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We profiled 1441 baseline plasma proteins in a memory\u2010clinic cohort (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a0518), followed\u2010up for 4 years. Proteins associating with baseline and longitudinal CeVD lesions (i.e., white matter hyperintensity volume, lacunes, cerebral microbleeds, and cortical infarcts) were reported. The prognostic value of CeVD\u2010associated proteins was evaluated for incident major cardiovascular\/cerebrovascular events (MACCE) and mortality. External validation of key proteins for mortality was performed in the plasma proteome of an independent cardiovascular cohort (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a02016).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>We report distinct and overlapping plasma proteins for baseline and longitudinal CeVD, representing diverse biological processes. Four proteins were prioritized as mediators of CeVD\u2010associated cognitive decline, and predictors of MACCE. These proteins were validated for incident mortality across both cohorts: neurofilament light chain (NEFL), latent\u2010transforming growth factor beta\u2010binding protein 2 (LTBP2), cysteine\u2010rich motor neuron 1 protein (CRIM1), and urokinase plasminogen activator surface receptor (PLAUR).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>The prognostic proteins prioritized in our study provide robust signals in two cohorts, representing potential mechanistic targets for CeVD and health outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71728","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T06:11:54Z","timestamp":1787206314000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Plasma proteomics of cerebrovascular disease, cognitive decline, and clinical outcomes"],"prefix":"10.1002","volume":"22","author":[{"given":"Ming Ann","family":"Sim","sequence":"first","affiliation":[{"name":"Department of Pharmacology Memory Aging and Cognition Centre, National University of Singapore  Singapore Singapore"},{"name":"Yong Loo Lin School of Medicine National University of Singapore  Singapore Singapore"},{"name":"Department of Intensive Care Medicine National University Health System  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saima","family":"Hilal","sequence":"additional","affiliation":[{"name":"Saw Swee Hock School of Public Health National University of Singapore  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper","family":"Tromp","sequence":"additional","affiliation":[{"name":"Saw Swee Hock School of Public Health National University of Singapore  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene S. 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