Cell type-specific histone acetylation profiling of Alzheimer's disease subjects and integration with genetics

We profile genome-wide histone 3 lysine 27 acetylation (H3K27ac) of 3 major brain cell types from hippocampus and dorsolateral prefrontal cortex (dlPFC) of subjects with and without Alzheimer's Disease (AD). We confirm that single nucleotide polymorphisms (SNPs) associated with late onset AD (LOAD) show a strong tendency to reside in microglia-specific gene regulatory elements. Despite this significant colocalization, we find that microglia harbor more acetylation changes associated with age than with amyloid-β (Aβ) load. In contrast, we detect that an oligodendrocyte-enriched glial (OEG) population contains the majority of differentially acetylated peaks associated with Aβ load. These differential peaks reside near both early onset risk genes (APP, PSEN1, PSEN2) and late onset AD risk loci (including BIN1, PICALM, CLU, ADAM10, ADAMTS4, SORL1, FERMT2), Aβ processing genes (BACE1), as well as genes involved in myelinating and oligodendrocyte development processes. Interestingly, a number of LOAD risk loci associated with differentially acetylated risk genes contain H3K27ac peaks that are specifically enriched in OEG. These findings implicate oligodendrocyte gene regulation as a potential mechanism by which early onset and late onset risk genes mediate their effects, and highlight the deregulation of myelinating processes in AD. More broadly, our dataset serves as a resource for the study of functional effects of genetic variants and cell type specific gene regulation in AD.