Prediabetes as a critical stage for risk of dementia and stroke: evidence from the UK Biobank and Mendelian Randomization.

BACKGROUND AND AIMS: Type 2 diabetes (T2D) is a recognized risk factor for dementia and stroke, but whether risks begin during prediabetes remains unclear. We aimed to determine the risks of these neurological conditions among individuals with prediabetes and the glycemic thresholds at which risks emerge. METHODS: We studied 432,887 adults (mean age, 57 years; 55% women) from the UK Biobank who were free of dementia or stroke at baseline, categorized by glycemic status (normoglycemia, prediabetes, and T2D). Incident dementia, stroke, and Magnetic Resonance Imaging (MRI)-derived brain markers, including brain volumes and white matter hyperintensity volumes, were assessed for these conditions. HbA1c was modeled continuously using natural cubic splines to assess linear and non-linear effects. Outcomes were estimated using Cox proportional hazards and linear regression models, adjusted for demographic, lifestyle, and clinical factors. Two-sample Mendelian randomization (MR) was used to test causality. RESULTS: During a median 13.7 years of follow-up, prediabetes (n=52,693) was associated with higher risks of vascular dementia (hazard ratio (HR):1.36; 95% confidence interval (CI): 1.14-1.61), stroke (HR:1.09; 95% CI: 1.01-1.16), ischemic stroke (HR:1.10; 95% CI: 1.02-1.19), and intracerebral hemorrhage (HR:1.19; 95% CI: 1.01-1.39) compared with normoglycemia, after adjustment for major confounding factors and across extensive sensitivity analyses. In the brain MRI cohort (N=39,996), gray matter volumes (β = -0.04, 95% CI -0.07 to -0.01) and hippocampal volumes (β = -0.03, 95% CI -0.06 to 0.00) were smaller, and log-transformed white matter hyperintensity volume (β = 0.04, 95% CI 0.01 to 0.07) was larger in prediabetes. Spline models indicated that adverse outcomes were associated with higher HbA1c levels, even before the diagnostic threshold for T2D was reached. Risks were further elevated in T2D. MR analyses supported causal effects of glycemia on dementia, stroke and hippocampal atrophy. CONCLUSION: Prediabetes is not a benign state: even modest HbA1c elevations are linked to vascular dementia, stroke, and brain structural decline. These risks emerge below current diagnostic glycemic thresholds, underscoring prediabetes as a critical stage for early intervention to preserve brain health. This study shows that even before diabetes develops, higher blood sugar (HbA1c) levels are linked to increased risks of vascular dementia, stroke, and brain damage.People with prediabetes had a higher chance of developing vascular dementia and stroke. Brain scans also showed earlier signs of shrinkage and damage.These risks appeared even before blood sugar reached the level used to diagnose diabetes, highlighting the importance of early monitoring and healthy lifestyle changes to reduce the risk of dementia and stroke.