A cell-type-resolved meta-analysis reveals glial DNA methylation changes associated with aging and Alzheimer's disease.

INTRODUCTION: Epigenome-wide association studies implicate DNA methylation in Alzheimer's disease (AD) pathology. Although recent studies identified epigenetic signatures within non-neuronal cell types in disease risk, the role of the methylome in glial cell types (i.e., astrocytes, oligodendrocytes) in biological aging and AD pathogenesis is unclear. METHODS: 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. RESULTS: We observed pronounced age-associated methylation signatures in astrocytes within the prefrontal cortex (PFC) and AD-associated methylation signatures in oligodendrocytes of the entorhinal cortex. Astrocytes and neurons within the PFC emerge as key players in Braak stage-associated methylation signatures. In oligodendrocytes, we observed amplification of age-related effects of DNA methylation signatures with AD. DISCUSSION: Our study expands on previous findings and reveals glial-specific methylation patterns associated with epigenetic aging and AD.