A Cell-Type–Resolved Meta-Analysis Reveals Glial DNA Methylation Changes Associated with Aging and Alzheimer’s Disease

Abstract Epigenome-wide association studies implicate DNA methylation in the development and progression of Alzheimer’s disease (AD). Although recent studies show that the epigenetics of non-neuronal cell types contribute to disease risk, the role of the methylome in individual glial cell types (i.e., astrocytes, oligodendrocytes) in biological aging and AD pathogenesis is unclear. In this study, we examined archived DNA methylation data across 13 cohorts and performed cell type deconvolution in silico to identify novel epigenetic signatures associated with aging and AD in glial cells. We observed pronounced age-associated methylation in astrocytes within the prefrontal cortex, whereas oligodendrocytes of the entorhinal cortex show the most differential methylation with AD status. Astrocytes, along with neurons, within the prefrontal cortex, emerge as key players in Braak stage-associated methylation, exhibiting strong concordance with previously reported associations at the brain tissue level. Age-associated changes in oligodendrocytes exhibit strong directional correlation with, and amplification of age-related effects with AD that affect neurodevelopmental processes, while AD-related methylation changes at age-associated sites in astrocytes diverge from those representative of normative aging processes. Our study expands on previous findings and reveals glial-specific methylation patterns associated with epigenetic aging and AD.