A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk
Open accessAbstract
The human brain vasculature is of great medical importance: its dysfunction causes disability and death 1, and the specialized structure it forms-the blood-brain barrier-impedes the treatment of nearly all brain disorders 2,3. Yet so far, we have no molecular map of the human brain vasculature. Here we develop vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the human brain through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 9 individuals with Alzheimer's disease and 8 individuals with no cognitive impairment. We identify brain-region- and species-enriched genes and pathways. We reveal molecular principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In Alzheimer's disease, we observe selective vulnerability of ECM-maintaining pericytes and gene expression patterns that implicate dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 genes that have been linked to Alzheimer's disease risk by genome-wide association studies (GWASs) are expressed in the human brain vasculature, and we confirm this by immunostaining. Vascular GWAS genes map to endothelial protein transport, adaptive immune and ECM pathways. Many are microglia-specific in mice, suggesting a partial evolutionary transfer of Alzheimer's disease risk. Our work uncovers the molecular basis of the human brain vasculature, which will inform our understanding of overall brain health, disease and therapy.
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Yang et al. found at least 30 of top 45 AD GWAS genes are highly expressed in human cerebrovasculature cells, suggesting thorough vascular and perivascular involvement in AD.
“Yang et al. found that actually at least 30 of the top 45 AD GWAS genes are highly expressed in human cerebrovasculature cells, suggesting thorough vascular and perivascular involvement in AD.135”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [135]
The study harmonized snRNA-seq data and associated donor metadata from the PFC from ten additional AD studies spanning 707 donors.
“To corroborate the results, we harmonized snRNA-seq data and associated donor metadata from the PFC from ten additional AD studies spanning 707 donors5–14.”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [11]
Previous studies described AD-associated molecular and cellular changes; however, cross-study comparisons are challenging without common cell annotations.
“Previous studies described AD-associated molecular and cellular changes5–15; however, cross-study comparisons are challenging without common cell annotations.”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [11]
Our sample sizes are similar to those reported in previous publications.
“but our sample sizes are similar to those reported in previous publications5–14”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [11]
CAMs clear harmful substances through phagocytosis, antigen presentation, and cytokine production.
“As immune surveillants, CAMs clear harmful substances through phagocytosis, antigen presentation, and cytokine production [364,368,371,372,373,374,375,376]”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [376]
The ‘Cells of the human brain vasculature’ section identifies brain border macrophages but does not describe these functions. The Discussion discusses debris clearance and neuroimmune surveillance, chiefly in relation to microglia and vascular cells; searches for phagocytosis, antigen presentation, and cytokine production found no passage attributing the claimed mechanisms to CAMs. Page numbers were not provided in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Several genome-wide association studies (GWAS) have implicated microglia as the primary cell type expressing AD genes.
“Several genome-wide association studies (GWAS) have also implicated microglia as the primary cell type expressing AD genes.82–85”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [85]
A single-nucleus RNA-sequencing analysis of the hippocampus and frontal cortex of AD patients found that 30 of the top 45 AD GWAS hits are expressed in brain vascular cells.
“A recent single-nucleus RNA-sequencing analysis of the hippocampus and frontal cortex of AD patients found that 30 of the top 45 AD GWAS hits are expressed in brain vascular cells.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [85]
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- Authors
- Yang, A. C., Vest, R. T., Kern, F., Lee, D. P., Agam, M., Maat, C. A., Losada, P. M., Chen, M. B., Schaum, N., Khoury, N., Toland, A., Calcuttawala, K., Shin, H., Pálovics, R., Shin, A., Wang, E. Y., Luo, J., Gate, D., Schulz-Schaeffer, W. J., Chu, P., Siegenthaler, J. A., McNerney, M. W., Keller, A., & Wyss-Coray, T.
- Affiliations
- University of California, San Francisco (US)
- Stanford Medicine (US)
- Icahn School of Medicine at Mount Sinai (US)
- VA Palo Alto Health Care System (US)
- Saarland University (DE)
- University of Colorado Anschutz (US)
- Corresponding author
- Yang, Andrew C.
- ORCID
- Venue
- Nature
- Published
- 2022-02-14
- Volume
- 603
- Issue
- 7903
- Pages
- 885-892
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9635042
- OpenAlex
- W4213366162
- Cited by
- 797
- References
- 86
- Citations by year
- 2026: 146 · 2025: 212 · 2024: 184 · 2023: 165 · 2022: 81 · 2021: 7 · 2020: 1
- FWCI
- 57.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Simons Foundation
- American Heart Association (19PABHI34580007)
- Cold Spring Harbor Laboratory
- Universität des Saarlandes
- NOMIS Stiftung
- National Institutes of Health (T32-AG0047126)
- National Institute on Aging (T32AG0047126, AG0047126, RF1AG059694, T32AG047126, P30AG066515)
- National Cancer Institute
- NIH Clinical Center
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- Alzheimer's disease risk, single-nucleus transcriptomics, pericytes, perivascular fibroblasts, meningeal fibroblasts, blood-brain barrier, extracellular matrix, endothelial cells, microglia, hippocampus, cerebral cortex
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cerebral Cortex, Disease Susceptibility, Hippocampus, Humans, Microglia, Pericytes, Mice, Genome-Wide Association Study, Transcriptome
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