Meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights 220 differentially methylated loci across cortex

Epigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six methylomic studies of Alzheimer’s disease (N=1,453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. At an experiment-wide significance threshold (P<1.238 x10) we identified 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex, with none in the cerebellum. Our cross-cortex meta-analysis (N=1,408 donors) identified 220 CpGs associated with neuropathology, annotated to 121 genes, of which 96 genes had not been previously reported at experiment-wide significance. Polyepigenic scores derived from these 220 CpGs explain 24.7% of neuropathological variance, whilst polygenic scores accounted for 20.2% of variance in these samples. The meta-analysis summary statistics are available in our online data resource ().