DNA Methylation,Genetics, and Modifiable Risk Factors of Dementia in a Nationally Representative, Multi-Ethnic Cohort

项目摘要 阿尔茨海默病及其相关痴呆（ADRD）代表了阿尔茨海默病的主要终末形式。 在美国，痴呆症影响着越来越多的老年人。ADRD的生物标志物 风险，特别是在易感人群中（ADRD风险不成比例地高， 少数民族、妇女、农村居民和教育程度较低的人），是一个关键的 知识差距。因此，具有足够样本量的研究，同时评估多个 特征，如教育程度，环境，社会，行为，生活方式， 地理，生物学和表观遗传学，将独特地定位于有效地测试因素或 造成和维持ADRD差异的因素组合。我们的目标是确定 表观遗传和环境因素共同导致ADRD风险， 差距。利用现有的表观遗传和遗传数据，充分表征痴呆表型， 和多样的风险因素数据，我们将分析一个人口代表性，多种族老龄化 健康与退休研究（HRS）我们的目标是（1）测试关联 DNA甲基化和痴呆表型之间的关系（流行，8年发病率），按 人种/种族和ADRD存活相关因素的效应改变检验（教育 （2）确定纵向措施之间的关联， ADRD和DNA甲基化的可改变风险因素，按人种/种族分层， 通过ADRD差异相关因素进行修改或调解;最后，（3）识别 控制DNA甲基化的遗传多态性，以及这些基因是否在 痴呆的结果，以评估DNA甲基化在疾病发展中的作用。本研究 可能会影响阿尔茨海默氏症的研究领域，并有助于公共卫生，因为它将 a）在多个人种/种族中确定DNA甲基化与ADRD的相关性; B）阐明 重要的生物表观遗传机制; c）确定组合和个体 表观遗传-环境相互作用对ADRD的贡献;以及d）考虑性别的影响， 教育程度、种族/族裔、较年轻的年龄组和城市/农村地位， 可以比较相对风险贡献的研究。在这里，我们有 有机会同时大大提高我们对遗传和 ADRD中环境病因学对健康差异的影响

PROJECT SUMMARY Alzheimer’s disease and its related dementias (ADRD) represent the leading terminal forms of dementia affecting a growing number of aging adults in the United States. Biomarkers of ADRD risk, particularly among susceptible populations (ADRD risk is disproportionately high among minorities, women, rural inhabitants, and people with lower education), represent a critical knowledge gap. Thus, studies with sufficient sample sizes, concurrently assessing multiple characteristics, such as educational attainment, environment, social, behavioral, lifestyle, geographic, biology, and epigenetics, will be uniquely positioned to effectively test factors or combinations of factors that create and sustain ADRD disparities. Our goal is to determine the joint epigenetic and environmental contributions to ADRD risk that underlie these health disparities. Using existing epigenetic and genetic data, well-characterized dementia phenotypes, and diverse risk factor data, we will analyze a population representative, multi-ethnic aging sample from the Health and Retirement Study (HRS). We aim to (1) test the associations between DNA methylation and dementia phenotypes (prevalent, 8-year incident), stratified by race/ethnicity and test for effect modification by ADRD disparity-related factors (educational attainment, sex, urban/rural); (2) identify associations between longitudinal measures of modifiable risk factors for ADRD and DNA methylation, stratified by race/ethnicity and test for effect modification or mediation by ADRD disparity-related factors; and finally, (3) identify genetic polymorphisms controlling DNA methylation and whether these are enriched in dementia outcomes to evaluate the role of DNA methylation in disease development. This study will likely impact the field of Alzheimer’s research and contribute to public health because it will a) establish the relevance of DNA methylation on ADRD in multiple race/ethnicities; b) elucidate important biological epigenetic mechanisms; c) determine the combined and individual epigenetic-environment interplay contributions to ADRD; and d) consider the effects of sex, educational attainment, race/ethnicity, younger age groups, and urban/rural status in the same study where comparisons of relative contribution to risk can be made. Here, we have the opportunity to simultaneously and substantially improve our understanding of the genetic and environmental etiologic contributions to health disparities in ADRD.