Exploratory evaluation of CAP1 and ROCK2 as candidate blood biomarkers for vascular cognitive impairment

Background Vascular cognitive impairment (VCI) is the second most common dementia etiology after Alzheimer's disease. However, plasma biomarkers of VCI remain insufficiently validated. Objective We aimed to identify plasma biomarker candidates for VCI by using integrated multi-omics analyses. Methods We prospectively recruited VCI patients and healthy controls (HCs), performed proteomic and metabolomic analyses with ELISA validation, and conducted plasma protein quantitative trait loci (pQTL)-based Mendelian randomization (MR) with VCI-related imaging phenotypes. Results Proteomics identified 871 differentially upregulated proteins, in 8 VCI patients compared to 6 HCs. Proteins containing YWHAZ, CLDN5, VCL, TPM4, TLN1, CAP1, ITGB3, GP1BB, and ROCK2 were further investigated. ELISA validation conducted on another 8 VCI patients and 8 HCs showed levels of CAP1 (257.1 ± 51.48 versus 204.7 ± 27.47 ng/L, 95% CI: 8.19–96.68, p = 0.0235) and ROCK2 (10.10 ± 2.417 versus 7.555 ± 1.835 ng/mL, 95% CI: 0.24–4.84, p = 0.0328) were significantly higher in the VCI group. CAP1 expression demonstrated a significant association with glycolysis-related metabolites, particularly lactate and the complex glycolysis score, based on adjusted rank correlation analysis (panel-wise FDR < 0.05). MR analysis utilizing plasma pQTL data and vascular dementia and its imaging-derived phenotypes suggested no evidence for a causal effect in either direction. Conclusions Plasma CAP1 and ROCK2 levels were observed elevated in individuals with VCI, with CAP1 showing metabolomic consistency in relation to glycolytic pathways. These findings provide preliminary exploratory signals suggesting that CAP1 and ROCK2 may merit further investigation in the context of VCI.