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

Abstract 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.