Human brain vascular multi-omics elucidates disease-risk associations

Affiliations

¹ Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
² Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Gladstone Institute of Data Science & Biotechnology, San Francisco, CA, USA; Medical Scientist Training Program and Biological and Medical Informatics Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
³ Gladstone Institute of Data Science & Biotechnology, San Francisco, CA, USA.
⁴ Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
⁵ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁶ Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
⁷ Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁸ Gladstone Institute of Data Science & Biotechnology, San Francisco, CA, USA; Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Chan Zuckerberg Biohub SF, San Francisco, CA, USA.
⁹ Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Gladstone Institute of Data Science & Biotechnology, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
¹⁰ Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Bakar Aging Research Institute, University of California, San Francisco, San Francisco, CA, USA. Electronic address: andrew.yang@gladstone.ucsf.edu.

PMID: 40730185
PMCID: PMC12321221 (available on 2026-07-28)
DOI: 10.1016/j.neuron.2025.07.001

Human brain vascular multi-omics elucidates disease-risk associations

Madigan M Reid et al. Neuron. 2025.

. 2025 Oct 1;113(19):3143-3161.e5.

doi: 10.1016/j.neuron.2025.07.001. Epub 2025 Jul 28.

Authors

Affiliations

¹ Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
² Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Gladstone Institute of Data Science & Biotechnology, San Francisco, CA, USA; Medical Scientist Training Program and Biological and Medical Informatics Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
³ Gladstone Institute of Data Science & Biotechnology, San Francisco, CA, USA.
⁴ Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
⁵ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁶ Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
⁷ Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁸ Gladstone Institute of Data Science & Biotechnology, San Francisco, CA, USA; Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Chan Zuckerberg Biohub SF, San Francisco, CA, USA.
⁹ Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Gladstone Institute of Data Science & Biotechnology, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
¹⁰ Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Bakar Aging Research Institute, University of California, San Francisco, San Francisco, CA, USA. Electronic address: andrew.yang@gladstone.ucsf.edu.

PMID: 40730185
PMCID: PMC12321221 (available on 2026-07-28)
DOI: 10.1016/j.neuron.2025.07.001

Abstract

Cerebrovascular dysfunction underlies many neurological disorders, yet how genetic variants in brain vascular cells drive disease risk remains unknown. We developed MultiVINE-seq to simultaneously profile RNA and chromatin accessibility in vascular, perivascular, and immune cells from 30 human brains. Mapping genome-wide association study (GWAS) data to our multi-omic atlas linked thousands of GWAS disease-risk variants to target cell types and genes, including 2,605 previously unmapped. We found cerebrovascular and neurodegenerative disease variants have distinct mechanisms: cerebrovascular disease variants disrupt extracellular matrix genes in endothelial, mural, and fibroblast cells important for vessel structural integrity, while Alzheimer's disease (AD) variants dysregulate inflammatory adaptor proteins in endothelial and immune cells. Notably, a lead AD variant enhances PTK2B expression in brain CD8 T cells, providing genetic evidence for adaptive immunity in AD pathogenesis. This work provides a key resource for interpreting genetic risk and reveals how variants in vascular cells drive divergent pathogenic mechanisms across neurological diseases.

Keywords: Alzheimer's disease; T cell; brain vasculature; cerebrovascular disease; macrophage; microglia; neurodegenerative disease; non-coding disease-risk variants; single-cell multi-omics; stroke.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

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Human brain vascular multi-omics elucidates disease-risk associations

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Human brain vascular multi-omics elucidates disease-risk associations

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