Multivariate associations between systemic inflammation, metabolic dysregulation, and cognitive performance in project FRONTIER

Abstract

Background Cognitive aging is heterogeneous, and growing evidence implicates chronic low-grade inflammation and metabolic dysregulation in neuropathology and cognitive decline. This study examined the multivariate relationship between inflammatory-metabolic biomarkers and neuropsychological performance in a large, community-based cohort of adults from rural West Texas enrolled in Project FRONTIER. Methods Participants aged ≥ 40 years who completed a study visit in the Project FRONTIER study were included (n = 1,357). Associations between systemic metabolic health and cognitive performance were examined using a domain-driven metabolic marker set and a cognitive variables set. Canonical correlation analysis (CCA) was used to assess shared variance between biomarker and cognitive domains, followed by structural equation modeling (SEM) using variables with the highest canonical loadings as an exploratory model. Analyses were conducted in R version 4.5.2. Results CCA revealed a significant multivariate association between inflammatory-metabolic biomarkers and cognitive performance. The first canonical correlation was 0.242 (95% CI: 0.171–0.310), accounting for 5.8% of the shared variance between the biological and cognitive domains. This association was statistically significant based on both Wilks’ lambda (p = 1.05 × 10–6) and permutation testing (Fisher combined p < 0.001) and remained stable in bootstrap validation (r = 0.255, 95% CI: 0.219–0.294, 5,000 samples). Among biomarkers, C-reactive protein showed the strongest loading (0.69), followed by gamma-glutamyl transferase (0.28), fasting blood sugar (0.21), abdominal circumference (0.20), and hemoglobin A1c (-0.18). Among cognitive measures, EXIT-25 (loading = −0.59) showed the strongest contribution, followed by Trail Making Test Part B (loading = −0.45), RBANS-visuospatial/constructional (loading = −0.41), clock drawing (loading = −0.31), and RBANS-Language (loading = −0.30). SEM showed acceptable fit and further supported the finding that a higher inflammatory-metabolic burden was associated with worse executive function after adjusting for age, sex, ethnicity, education, and income (β = −0.310, standardized β = −0.202, p < 0.001). Conclusion Systemic inflammation and metabolic dysregulation were associated with poorer cognitive performance, particularly executive dysfunction, in this rural aging cohort. These findings, while modest in effect size, support the importance of cardiometabolic health in cognitive aging, motivating future longitudinal and mechanistic studies.