ArticleStroke2026
Multiomics Profiling Supports Cathepsin B as a Protective Factor in White Matter Hyperintensities and Cognition.
Article in Stroke, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Authors and funding
10 authors.
Funding
Abstract
backgroundWhite matter hyperintensities (WMH) are a common brain magnetic resonance imaging marker of cerebral small vessel disease and a major risk factor for stroke and dementia, yet the molecular mechanisms governing lesion formation remain incompletely understood. We sought to identify circulating proteins that lie upstream of WMH and influence related clinical manifestations.
methodsWe conducted a 4-stage proteogenomic study. Stage 1 tested a WMH polygenic risk score against 2923 plasma proteins in 52 560 UK Biobank participants (mean age, 56.8 years, 53.9% female, 94.0% White), and candidate proteins against WMH volume in the neuroimaging subset (n=5443; mean age 54.2 years, 53.5% female). Stage 2 applied bidirectional Mendelian randomization, colocalization, and local genetic correlation using cis protein quantitative trait locus and cis expression quantitative trait locus instruments from plasma, vascular, and brain tissue. Stage 3 analyzed single-nucleus RNA sequencing of 8 postmortem periventricular white matter samples (4 WMH lesions, 4 controls; mean age, 81 years; 50% female). Stage 4 tested circulating and genetically predicted protein levels against general cognitive ability.
resultsStages 1 and 2 converged on CTSB (cathepsin B) and ECHDC3 (enoyl-coenzyme A hydratase domain-containing 3). Higher plasma CTSB was associated with lower WMH volume (β=-0.09 [95% CI, -0.13 to -0.05]; n=5260), and Mendelian randomization estimates were directionally consistent across all 5 instrument sets (plasma protein quantitative trait locus β=-0.052 [95% CI, -0.064 to -0.040]), with concordant effects on white matter microstructure, perivascular spaces, and lacunar stroke. Single-nucleus RNA sequencing showed CTSB downregulation within lesions, predominantly in astrocytes (log
conclusionsMultimodal proteogenomic evidence nominates CTSB as a lesion-suppressed protein associated with lower WMH burden and better cognition, and a candidate therapeutic target for cerebral small vessel disease.
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