Background: Cerebral small vessel disease (CSVD) is a leading cause of stroke and dementia, with white matter hyperintensities (WMH) and lacunar stroke as its two principal neuroimaging subtypes. Although these subtypes frequently co-occur, whether their underlying molecular mechanisms are independent has not been systematically examined at the genetic level. This study aimed to apply proteome-wide Mendelian randomization (MR) to test whether the causal protein profiles of WMH and lacunar stroke are distinct, and to identify subtype-specific candidate targets. Methods: We employed a two-sample MR design. Genetic instruments for 1954 plasma proteins were derived from a large-scale proteogenomic dataset (N = 54,219). Outcome data came from the largest available GWAS for lacunar stroke (7338 cases, 225,258 controls) and WMH burden (N = 51,065). The Wald ratio method was used for primary MR analysis, with colocalization, SMR, and pleiotropy checks performed to assess robustness. Results: After FDR correction, seven proteins showed causal associations with lacunar stroke (TMPRSS5, WARS, KIAA0319, MMP12, CD40, FURIN, GRK5), and five with WMH burden (EFNA1, DNAJC21, MPI, BTN3A2, BTN2A1). There was no overlap between the two FDR-significant sets. Conclusions: These findings show no overlapping FDR-significant plasma protein associations between WMH and lacunar stroke, suggesting largely independent molecular mechanisms. Subtype stratification should be considered in future CSVD trial design. Several identified targets—including FURIN, WARS, and BTN3A2—have existing investigational agents, nominating them for further pharmacological evaluation.
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