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Despite the importance of the cerebrovasculature in maintaining normal brain physiology and in understanding neurodegeneration and CNS drug delivery1, human cerebrovascular cells remain poorly characterized due to their sparsity and dispersion. Here, we perform the first single-cell characterization of the human cerebrovasculature using both ex vivo fresh tissue experimental enrichment and post mortem in silico sorting of human cortical tissue samples. We capture 16,681 cerebrovascular nuclei across 11 subtypes, including endothelial cells, mural cells, and three distinct subtypes of perivascular fibroblasts along the vasculature. We uncover human-specific expression patterns along the arteriovenous axis and determine previously uncharacterized cell type-specific markers. We use our newly discovered human-specific signatures to study changes in 3,945 cerebrovascular cells of Huntington’s disease patients, which reveal an activation of innate immune signaling in vascular and glial cell types and the concomitant reduction to proteins critical for maintenance of blood-brain barrier integrity. Finally, our study provides a comprehensive resource molecular atlas of the human cerebrovasculature to guide future biological and therapeutic studies.

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