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BackgroundInflammation is implicated in the pathogenesis of dementia. However, its role in the vascular cognitive burden and the clinical stage of Alzheimer's disease (AD) remains controversial.ObjectiveThis study aimed to explore the association of plasma inflammatory proteins with vascular cognitive burden and clinical stage of AD by using a multi-method approach.MethodsWe included 330 individuals with complete plasma protein profiles, Hachinski Ischemia Scale scores, and cognitive function status between September 13, 2005, and October 24, 2007. We employed generalized linear models, restricted cubic splines, and the inverse variance weighting (IVW) method for two-sample Mendelian randomization (MR) to investigate the correlation between inflammatory biomarkers and dementia. We employed the random forest algorithm to build predictive models and utilized SHapley Additive exPlanations (SHAP) analysis for feature importance and interpretability.ResultsAD clinical stage exhibited significant associations with cortisol, C-peptide, tumor necrosis factor receptor-2 (TNFR-2) and interleukin-16 (IL-16, all p < 0.05). Similarly, the vascular cognitive burden was significantly correlated with C-peptide, carcinoembryonic antigen and TNFR-2 (all p < 0.05). These observational findings were corroborated by SHAP analysis. Subsequent MR analysis further revealed a weak negative causal relationship between AD and IL-16 (p_IVW = 0.003; OR_IVW = 0.981; 95% CI: 0.969-0.994).ConclusionsOur study identified several inflammatory proteins correlated with the vascular cognitive burden and AD clinical stage, providing exploratory evidence for future mechanistic and interventional research.