Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 0 0 2026 09 09 1 19 Sai Qi First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China AND National Clinical Research Center for Chinese Medicine, Tianjin, China AND Tianjin University of Traditional Chinese Medicine, Tianjin, China Xuezhu Zhang First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China AND National Clinical Research Center for Chinese Medicine, Tianjin, China 2026 03 11 2026 05 03 Vascular cognitive impairment (VCI) and vascular dementia (VaD) are major clinical consequences of cerebrovascular injury, with cerebral small vessel disease (CSVD) serving as their most common structural substrate. Although neuroimaging and cognitive assessment remain central to diagnosis and follow-up, accessible blood-based tools for early risk identification and progression monitoring are still limited. Emerging evidence suggests that peripheral immune dysregulation contributes to CSVD progression through chronic inflammatory imbalance, endothelial dysfunction, blood-brain barrier vulnerability, and inflammation-coagulation coupling. Blood biomarkers have therefore attracted increasing interest, ranging from routine inflammatory proteins and blood cell–derived indices to markers related to endothelial activation, barrier injury, extracellular matrix remodeling, and neural injury. Current evidence indicates that most single biomarkers have limited specificity and variable reproducibility, whereas panel-based approaches may offer better translational potential. In this review, we summarize the biological rationale and clinical evidence for peripheral immune and blood biomarkers in VCI/CSVD, and propose a time-layer and panel-oriented framework to distinguish background risk markers, pathway-activity markers, and downstream injury markers. We further discuss key methodological issues, including disease heterogeneity, sampling windows, repeated measurements, medication effects, external validation, and model transportability. Overall, near-term clinical progress is more likely to come from parsimonious multimarker panels integrated with imaging progression and cognitive trajectories than from any single biomarker. Future studies should prioritize standardized sampling, longitudinal design, and multicenter validation to support risk stratification and biomarker-guided intervention research.  https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4774 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4774/2419