Early oligodendrocyte dysfunction signature in Alzheimer's disease: Insights from DNA methylomics and transcriptomics
INTRODUCTION: Much research into the aetiology of Alzheimer's disease (AD) has focused on neuronal cell types, while the contribution of glial cells, including oligodendrocytes (OLGs), has often been overlooked. Altered DNA methylation, an epigenetic modification that can influence gene expression, is well documented in AD, yet cell-type-specific investigations remain limited. In this study, we examine DNA methylation signatures associated with OLGs across multiple brain regions in AD to better understand the role of DNA methylation and OLGs in the disease, and how such changes may impact gene expression. METHODS: We performed weighted-gene correlation network analysis (WGCNA) on multiple omics AD datasets across species: human DNA methylation datasets across 4 brain regions, human brain single-nuclei RNA sequencing data and mouse brain RNA sequencing data. We then investigated networks to identify disease-associated modules enriched for OLG genes, before running comparisons across such modules. RESULTS: We identified a DNA methylation signature associated with AD, enriched for OLGs, and preserved across brain regions. Genes within this signature showed altered expression in OLGs, confirming cell-type specificity and relevance to AD. Dysregulated signatures were observed across multiple disease stages, revealing a conserved pattern of OLG dysfunction from early to late stages and highlighting OLG alterations as a key feature of early AD pathogenesis. DISCUSSION: We reveal a consistent pattern of OLG dysfunction spanning early to late stages of AD, across DNA methylation and gene expression. Our findings implicate early OLG-associated DNA methylation changes as a potential initiating factor in disease pathogenesis.