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

项目总结 阿尔茨海默病及其相关痴呆(ADRD)是阿尔茨海默病的主要终末型 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风险在 少数民族、妇女、农村居民和受教育程度较低的人)，代表着一个关键的 知识鸿沟。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在有效测试因素或 造成和维持ADRD差异的各种因素的组合。我们的目标是确定 表观遗传和环境共同导致ADRD风险，这些风险是这些健康的基础 差距。利用现有的表观遗传学和遗传学数据，充分描述了痴呆症的表型， 和多样的危险因素数据，我们将分析一个具有代表性的人口、多民族老龄化 样本来自健康和退休研究(HRS)。我们的目标是(1)测试这些关联 DNA甲基化和痴呆症表型之间的关系(流行，8年事件)，按 种族/民族和ADRD差异相关因素的效果修正测试(教育 获得程度、性别、城市/农村)；(2)确定纵向测量之间的联系 ADRD和DNA甲基化的可修改风险因素，按种族/民族分层，并进行 ADRD差异相关因素的影响修正或调节；(3)识别 控制DNA甲基化的遗传多态以及这些基因是否富含 评估DNA甲基化在疾病发展中的作用的痴呆结果。本研究 可能会影响阿尔茨海默氏症的研究领域，并为公共健康做出贡献，因为它将 A)确定DNA甲基化与ADRD在多种族/民族中的相关性；b)阐明 重要的生物表观遗传机制；c)决定组合和个体 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/民族、年轻年龄组和城乡地位相同 可以进行风险相对贡献比较的研究。在这里，我们有 有机会同时大幅提高我们对基因和 环境病因学对ADRD健康差异的贡献。

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.