Multiomics Profiling Supports Cathepsin B as a Protective Factor in Cerebral Small Vessel Disease

White matter hyperintensities (WMH) are a common brain MRI 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. Here, we combined large-scale proteomic and genomic data with tissue- and single-nucleus transcriptomic validation to identify circulating proteins that influence WMH volume and its downstream clinical manifestations. Association and Mendelian Randomization analyses of WMH volume and 2,923 plasma proteins in 52,560 UK Biobank participants identified the lysosomal protease cathepsin B (CTSB) and the mitochondrial enzyme Enoyl-CoA Hydratase Domain Containing 3 (ECHDC3) as the top candidates associated with WMH volume. Single-nucleus RNA sequencing of post-mortem periventricular white matter from 8 individuals (4 with WMH lesions and 4 matched controls) revealed a marked downregulation of CTSB in WMH lesions, predominantly in astrocytes and oligodendrocytes, whereas ECHDC3 expression was unchanged between cases and controls. In the UK Biobank, higher plasma CTSB levels and a cis-pQTL polygenic score each predicted better general cognitive ability, independent of vascular risk factors, whereas ECHDC3 showed no cognitive association. Together, these multimodal analyses across different studies point to CTSB as a lesion-suppressed, cognition-enhancing factor and a plausible therapeutic target for mitigating the effects of WMH and preserving brain health.