Pre-diabetes as a Critical Stage for Risk of Dementia and Stroke: Evidence from the UK Biobank and Mendelian Randomization

Background and AimsType 2 diabetes (T2D) is a recognized risk factor for dementia and stroke, but whether risks begin during pre-diabetes remains unclear. We aimed to determine the risks of these neurological conditions with pre-diabetes and the glycemic thresholds at which risks emerge. MethodsWe studied 432,285 adults (mean age, 57 years; 55% women) from the UK Biobank who were free from prior dementia or stroke at baseline. Glycemic status (normoglycemia, pre-diabetes, T2D) was defined by HbA1c. Incident dementia, stroke, and MRI-derived brain markers, including brain volumes and white matter hyperintensity volumes, were assessed for these conditions. HbA1c was modeled continuously to assess non-linear effects. Outcomes were estimated using competing risks and linear regression models, adjusted for demographic, lifestyle, and clinical factors. Two-sample Mendelian randomization (MR) was used to test causality. ResultsDuring a median 13.7 years of follow-up, pre-diabetes was associated with higher risks of Alzheimers disease (HR:1.30; 95% CI: 1.16-1.45), vascular dementia (HR:1.50; 95% CI: 1.28-1.7), and all-cause stroke (HR:1.24; 95% CI: 1.16-1.33), independent of other vascular risk factors. On brain MRI (N=3,723), total and grey matter volumes and hippocampal volumes were smaller, and white matter hyperintensity volume was larger in pre-diabetes. Spline models indicated that adverse outcomes emerged at HbA1c levels around 40-45 mmol/mol, below the diabetes threshold. Risks were further elevated in T2D. MR analyses supported causal effects of glycemia on Alzheimers disease, stroke, and hippocampal atrophy. ConclusionPre-diabetes is not a benign state: even modest HbA1c elevations are linked to dementia, stroke, and brain structural decline. These risks emerge below current diagnostic glycemic thresholds, underscoring pre-diabetes as a critical stage for early intervention to preserve brain health. Lay SummaryThis study shows that even before diabetes develops, higher HbA1c levels are linked to increased risks of dementia, stroke, and brain damage. O_LIPeople with pre-diabetes had a higher chance of developing Alzheimers disease, other forms of dementia, such as vascular dementia, and stroke. Brain scans also showed earlier signs of shrinkage and damage. C_LIO_LIThese 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. C_LI