The coexistence of coronary artery disease (CAD) and cognitive impairment has become a common clinical phenomenon. However, there is currently limited research on the etiology of this disease cluster, discovery of biomarkers, and identification of precise intervention targets.We explored the causal connections between gut microbiota, blood metabolites, and the disease cluster of CAD combined with cognitive impairment through two-sample Mendelian randomization (TSMR). Additionally, we determine the gut microbiota and blood metabolites with the strongest causal associations using Bayesian model averaging multivariate Mendelian randomization (MR-BMA) analysis. Furthermore, we will investigate the mediating role of blood metabolites through a two-step Mendelian randomization design.We identified gut microbiota that had significant causal associations with cognitive impairment. Additionally, we also discovered blood metabolites that exhibited significant causal associations with both CAD and cognitive impairment. According to the MR-BMA results, the free cholesterol to total lipids ratio in large very low density lipoprotein (VLDL) was identified as the key blood metabolite significantly associated with CAD. Similarly, the cholesteryl esters to total lipids ratio in small VLDL emerged as the primary blood metabolite with a significant causal association with dementia with lewy bodies (DLB). For the two-step Mendelian randomization analysis, we identified blood metabolites that could potentially mediate the association between genus Butyricicoccus and CAD in the potential causal links.Our study utilized Mendelian randomization (MR) to identify the gut microbiota features and blood metabolites characteristics associated with the disease cluster of CAD combined with cognitive impairment. These findings will provide a meaningful reference for the identification of biomarkers for the disease cluster of CAD combined with cognitive impairment as well as the discovery of targets for intervention to address the problems in the clinic.Copyright © 2024 Xu, Liu, Wang, Liu, Xian, Xu and Liu.