Epigenetic Risk Factors for AD Age at Onset and Health Disparities: HABLE Epigenetics Study

The long-term goal of this research is to examine the link between DNA methylation patterns and presence and progression of Alzheimer’s disease (AD) among Mexican Americans (MA) and non-Hispanic whites (NHW). Here we will address the aims of PAR-19-070 (Research on Current Topics in Alzheimer's Disease and Its Related Dementias) – NOT-AG-18-047 – by leveraging the ongoing HABLE cohort (R01AG054073) to identify the epigenetic factors associated with presence and progression of AD among MAs and NHWs. In our prior work and recent HABLE data, we examined DNA methylation patterns among n= 90 age, gender and diagnosis-matched participants leveraging the HABLE Biorepository (MCI n=45, controls n=45). We identified 10 CpG sites and four regions to be differentially methylated in normally aging controls relative to individuals diagnosed with MCI. Functional gene-set analysis identified four gene sets as significant. Gene ontology and pathway analysis highlighted neuronal cell death, metabolic dysfunction and inflammatory processes. Using Bayes gene set enrichment, we found MCI diagnosis was associated with processes converging on hypertension, diabetes, loss of hearing and olfaction, synaptic transporter activity and inflammation. These results link peripheral metabolic dysregulation and inflammation with cognitive decline and suggest that cognitive decline in MAs is a manifestation of factors related to metabolic stress. By leveraging the HABLE Biorepository, we will conduct a longitudinal Epigenome-Wide Association Study (EWAS) on biorepository data from n=1800 HABLE (n=900 MA; n=900 NHW) participants to identify differentially methylated DNA in circulating leukocytes to address two Specific Aims: Aim 1. Identify DNA methylation patterns in leukocytes that are associated with presence and progression of Alzheimer’s disease among Mexican Americans and non-Hispanic whites. Aim 2. Identify DNA methylation patterns in leukocytes that covary with prevalence and progression of AT(N) defined biomarkers of AD among Mexican Americans and non-Hispanic whites. Aim 1 results will be validated by comparison with data from a funded project (1R01AG061022-01) that is assessing the role of leukocyte meDNA in AD etiology in the SOL-INCA cohort. Aim 2 results for meDNA patterns associated with amyloid burden will be compared to data from the New IDEAS study. The current proposal is highly significant and innovative: 1) The proposed work is the first large-scale longitudinal examination of meDNA patterns associated with AT(N) Framework-defined pathological markers of AD among MAs; 2) this study directly meets NIA-defined milestones for AD/ADRD research among diverse populations; 3) data from this study will be merged with the HABLE database and made publicly available to the scientific community and the Alzheimer’s Disease Sequencing project (ADSP) and ADSP-Functional Genomics Consortium (ADSP-FGC).