The brain neurovascular epigenome and its association with dementia.

Cerebral small vessel disease (SVD) is frequently comorbid with Alzheimer's disease (AD), and brain endothelial cells (BECs) express genes associated with AD genetic risk. However, the epigenome of neurovascular cells and its intersection with genetic risk remain unexplored. Here, we generated gene regulomes for human BECs, mural cells, and other brain cell types and showed that AD heritability is primarily immune related, with a modest BEC enrichment. On the other hand, SVD heritability is enriched across the neurovascular unit, including astrocytes. Enhancer-to-gene interactomes implicated disease-distinct putative risk genes associated with amyloid and phospholipid processes in AD and senescence-associated pathways in SVD. Motifs for putative partners of lineage-determining transcription factors (TFs) in microglia and BECs were enriched for AD and SVD variants linked to disease-associated genes. In silico screening of compounds implicated vitamin D receptor agonists, mammalian target of rapamycin (mTOR), histone deacetylase (HDAC), and vascular endothelial growth factor receptor (VEGFR) inhibitors for AD. Our findings highlight regulatory mechanisms and therapeutic targets within the neurovascular system.