Insulin resistance–related metabolic burden, white matter microstructure, and cognitive change: the HABS-HD study

Background Insulin resistance–related metabolic burden is associated with cognitive aging, but the relevant white matter microstructural features remain unclear. We examined statistical indirect associations between metabolic indices and cognition through tract-level white matter measures, including associations with subsequent cognitive change. Methods Cross-sectional and longitudinal analyses used Health and Aging Brain Study–Health Disparities (HABS-HD) data. Exposures were the triglyceride–glucose (TyG) index and its composites with waist-to-height ratio (TyG-WHtR) and visceral adiposity index (TyG-VAI). Candidate mediators were axial and radial diffusivity (RD) in 32 white matter tracts; outcomes covered six cognitive domains. High-dimensional mediation analysis with within-model false discovery rate (FDR) correction selected candidate pathways, supplemented by model-level multiplicity analyses. Selection stability was assessed using 1,000 participant-level bootstrap samples. All candidates underwent longitudinal mixed-effects analysis, with indirect estimates calculated as baseline exposure–white matter coefficients multiplied by white matter-by-time coefficients. Intervals used 2,000 participant-level cluster bootstrap samples. Sensitivity analyses adjusted for white matter hyperintensity (WMH) volume and covariate-by-time interactions. Results Of 2,606 participants, 788 had two cognitive assessments a median of 2.17 years apart. Fourteen candidate pathways were selected, all involving RD and TyG or TyG-WHtR; 11 had 95% conditional Monte Carlo uncertainty intervals excluding zero. Two of 36 models met the supplementary model-level FDR criterion. Five longitudinal pathways had negative indirect estimates with 95% bootstrap intervals excluding zero: four involved right cingulum RD and processing speed or executive function, and one involved right superior corona radiata RD and processing speed. Four also met the FDR criterion for RD-by-time interactions. The TyG-WHtR–right cingulum RD–executive function indirect estimate was -0.0054 per year (95% bootstrap interval, -0.0110 to -0.0009). Selection frequencies ranged from 6.7% to 42.0%. After WMH and WMH-by-time adjustment, intervals excluded zero for two of these five pathways, decreasing to one with additional core covariate-by-time interactions. Conclusion Triglyceride–glucose index and TyG-WHtR showed statistical indirect associations with cognition through white matter RD, with some pathways associated with subsequent cognitive change. Limited selection stability and sensitivity to WMH and covariate-by-time adjustment warrant evaluation in independent cohorts.