Abstract
BACKGROUND: Aging is a major risk factor for Alzheimer's disease (AD), but the molecular processes linking aging to AD remain unclear. Epigenetic modifications, particularly DNA methylation (DNAm), play a crucial role in understanding aging and AD. METHOD: We studied brain DNA methylation (DNAm) changes in normal aging versus AD in late life. We performed a comprehensive meta‐analysis of two large cohorts of postmortem prefrontal cortex samples from subjects over 65 years old. Our analysis adjusted estimated cell‐type proportions (i.e., the proportion of neurons), sex, and batch effects, and corrected for inflation and multiple testing. RESULT: We identified numerous DNAm differences consistently associated with aging in both cohorts, highlighting key genes such as ELOVL2, ISM1, and KLF14, which are implicated in various aging processes. These DNAm differences are predominantly hypermethylated, enriched in promoter regions, and associated with genes involved in immune processes and metabolic functions. Our results also revealed significant overlaps between aging‐associated DNAm differences and those involved in AD, supporting the hypothesis that aging and AD are interconnected at the molecular level. Intriguingly, nearly all DNAm differences significantly associated with both age (at death) and AD Braak stage showed concordant effect sizes in the same direction. CONCLUSION: Our study provides valuable insights into the aging‐associated epigenetic landscape and its potential implications for AD. As aging and AD are intertwined, targeting age‐related epigenetic modifications may offer new therapeutic strategies for AD.