The APOE isoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia in a xenotransplantation model of Alzheimer’s disease

Microglia play a key role in the response to amyloid beta in Alzheimer’s disease (AD). In this context, a major transcriptional response of microglia is the upregulation of APOE , the strongest late-onset AD risk gene. Of its three isoforms, APOE2 is thought to be protective, while APOE4 increases AD risk. We hypothesised that the isoforms functionally alter microglia by shaping their transcriptomic and chromatin landscapes. We used RNA- and ATAC-sequencing to profile gene expression and chromatin accessibility of human microglia isolated from a xenotransplantation model of AD. We identified widespread transcriptomic and epigenomic differences which are dependent on APOE genotype, and are corroborated across the profiling assays. Our results indicate that impaired microglial proliferation, migration and immune responses may contribute to the increased risk for late-onset AD in APOE4 carriers, while increased DNA-binding of the vitamin D receptor in APOE2 microglia may contribute to the isoform’s protective role.