，然后在来自国家老龄化研究所-晚发性阿尔茨海默病研究（NIA-LOAD）的非DS队列中。我们将把Tycko博士的表观遗传学项目中发现的基因变异与血液相关的表型联系起来。

The overall aim of this project is to determine the contribution of genetic variants to age at onset and risk of Alzheimer's disease (AD) in adults with Down syndrome (DS). Linkage and association studies have provided evidence for significant genetic influences on risk for AD, but the role for most of these genetic factors has not been investigated in adults with DS. Adults with DS over-express the p amyloid precursor protein (APP), have early onset of AD neuropathology and high risk for dementia. However, there is a wide range of age at onset of AD and not all adults with DS develop AD, suggesting the importance of additional determinants of risk. In previous work, we made several key observations that support the hypothesis that genetic and environmental factors can contribute to age at onset and risk of AD in DS. We propose now to determine the contribution of genetic variants that may influence cognitive function, risk for AD, age at onset of AD, and differences in AB peptide levels in a large cohort of adults with DS from our current project. We will take advantage of the deep phenotyping and repeated assessments that have been accomplished since the inception of this study. The cohort has completed up to 6 follow-up assessments and we have a large sample of incident AD cases whose onset and progression has been well documented. We have stored DNA, neuropsychological and functional status test scores, medical history, AP peptide levels, and dementia status on 366 men and women with DS and will recruit and follow an additional 150 nondemented participants in conjunction with Subprojects 1 and 2. Thus, we are in a unique position to relate genetic variants to a range of AD-related phenotypes. We will conduct an analysis of a broad panel of candidate genes for AD in adults with DS. We will fine map candidate genes using the lllumina GoldenGate custom array. Analyses will focus first on variants which have been identified in prior genome wide linkage or association studies, in meta-analyses, and that have been implicated in AD pathogenesis, including regions that are biologically important to screen, as well as candidate genes on chromosome 21 which are triplicated in adults with DS. We will perform allelic and genotypic association studies to identify polymorphisms that confer the strongest influence on (1) risk for AD; (2) age at onset of AD; (3) levels and rate of change in AB peptides in demented and nondemented adults; and (4) cognitive function. Then we will use the SNPs with robust significant associations with AD to confirm the associations in independent replication datasets, first in a large well characterized cohort of adults with DS and then in non-DS cohorts from the National Institute on Aging- Late Onset Alzheimer's Disease Study (NIA-LOAD). We will relate variants in genes identified in Dr. Tycko's epigenetic project to blood-related phenotypes.