Early oligodendrocyte dysfunction signature in Alzheimer’s disease: Insights from DNA methylomics and transcriptomics
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INTRODUCTION
Alzheimer’s disease (AD) research has largely focused on neurons, with glial contributions, particularly from oligodendrocytes (OLGs), often overlooked. DNA methylation alterations are well documented in AD, but cell-type-specific insights remain limited. Here, we investigate OLG-associated DNA methylation across brain regions to further understand its role in AD.
METHODS
We applied weighted-gene correlation network analysis (WGCNA) to human DNA methylation data from four brain regions, human brain single-nuclei RNA sequencing, and mouse brain RNA sequencing. Networks were examined to identify disease-associated modules enriched for OLG genes and compared across datasets.
RESULTS
We identified an AD-associated DNA methylation signature enriched for OLGs, which was preserved across brain regions, and linked to altered OLG gene expression. Dysregulated signatures spanned multiple disease stages, suggesting early OLG alterations are consistent features of AD.
DISCUSSION
Our findings implicate early OLG-specific DNA methylation changes as a potential initiating factor of AD pathogenesis.
