Faculty, Staff and Student Publications

Publication Date

12-1-2025

Journal

Nature Aging

DOI

10.1038/s43587-025-01006-w

PMID

41266628

PMCID

PMC12705447

PubMedCentral® Posted Date

11-20-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia with no specific treatment, of which molecular mechanisms remain poorly understood. To identify potential biomarkers and therapeutic targets, we applied Mendelian randomization to examine over 2,500 proteins measured in plasma and, uniquely, cerebrospinal fluid, in relation to magnetic resonance imaging (MRI) markers of cSVD in more than 40,000 individuals. Here we show that 49 proteins are associated with MRI markers of cSVD, most prominently in cerebrospinal fluid. We highlight associations that are consistent across platforms and ancestries, and supported by complementary observational analyses, and we explore differences between fluids. The proteins are enriched in pathways related to the extracellular matrix, immune response and microglial activity. Many also associate with stroke and dementia, and several correspond to existing drug targets. Together, these findings reveal a robust biological fingerprint of cSVD and highlight opportunities for biomarker and drug discovery and repositioning.

Keywords

Cerebral Small Vessel Diseases, Humans, Biomarkers, Magnetic Resonance Imaging, Proteogenomics, Mendelian Randomization Analysis, Male, Female, Aged, Cerebrovascular disorders, Neurovascular disorders

Published Open-Access

yes

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