Cardiovascular

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

TL;DR

Four plasma proteins—NEFL, LTBP2, CRIM1, and PLAUR—were identified as mediators of CeVD-associated cognitive decline, predictors of MACCE, and validated for incident mortality across two independent cohorts.

Key Findings

A total of 1441 baseline plasma proteins were profiled in a memory-clinic cohort and associations with multiple cerebrovascular disease lesion types were identified.

  • The memory-clinic cohort included N=518 participants followed up for 4 years.
  • CeVD lesions examined included white matter hyperintensity volume, lacunes, cerebral microbleeds, and cortical infarcts.
  • An independent cardiovascular cohort of N=2016 was used for external validation.
  • Total participants across both independent longitudinal Southeast-Asian cohorts: N=2534.

Distinct and overlapping plasma proteins were identified for baseline and longitudinal CeVD, representing diverse biological processes.

  • Proteins were associated with both cross-sectional (baseline) CeVD lesions and longitudinal changes in CeVD lesions over the 4-year follow-up.
  • The proteomic signatures reflected diverse biological processes underlying cerebrovascular disease.
  • Both shared and lesion-type-specific proteins were reported across the four CeVD lesion subtypes.

Four proteins were prioritized as mediators of CeVD-associated cognitive decline and predictors of major cardiovascular/cerebrovascular events (MACCE).

  • The four prioritized proteins were 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).
  • These proteins were identified through mediation analyses linking CeVD to cognitive decline.
  • Prognostic value was evaluated for incident MACCE in addition to cognitive outcomes.

NEFL, LTBP2, CRIM1, and PLAUR were validated as predictors of incident mortality across both the memory-clinic and independent cardiovascular cohorts.

  • External validation was performed in the plasma proteome of an independent cardiovascular cohort (N=2016).
  • All four proteins showed robust prognostic signals for mortality in both cohorts.
  • These proteins represent potential mechanistic targets for CeVD and health outcomes.

The study evaluated the prognostic value of CeVD-associated proteins for incident major cardiovascular/cerebrovascular events (MACCE) and mortality.

  • Prognostic analyses were conducted within the longitudinal memory-clinic cohort (N=518, 4-year follow-up).
  • MACCE was used as a composite clinical outcome endpoint.
  • Mortality was assessed as a separate outcome and validated externally in the cardiovascular cohort (N=2016).

What This Means

This research suggests that specific proteins circulating in the blood may serve as early warning signals for brain blood vessel disease (cerebrovascular disease), cognitive decline, and serious health events like strokes, heart attacks, and death. The researchers analyzed over 1,400 proteins in blood samples from more than 2,500 people across two independent study groups in Southeast Asia, following participants over four years to track changes in brain lesions, thinking ability, and clinical outcomes. They found that different proteins were linked to different types of brain lesions, and that these protein patterns represent a variety of biological processes involved in cerebrovascular disease. Four proteins in particular stood out: NEFL (a marker of nerve cell damage), LTBP2 (involved in tissue structure and signaling), CRIM1 (related to nerve and blood vessel development), and PLAUR (involved in cell movement and inflammation). These four proteins were not only linked to brain lesions and cognitive decline, but also predicted who was more likely to experience major cardiovascular or cerebrovascular events and death. Importantly, these findings held up in a completely separate group of over 2,000 people with cardiovascular disease, strengthening confidence in the results. This research suggests that measuring these four proteins in the blood could potentially help identify people at higher risk of brain disease progression and serious health complications before they occur. The proteins may also point to new biological targets for future treatments aimed at preventing or slowing cerebrovascular disease and its consequences.

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Citation

Sim M, Hilal S, Tromp J, Tan E, Doecke J, Liew O, et al.. (2026). Plasma proteomics of cerebrovascular disease, cognitive decline, and clinical outcomes.. Alzheimer's & dementia : the journal of the Alzheimer's Association. https://doi.org/10.1002/alz.71728