Evaluating 1,400 Plasma Proteins to Identify Biomarkers for Cerebrovascular Pathology and Adverse Health Outcomes

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Summary of  Alzheimer’s & Dementia  https://doi.org/10.1002/alz.71728
Dr. Ming Ann Sim et al.

Points

National University of Singapore researchers analyzed over fourteen hundred plasma proteins across two independent cohorts to identify biomarkers associated with cerebrovascular disease and cognitive decline.
Longitudinal neuroimaging and cognitive evaluations of five hundred eighteen memory clinic participants mapped dynamic protein changes against white matter hyperintensities microbleeds and cortical infarcts.
Statistical analysis prioritized four key plasma proteins mediating cognitive decline and predicting major adverse cardiovascular events: neurofilament light chain, LTBP2, CRIM1, and PLAUR.
External validation across an independent Singaporean cohort confirmed that the four identified plasma biomarkers were consistently associated with incident overall mortality.
Authors concluded that blood based protein signatures can complement brain imaging to facilitate earlier risk identification and personalized preventive strategies for cerebrovascular disease.

Summary

This longitudinal cohort study evaluated plasma proteomic signatures to identify biomarkers for cerebrovascular disease (CeVD) progression, cognitive decline, major adverse cardiovascular and cerebrovascular events (MACCE), and overall mortality. Published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association by researchers at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), the investigation addressed the lack of large-scale protein profiling studies tracking CeVD in Southeast Asian populations. Given that CeVD significantly contributes to vascular cognitive impairment and stroke, the research sought to map plasma proteins against neuroimaging markers of microvascular damage to improve early risk stratification.

The discovery phase analyzed 518 participants from a Singapore memory clinic cohort who underwent serial brain magnetic resonance imaging (MRI), cognitive testing, and broad-scale proteomic profiling evaluating more than 1,400 plasma proteins. Proteins were mapped against baseline and longitudinal CeVD lesion burden, including white matter hyperintensities, lacunes, cerebral microbleeds, and cortical infarcts. The analysis identified four prioritized plasma proteins operating as key mediators of CeVD-associated cognitive decline and predictors of MACCE: 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 four biomarker targets were subsequently validated for incident mortality across a second independent Singaporean validation cohort.

The authors conclude that plasma profiling of NEFL, LTBP2, CRIM1, and PLAUR provides a viable non-invasive approach to track CeVD progression and predict adverse cardiovascular and neurological outcomes. Incorporating these novel blood-based biomarkers into routine clinical evaluation could complement conventional neuroimaging, enabling earlier, personalized risk assessment and targeted preventive interventions in high-risk patient populations.

Link to the article: https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.71728

References

Sim, M. A., Hilal, S., Tromp, J., Tan, E. S. J., Doecke, J., Liew, O. W., Cai, V. Y., Chan, S. P., Chong, E. J. Y., Toh, A., Yeow, T. B., Venketasubramanian, N., Barascuk‐Michaelsen, N., Sim, D., Leong, G. K. T., Yeo, D. P. S., Ong, H. Y., Ling, L. H., Lam, C., … Chen, C. L. H. (2026). Plasma proteomics of cerebrovascular disease, cognitive decline, and clinical outcomes. Alzheimer’s & Dementia, 22(8), e71728. https://doi.org/10.1002/alz.71728