Genetic Epidemiology of Alzheimer's Disease in African Americans

描述（由申请人提供）：许多研究发现，非裔美国人的非家族性阿尔茨海默病（AD）的患病率和发病率明显高于白种人。然而，由于部分用于诊断AD的认知测试在非裔美国人中特异性较低，因此尚不清楚误诊是否导致了这些发现。如果阿尔茨海默病的发病率确实升高了，这些研究表明，不同的遗传或环境因素可能会影响非裔美国人患阿尔茨海默病的风险。虽然APOE D4等位基因（AD的主要遗传风险因素）在非裔美国人中更为常见，但相对风险略低于其他人群。有可能APOE与AD的关联被心脑血管疾病的存在和严重程度所改变。目前的提案将通过在非裔美国人中进行AD遗传关联研究来解决这些问题，这些研究具有精心改进的表型，包括认知测试表现，心血管健康和脑成像数据。我们建议在纽约市哥伦比亚大学、北卡罗来纳州杜克大学和北卡罗来纳农工州立大学以及田纳西州范德比尔特大学这四个专门从事AD评估并服务于大量非裔美国人的地点进行一项合作研究。我们将1)通过结合我们过去关于文化和教育经历对认知测试表现的作用的研究，完善非裔美国人AD的表型，以提供AD的准确诊断，收集与亚临床心血管疾病相关的生物标志物，并获得MRI脑图像，以量化白质高密度体积、梗死负担和全脑；2)我们将测试匹配的非裔美国人AD病例和对照中选择的候选基因的相关性，并检查心脑血管疾病作为潜在风险修饰因素的影响；3)我们将研究候选基因和一些数量性状之间的基因型-表型关系，包括学习和记忆的测量表现、AD发病年龄和心脑血管疾病负担。

DESCRIPTION (provided by applicant): A number of studies have found that African Americans have significantly higher prevalence and incidence of non-familial Alzheimer's Disease (AD) than Caucasians. However, because the cognitive tests used in part to diagnose AD have low specificity among African Americans, it is unclear whether misdiagnosis contributed to these findings. If rates of AD are in fact elevated, these studies suggest that different genetic or environmental factors may influence AD risk among African Americans. While the APOE D4 allele, the major genetic risk factor for AD, is more frequent among African Americans, the relative risk is somewhat lower than in other populations. It is possible that the association of APOE with AD is modified by the presence and severity of cardiovascular and cerebrovascular disease. The current proposal will address these issues by conducting a genetic association study of AD among African Americans with a carefully refined phenotype, including cognitive test performance, cardiovascular health, and brain imaging data. We propose a collaborative study to be conducted at four sites which specialize in assessment of AD and serve large populations of African Americans: Columbia University in New York City, Duke University and North Carolina A&T State University in North Carolina, and Vanderbilt University in Tennessee. We will 1) refine the phenotype of AD among African Americans by incorporating our past work on the role of cultural and educational experience on cognitive test performance in order to provide accurate diagnoses of AD, collect biomarkers related to subclinical cardiovascular disease, and obtain MRI brain images to quantify volume of white matter hyperintensities, infarct burden, and total brain; 2) we will test the association of select candidate genes in matched African American AD cases and controls, and examine the effect of cardiovascular and cerebrovascular disease as potential modifiers of risk; and 3) we will examine genotype- phenotype relations among candidate genes and several quantitative traits, including performance on measures of learning and memory, age at onset of AD, and cardiovascular and cerebrovascular disease burden.