Estimated Glucose Disposal Rate and Risk of Stroke and Dementia in Nondiabetics: A UK Biobank Prospective Cohort Study

BACKGROUND: – The estimated glucose disposal rate (eGDR) is a validated surrogate marker of insulin resistance. However, its association with stroke and dementia in nondiabetic populations remains insufficiently investigated. METHODS: – This prospective cohort study included nondiabetic participants from the UK Biobank. The outcomes in this study were stroke, ischemic stroke, hemorrhagic stroke, all-cause dementia, vascular dementia, and Alzheimer disease. Multivariable Cox regression and restricted cubic splines were used to examine the associations between eGDR and outcomes. Polygenic risk score analyses were applied to investigate interactions between eGDR and genetic risk. RESULTS: – Overall, 430 093 participants were included. During a follow-up of around 13.5 years, 10 307 stroke cases and 11 137 all-cause dementia cases were recorded. Restricted cubic splines analyses indicated nonlinear associations between eGDR and the risks of stroke and vascular dementia. Below specific thresholds (<7.64 for stroke, <7.60 for ischemic stroke, <7.75 for hemorrhagic stroke, and <8.31 for vascular dementia), eGDR levels were not significantly associated with these outcomes except a modest inverse association with overall stroke risk (hazard ratio [HR] 0.97 [95% CI, 0.95–0.99]; P=0.012). In contrast, above these thresholds, higher eGDR levels were associated with significantly reduced risks of stroke (HR, 0.80 [95% CI, 0.78–0.82]; P<0.001), ischemic stroke (HR, 0.80 [95% CI, 0.78–0.81]; P<0.001), hemorrhagic stroke (HR, 0.81 [95% CI, 0.78–0.84]; P<0.001), and vascular dementia (HR, 0.89 [95% CI, 0.84–0.94]; P<0.001). A linear inverse relationship was observed between eGDR and all-cause dementia and Alzheimer disease. The HR in the highest versus lowest quartile was 0.81 (95% CI, 0.75–0.88) for all-cause dementia and 0.73 (95% CI, 0.64–0.84) for Alzheimer disease. Stratified polygenic risk score analyses revealed a synergistic interaction between reduced eGDR and elevated genetic susceptibility. CONCLUSIONS: – eGDR exhibited nonlinear associations with stroke and vascular dementia risk and linear inverse associations with all-cause dementia and Alzheimer disease in nondiabetic populations.