Methylation differences in Alzheimer’s disease neuropathologic change in the aged human brain

AD neuropathologic change (ADNC) is known to be associated with numerous DNA methylation changes in the human brain, but the oldest old (>90 years) have so far been underrepresented in epigenetic studies of ADNC. Our study participants were individuals aged over 90 years (n= 47) from The 90+Study. We analyzed DNA methylation from bulk samples in eight precisely dissected regions of the human brain: middle frontal gyrus, cingulate gyrus, entorhinal cortex, dentate gyrus, CA1, substantia nigra, locus coeruleus and cerebellar cortex. We deconvolved our bulk data into cell type specific (CTS) signals using computational methods (EpiSCORE, TCA). CTS methylation differences were analyzed across different levels of ADNC. The highest amount of ADNC related methylation differences was found in neurons of the dentate gyrus, a region that has so far been underrepresented in large scale multi-omic studies. Amongst others, higher amyloid plaque burden was associated with promoter hypomethylation of the Presenilin enhancer 2 (PEN-2) gene, one of the rate limiting genes in the formation of γ-secretase, a multicomponent complex that is responsible in part for the endoproteolytic cleavage of amyloid precursor protein into amyloid β peptides. In addition to novel ADNC related DNA methylation changes, we present the most detailed array-based methylation survey of the old aged human brain to date. Our open-sourced dataset can serve as a brain region reference panel for future studies and help advance research in aging and neurodegenerative diseases. DNA from 8 different brain regions from 47 individuals was extracted, bisulfite converted and hybridised to the Illumina Infinium 850k Human Methylation Beadchip. Replicates and low-quality samples were removed, leading to a total of 321 samples for which raw and processed data was uploaded to GEO. Processed data files include bulk and cell type specific data.