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

项目摘要

PROJECT SUMMARY ABSTRACT In the US, Alzheimer’s disease and related dementias (ADRD) disproportionally affect marginalized racial and ethnic groups, after accounting for healthcare utilization and other major risk factors. Epigenetic measures, such as DNA methylation, hold great promise as indicators of adverse changes at a molecular level resulting from contextual effects, potentially identifying health disparities long before the health outcomes are observable. DNA methylation is a powerful tool to locate the sources and consequences of inequalities, further revealing the complex web of factors (e.g. biological, social-contextual) that drive health disparities. Using epigenetic and genetic data, well-characterized dementia phenotypes, and diverse risk factor data, the grant analyzes a population representative, multi-ethnic aging sample from the Health and Retirement Study (HRS). Taking advantage of Mr. Higgins Tejera’s expertise in biostatistics applied in a large, diverse cohort, he proposes to use the analytic framework of the parent grant to expand to deeply investigate the role of inflammatory biomarkers in dementia. The first aim of his expansion will estimate the prospective associations between markers of inflammation (e.g., hsCRP, IL-6, TNF-alpha, Cysteine-C) and incident dementia using longitudinal regression analyses. The second aim proposes a Mendelian randomization analysis of the causal effect of systemic inflammation on incident dementia. The third aim tests whether the relationship between systemic inflammation and dementia is mediated by DNA methylation. To determine whether race/ethnicity modifies these relationships, race/ethnicity-dependent relationships will be explored in all aims. This diversity supplement will expand our understanding of the roles of systemic inflammation and DNA methylation, two important ways that social inequality may be biologically embedded, on dementia risk. Mr. Higgins Tejera’s career goal is to be an independent researcher studying disparities and neuropsychiatric disorders at an academic institute. To support his career development, during this grant period he will receive training on: 1) advanced statistical analyses and results interpretation, including repeated measures and mediation analyses, 2) epidemiologic causal methods through the application of Mendelian randomization for inferring causal relationships, 3) biological and social-contextual factors underlying health disparities, 4) research communication through peer review and academic conferences, 5) faculty development and leadership. Training in these areas will prepare Mr. Higgins Tejera for an impactful research career.