Plasma proteomics of cerebrovascular disease, cognitive decline, and clinical outcomes

The plasma proteomic signatures underlying cerebrovascular disease (CeVD) remains poorly understood.

A total of N = 2534 participants across two independent longitudinal Southeast-Asian cohorts were included. We profiled 1441 baseline plasma proteins in a memory-clinic cohort (N = 518), followed-up 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-associated 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 = 2016).

We report distinct and overlapping plasma proteins for baseline and longitudinal CeVD, representing diverse biological processes. Four proteins were prioritized as mediators of CeVD-associated cognitive decline, and predictors of MACCE. These proteins were validated for incident mortality across both cohorts: neurofilament light chain (NEFL), latent-transforming growth factor beta-binding protein 2 (LTBP2), cysteine-rich motor neuron 1 protein (CRIM1), and urokinase plasminogen activator surface receptor (PLAUR).

The prognostic proteins prioritized in our study provide robust signals in two cohorts, representing potential mechanistic targets for CeVD and health outcomes.