Abstract

Cerebrovascular breakdown occurs early in Alzheimers Disease (AD), but its cell-type-specific molecular basis remains uncharacterized. Here, we characterize single-cell transcriptomic differences in human cerebrovasculature across 220 AD and 208 control individuals and across 6 brain regions. We annotate 22,514 cerebrovascular cells in 11 subtypes of endothelial, pericyte, smooth muscle, perivascular fibroblast, and ependymal cells, and how they differ in abundance and gene expression between brain regions. We identify 2,676 AD-differential genes, including lower expression of PDGFRB in pericytes, and ABCB1 and ATP10A in endothelial cells. These AD-differential genes reveal common upstream regulators, including MECOM, EP300, and KLF4, whose targeting may help restore vasculature function. We find coordinated vasculature-glial-neuronal co-expressed gene modules supported by ligand-receptor pairs, involved in axon growth/degeneration and neurogenesis, suggesting mechanistic mediators of neurovascular unit dysregulation in AD. Integration with AD genetics reveals 125 AD-differential genes directly linked to AD-associated genetic variants (through vasculature-specific eQTLs, Hi-C, and correlation-based evidence), 559 targeted by AD-associated regulators, and 661 targeted by AD-associated ligand-receptor signaling. Lastly, we show that APOE4-genotype associated differences are significantly enriched among AD-associated genes in capillary and venule endothelial cells, and subsets of pericytes and fibroblasts, which underlie the vascular dysregulation in APOE4-associated cognitive decline. Overall, our multi-region molecular atlas of differential human cerebrovasculature genes and pathways in AD can help guide early-stage AD therapeutics.