Proteomics and the Risk of Incident Embolic and Thrombotic Stroke

Objective Personalized approaches to ischemic stroke diagnosis are needed. We determine differences in proteomic signatures of incident embolic (EIS) and thrombotic stroke (TIS) by age and resultant pathways using large‐scale proteomics. Methods Participants in the Atherosclerosis Risk in Communities Study (ARIC) from visit 2 (V2, 1990–1992) until 2020 without prevalent stroke with available SomaScan data (4,955 protein targets) at V2 (mid‐life, n = 10,929), and then again at visit 5 (V5, 2011–2013, n = 4,463) were included. Covariate adjusted Cox hazard models determined the association between proteins, and adjudicated incident EIS or TIS from V2 to V5 and from V5 to 2020. Results Among 10,929 participants (56% female, 23% Black, follow‐up ~20 years), 20 proteins measured in mid‐life were associated with either EIS (n = 168) or TIS (n = 459) in mid‐life, and 4 measured in late‐life were associated with late‐life stroke (73 EIS and 124 TIS events) at the Bonferroni threshold p < 1E−5. In mid‐life, N‐terminal pro‐B‐type natriuretic peptide (NPPB) was significantly associated with EIS, but not TIS ( p ‐difference = 9.14E−7). Nineteen mid‐life proteins were strongly associated with TIS; 7 strongly associated with TIS and only nominally ( p < 0.05) with EIS and the remaining 12 with TIS only. In late‐life, NPPB, serine protease inhibitor Kazal‐type 4, oligodendrocyte‐myelin‐glycoprotein, and neurocan‐core protein were significantly associated with EIS, but not TIS. Ingenuity Pathway Analysis tools implicated cancer for EIS‐associated proteins, whereas TIS pathways reflected cell‐structure and atherogenesis. Interpretation We identified plasma proteins associated with risk of EIS versus TIS reflecting distinct stroke mechanisms: cardiac dysfunction protein in EIS (eg, NPPB) and inflammation dysregulation in TIS (eg, interleukins). ANN NEUROL 2025;98:1125–1135