Relationship Between Glycemia and Cognitive Function, Structural Brain Outcomes, and Dementia: A Mendelian Randomization Study in the UK Biobank

We investigated the relationship between glycemia and cognitive function, brain structure and incident dementia using bidirectional Mendelian randomization (MR). Data were from the UK Biobank (n = similar to 500,000). Our exposures were genetic instruments for type 2 diabetes (157 variants) and HbA(1c) (51 variants) and our outcomes were reaction time (RT), visual memory, hippocampal volume (HV), white matter hyperintensity volume (WMHV), and Alzheimer dementia (AD). We also investigated associations between genetic variants for RT (43 variants) and diabetes and HbA(1c). We used conventional inverse-variance-weighted (IVW) MR alongside MR sensitivity analyses. Using IVW, genetic liability to type 2 diabetes was not associated with RT (exponentiated beta [exp beta] = 1.00 [95% CI 1.00; 1.00]), visual memory (exp beta = 1.00 [95% CI 0.99; 1.00]), WMHV (exp beta = 0.99 [95% CI 0.97; 1.01]), HV (beta -coefficient mm(3) = -2.30 [95% CI -12.39; 7.78]) or AD (odds ratio [OR] 1.15 [95% CI 0.87; 1.52]). HbA(1c) was not associated with RT (exp beta = 1.00 [95% CI 0.99; 1.02]), visual memory (exp beta = 0.99 [95% CI 0.96; 1.02]), WMHV (exp beta = 1.03 [95% CI 0.88; 1.22]), HV (beta = -21.31 [95% CI -82.96; 40.34]), or risk of AD (OR 1.09 [95% CI 0.42; 2.83]). IVW showed that reaction time was not associated with diabetes risk (OR 0.94 [95% CI 0.54; 1.65]), or with HbA(1c) (beta -coefficient mmol/mol = -0.88 [95% CI = -1.88; 0.13]) after exclusion of a pleiotropic variant. Overall, we observed little evidence of causal association between genetic instruments for type 2 diabetes or peripheral glycemia and some measures of cognition and brain structure in midlife.

Automated summary

The study found little evidence of causal association between genetic instruments for type 2 diabetes or peripheral glycemia and some measures of cognition and brain structure in midlife.