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症（DS）成人阿尔茨海默病（AD）发病年龄和风险的影响。连锁和关联研究已经提供了证据，表明遗传因素对AD风险有显著影响，但大多数遗传因素在成人退行性痴呆患者中的作用尚未得到调查。成人退行性痴呆患者p淀粉样前体蛋白（APP）过表达，早发性AD神经病理，痴呆风险高。然而，阿尔茨海默病的发病年龄范围很广，并不是所有患有退行性痴呆的成年人都会发展为阿尔茨海默病，这表明了其他风险决定因素的重要性。在之前的工作中，我们做了几个关键的观察，支持遗传和环境因素可以影响DS的发病年龄和AD风险的假设。我们现在建议确定遗传变异的贡献，这些变异可能影响认知功能，AD的风险，AD发病年龄，以及我们当前项目中大量成年DS患者AB肽水平的差异。我们将利用自本研究开始以来已经完成的深度表型和重复评估。该队列已经完成了多达6次的随访评估，我们有大量的AD病例样本，其发病和进展都有很好的记录。我们已经存储了366名退行性痴呆患者的DNA、神经心理和功能状态测试分数、病史、AP肽水平和痴呆状态，并将招募和跟踪一名患者

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.