Abstract
BACKGROUND: The aim was to investigate the potential therapeutic targets for ischemic stroke (IS) and vascular dementia (VD). METHODS: We assessed the causal effects of 2943 plasma proteins on IS and VD using a two-sample Mendelian randomization (MR) framework. Results were validated via summary data-based MR (SMR) analysis. A two-step mediation MR analysis was conducted to elucidate potential causal mechanisms by which plasma proteins influence IS and VD through risk factors. We performed a phenome-wide association study (PheWAS) MR analysis to explore side effects and additional indications for IS and VD-associated plasma proteins. We established middle cerebral artery occlusion and reperfusion (MCAO/R) and VD rat models to verify potential therapeutic targets for IS and VD. RESULTS: Genetically predicted plasma levels of six proteins demonstrated causal relationships with both IS and VD. SMR analysis validated four of these proteins (CD40, F11, F2, and Furin). Atrial fibrillation (AF), type 2 diabetes (T2D), low-density lipoprotein (LDL), and diastolic blood pressure (DBP) were causally associated with the risk of IS and VD, indicating common risk factors. CD40 and Furin associations with IS and VD appeared to be mediated by AF or DBP. The mechanisms of action of IS- and VD-related proteins primarily involve the complement and coagulation cascade. In vivo experiments confirmed that CD40, Furin, F11, and integrin alpha-V (ITGAV) were causally associated with IS and VD. CONCLUSIONS: Our findings illuminate causal pathways and potential therapeutic targets for IS and VD. We identified six plasma proteins with causal relationships to IS, VD, and their risk factors, providing insights into using these proteins as therapeutic targets for IS and VD.