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

具有全国代表性的多种族队列中痴呆症的 DNA 甲基化、遗传学和可改变的危险因素

• 批准号: 10605184
• 负责人: Kelly Marie Bakulski
• 金额: $ 75.15万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605184
• 关键词: Adult; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Base Sequence; Behavioral; Biological; Biology; Black race; Blood Pressure; Body mass index; Characteristics; Clinical assessments; Cognition; Collaborations; Complex; DNA Methylation; Data; Databases; Dementia; Development; Diabetes Mellitus; Disease; Disparity; Education; Ensure; Environment; Environmental Risk Factor; Epidemiology; Epigenetic Process; Ethnic Origin; Ethnic Population; Etiology; Evaluation; Genetic; Genetic Polymorphism; Genetic Risk; Genome; Geography; Goals; Health; Health and Retirement Study; Hispanic; Human; Individual; Inequality; Internet; Intervention; Investigation; Joints; Knowledge; Life Cycle Stages; Life Style; Measures; Mediation; Mediator; Memory; Minority; Modeling; Modification; Molecular; Neurocognitive; Not Hispanic or Latino; Outcome; Personal Satisfaction; Persons; Phenotype; Physical activity; Physiological; Population; Positioning Attribute; Predisposition; Prevalence; Protocols documentation; Public Health; Race; Recording of previous events; Research; Risk; Risk Factors; Role; Rural; Sample Size; Sampling; Site; Smoking; Social Environment; Source; Testing; United States; Woman; Work; age group; biomarker identification; cognitive testing; cohort; dementia risk; demographics; depressive symptoms; epigenetic marker; health disparity; improved; methylation testing; modifiable risk; multi-ethnic; novel strategies; peripheral blood; potential biomarker; pre-clinical; prediction algorithm; psychosocial; racial diversity; racial population; sex; social; social factors; symposium; tool

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.

项目概要 阿尔茨海默氏病及其相关痴呆症 (ADRD) 是主要的终末期疾病形式 痴呆症影响着美国越来越多的老年人。 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）是一个关键群体 知识差距。因此，具有足够样本量的研究，同时评估多个 特征，例如教育程度、环境、社会、行为、生活方式、 地理、生物学和表观遗传学将处于独特的地位，可以有效地测试因素或 造成和维持 ADRD 差异的因素组合。我们的目标是确定 表观遗传和环境对 ADRD 风险的共同贡献是这些健康的基础 差异。利用现有的表观遗传和遗传数据、充分表征的痴呆表型， 和多样化的危险因素数据，我们将分析具有人口代表性、多种族的老龄化 健康与退休研究 (HRS) 的样本。我们的目标是 (1) 测试关联 DNA 甲基化和痴呆表型之间（普遍，8 年事件），分层 种族/族裔以及 ADRD 差异相关因素（教育 成就、性别、城市/农村）； (2) 确定纵向测量之间的关联 ADRD 和 DNA 甲基化的可改变危险因素，按种族/民族分层并进行测试 ADRD 差异相关因素的影响修正或调节；最后，（3）确定 控制DNA甲基化的遗传多态性以及它们是否富含 痴呆症结果评估 DNA 甲基化在疾病发展中的作用。这项研究 可能会影响阿尔茨海默病的研究领域并为公众健康做出贡献，因为它将 a) 确定 DNA 甲基化与多个种族/族裔 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； d) 考虑性的影响， 受教育程度、种族/民族、年轻群体以及城市/乡村状况 可以对风险的相对贡献进行比较的研究。在这里，我们有 有机会同时并大幅提高我们对遗传和 环境病因对 ADRD 健康差异的影响。