Integrative epigenomic landscape of Alzheimer’s Disease brains reveals oligodendrocyte molecular perturbations associated with tau

Alzheimer's disease (AD) brains have variable neuropathologic and biochemical changes. Capturing epigenetic factors associated with this variability can reveal novel biological insights into AD pathophysiology. Here, we conduct an epigenome-wide association study of DNA methylation in 472 AD brains with neuropathologic and biochemical brain protein levels core to AD pathogenesis. Using a novel regional methylation (rCpGm) approach, we identify 5478 significant associations, 99.7% of which associate with tau biochemical measures, and 93 concordant associations in external datasets. Transcriptome-methylome integration reveals enrichment in oligodendrocyte genes, including known AD risk gene BIN1, myelination genes MYRF, MBP and MAG previously implicated in AD, and novel genes like LDB3. Further characterization of these perturbations in independent AD and primary tauopathy datasets highlights consistent tau-related associations. In summary, we uncover the integrative epigenomic landscape of AD, demonstrate tau-related oligodendrocyte gene perturbations as a common potential pathomechanism across tauopathies and share findings via our Multiomic Atlas.