The brain neurovascular epigenome and its association with dementia

Cerebral small vessel disease (SVD) is frequently comorbid with Alzheimer's disease (AD) and vascular brain endothelial cells (BECs) are enriched for the expression of genes associated with AD genetic risk. However, the gene regulatory landscapes of neurovascular cells and their intersection with genetic risk for disease remains unexplored. Here we have generated gene regulomes for human BECs, mural cells and other brain cell types to show that AD heritability is primarily immune-related and that it shows modest enrichment in BECs. By contrast, genetic risk for SVD is enriched across cells of the neurovascular unit, including astrocytes. Enhancer-to-gene interactomes implicate amyloid processes in both AD and SVD, though the risk genes are mostly distinct for the two disorders. Motifs for putative partners of lineage transcription factors in microglia and BECs were enriched for AD and SVD variants at genes linked to disease pathways. Gene prioritization and enrichment analyses further identified potential repurposable drugs for AD. Our findings highlight novel regulatory mechanisms and therapeutic targets within the neurovascular system. Overall design: H3K27ac CUT&Tag on ERG+, NeuN+, NOTCH3+, PU.1+, OLIG2+ and RFX4+ sorted cortical nuclei from aged postmortem tissue. H3K4me3 CUT&Tag on ERG+, NeuN+, NOTCH3+, PU.1+, OLIG2+ and RFX4+ sorted cortical nuclei from aged postmortem tissue.