Prediabetes as a critical stage for risk of dementia and stroke: evidence from the UK Biobank and Mendelian Randomization.
Level 3 - non-randomized controlled study
Prospective non-randomized cohort study with Mendelian randomization analysis
PubMed 42152767 · doi:10.1093/eurjpc/zwag278
What was done
The authors examined 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 type 2 diabetes). Over a median 13.7 years of follow-up, incident dementia, stroke, and brain MRI markers (in 39,996 participants) were tracked. Analyses used multivariable Cox proportional hazards models, natural cubic splines for HbA1c, linear regression for MRI outcomes, and two-sample Mendelian randomization to evaluate causality.
What was found
Prediabetes (n=52,693) was associated with higher risks of vascular dementia (hazard ratio [HR] 1.36; 95% CI 1.14-1.61), total 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. In the MRI subset, prediabetes was associated with smaller gray matter volume (β = -0.04, 95% CI -0.07 to -0.01), smaller hippocampal volume (β = -0.03, 95% CI -0.06 to 0.00), and greater white matter hyperintensity volume (β = 0.04, 95% CI 0.01 to 0.07). Mendelian randomization supported causal links between glycemia and dementia, stroke, and hippocampal atrophy.
Why it matters
These findings show that cerebrovascular and neurodegenerative risks emerge during prediabetes before type 2 diabetes diagnostic thresholds are reached. This identifies prediabetes as an important target window for lifestyle and clinical interventions to protect long-term brain health.
Limits
The UK Biobank population is predominantly of European ancestry and subject to healthy volunteer selection bias. Glycemic status was assessed at baseline, so transitions between glycemic states over the 13.7-year follow-up were not accounted for in the abstract. Mendelian randomization remains susceptible to horizontal pleiotropy, and non-vascular dementia subtypes were not detailed.
Cited by
- supports An HbA1c level of 6.0% is associated with an increased risk of dementia and brain shrinkage.