Integrative Epigenomic Landscape of Alzheimer’s Disease Brains Reveals Oligodendrocyte Molecular Perturbations Associated with Tau

Alzheimer’s disease (AD) brains are characterized by neuropathologic and biochemical changes that are highly variable across individuals. Capturing epigenetic factors that associate with this variability can reveal novel biological insights into AD pathophysiology. We conducted an epigenome-wide association study of DNA methylation (DNAm) in 472 AD brains with neuropathologic measures (Braak stage, Thal phase, and cerebral amyloid angiopathy score) and brain biochemical levels of five proteins (APOE, amyloid-β (Aβ)40, Aβ42, tau, and p-tau) core to AD pathogenesis. Using a novel regional methylation (rCpGm) approach, we identified 5,478 significant associations, 99.7% of which were with brain tau biochemical measures. Of the tau-associated rCpGms, 93 had concordant associations in external datasets comprising 1,337 brain samples. Integrative transcriptome-methylome analyses uncovered 535 significant gene expression associations for these 93 rCpGms. Genes with concurrent transcriptome-methylome perturbations were enriched in oligodendrocyte marker genes, including known AD risk genes such as BIN1 , myelination genes MYRF, MBP and MAG previously implicated in AD, as well as novel genes like LDB3 . We further annotated the top oligodendrocyte genes in an additional 6 brain single cell and 2 bulk transcriptome datasets from AD and two other tauopathies, Pick’s disease and progressive supranuclear palsy (PSP). Our findings support consistent rCpGm and gene expression associations with these tauopathies and tau-related phenotypes in both bulk brain tissue and oligodendrocyte clusters. In summary, we uncover the integrative epigenomic landscape of AD and demonstrate tau-related oligodendrocyte gene perturbations as a common potential pathomechanism across different tauopathies.