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

INTRODUCTION

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

METHODS

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).

RESULTS

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).

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