Systemic inflammation mediates the link between cardiometabolic multimorbidity and cognitive function among older U.S. adults: evidence from NHANES

Existing studies suggest that cardiometabolic multimorbidity (CMM) affects cognitive function, but the role of systemic inflammation in this association remains unclear. Therefore, investigating the mechanistic role of systemic inflammation in the link between CMM and cognitive decline is crucial. This study included 2492 adults aged ≥60 years from the 2011 to 2014 National Health and Nutrition Survey. Cognitive function was assessed using 3 validated tests. Inflammatory biomarkers - systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-platelet ratio (NPR), and white blood cell count - were integrated into a Comprehensive Inflammation Score (CIS) using principal component analysis. Weighted multivariate linear regression model were used to examine the associations among CMM, cognitive function, and inflammatory biomarkers. Restrictive cubic splines were used to explore the nonlinear relationship between systemic inflammation and cognitive function, and the bootstrap method was applied to examine the mediating role of systemic inflammation in the CMM-cognition relationship. Results showed that CMM was significantly associated with poorer Digit Symbol Substitution Test (DSST) performance (β = -6.57, 95% confidence interval [CI]: -8.44 to -4.70, P < .001), and higher systemic inflammation (NLR: β = 0.075, 95% CI: 0.040 to -0.111, P < .001). Systemic inflammation was also associated with poorer cognitive performance (NPR-Consortium to Establish a Registry for Alzheimer Disease: β = -2.21, 95% CI: -3.58 to -0.84, P = .007; LMR-Animal Fluency Test: β = 1.56, 95% CI: 0.25 to 2.87, P = .034; NPR-DSST: β = -5.93, 95% CI: -10.67 to -1.18, P = .017), and nonlinear associations were observed between inflammation and cognitive outcomes. Mediation analyses revealed that the SII, NLR, and LMR significantly mediated the association between CMM and DSST (SII: β = 0.053, 95% CI: 0.002 to 0.128; NLR: β = 0.133, 95% CI: 0.043 to 0.248; LMR: β = 0.118, 95% CI: 0.036 to 0.226), while NPR and CIS mediated the CMM-Consortium to Establish a Registry for Alzheimer Disease relationship (NPR: β = -0.051, 95% CI: -0.104 to -0.004; CIS: β = -0.034, 95% CI: -0.074 to -0.001). These results indicate that systemic inflammation may be a central pathway through which CMM contributes to cognitive dysfunction.