Brain DNA methylation, APOE genotype and Alzheimer's disease neuropathology in a large postmortem cohort

DNA methylation (DNAm) plays a critical role in Alzheimer's disease (AD). Previous epigenome-wide association studies using 450K arrays captured limited CpG coverage and often focused on a single neuropathological measure. Here we profiled DNAm in 1,250 postmortem prefrontal cortex samples from the Rush Alzheimer's Disease cohorts using the Infinium MethylationEPIC v2 array (~930,000 CpGs) and performed epigenome-wide association studies of multiple neuropathologic measures, including AD diagnosis, amyloid-β and tau tangles. We identified 107 differentially methylated probes associated with AD neuropathology, 38 of which were replicated in an independent cohort (n = 139). DNAm also partially mediated the effect of APOE genotype on AD diagnosis (proportion mediated: 8.6%, P = 2 × 10⁻⁶). Moreover, 39 identified genes (for example, RIN3, LGMN, LHPP) were differentially expressed across major brain cell types, including neurons and astrocytes. These findings expand the epigenetic landscape of AD neuropathology and reveal DNAm as a mediator of APOE-related genetic risk.