Genetic Epidemiology of Alzheimer's Disease in African Americans

描述(申请人提供)：多项研究发现，非裔美国人非家族性阿尔茨海默病(AD)的患病率和发病率明显高于高加索人。然而，由于部分用于诊断AD的认知测试在非裔美国人中的特异性较低，目前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很高，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AD的风险。虽然AD的主要遗传风险因素APOE D4等位基因在非裔美国人中更常见，但相对风险略低于其他人群。载脂蛋白E与AD的相关性可能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的遗传关联研究来解决这些问题，该研究具有仔细改进的表型，包括认知测试表现、心血管健康和脑成像数据。我们建议在四个专门评估AD并服务于大量非裔美国人的地点进行合作研究：纽约市的哥伦比亚大学、北卡罗来纳州的杜克大学和北卡罗来纳A&T州立大学以及田纳西州的范德比尔特大学。我们将1)结合我们过去在文化和教育经验对认知测试表现的作用方面的工作，提炼非裔美国人中的AD表型，以提供准确的AD诊断，收集与亚临床心血管疾病相关的生物标记物，并获得MRI脑图像，以量化白质高信号体积、脑梗塞负担和总脑；2)我们将在匹配的非裔美国人AD病例和对照中测试选定候选基因的关联性，并检验心脑血管疾病作为潜在的风险修饰物的作用；3)我们将检查候选基因和几个数量性状之间的基因型-表型关系，包括在学习和记忆方面的表现，阿尔茨海默病发病年龄，以及心脑血管疾病负担。

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.