Insulin resistance–related metabolic burden, white matter microstructure, and cognitive change: the HABS-HD study
5 affiliations
- 1Department of Radiology, The Second Affiliated Hospital of Xiamen Medical College , ,
- 2Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Hunan University of Medicine , ,
- 3Department of Cardiology, Xiamen Humanity Hospital, Fujian Medical University, Xiamen , ,
- 4Department of Neurology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University , ,
- 5Department of Radiology, The First Affiliated Hospital of Hunan University of Medicine , ,
Abstract
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.
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BibTeX
@article{li2026insulin,
title = {{Insulin resistance–related metabolic burden, white matter microstructure, and cognitive change: the HABS-HD study}},
author = {Huaiyi Li and Zhiliang Tian and Xiaoqian Wang and Weiwei Gao and Jingjing She},
journal = {Frontiers in neuroscience},
year = {2026},
month = oct,
doi = {10.3389/fnins.2026.1967890},
url = {https://europepmc.org/article/PMC/PMC13668860},
note = {CC BY},
}
RIS
TY - JOUR
TI - Insulin resistance–related metabolic burden, white matter microstructure, and cognitive change: the HABS-HD study
AU - Huaiyi Li
AU - Zhiliang Tian
AU - Xiaoqian Wang
AU - Weiwei Gao
AU - Jingjing She
PY - 2026
DA - 2026/10/01
JO - Frontiers in neuroscience
DO - 10.3389/fnins.2026.1967890
UR - https://europepmc.org/article/PMC/PMC13668860
AB - 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.
SN - 1662-4548
SN - 1662-453X
ER -