The Relationship Between Glycaemia, Cognitive Function, Structural Brain Outcomes and Dementia: A Mendelian Randomisation Study in the UK Biobank.

We investigated the relationship between glycaemia and cognitive function, brain structure and incident dementia using bidirectional Mendelian randomisation (MR). Data were from UK Biobank (n∼500,000). Our exposures were genetic instruments for type-2 diabetes (157 variants) and HbA1c (51 variants) and our outcomes were reaction time (RT), visual memory, hippocampal and white matter hyperintensity volumes, Alzheimer’s dementia (AD). We also investigated associations between genetic variants for RT (43 variants) and, diabetes and HbA1c. We used conventional inverse-variance weighted (IVW) MR, alongside MR sensitivity analyses. Using IVW, genetic liability to type-2 diabetes was not associated with reaction time (exponentiated s=1.00, 95%CI=1.00; 1.00), visual memory (exps=1.00, 95%CI=0.99; 1.00), white matter hyperintensity volume (WMHV) (exps=0.99, 95%CI=0.97; 1.01), hippocampal volume (HV) (s coefficient mm3=4.56, 95%CI=-3.98; 13.09) or AD (OR 0.89, 95%CI=0.78; 1.01). HbA1c was not associated with RT (exps=1.01, 95%CI=1.00; 1.01), WMHV (exps=0.94, 95%CI=0.81; 1.08), HV (s=7.21, 95%CI=-54.06; 68.48), or risk of AD (OR 0.94, 95%CI=0.47; 1.86), but HbA1c was associated with visual memory (exps=1.06, 95%CI=1.05; 1.07) using a weighted median. IVW showed that reaction time was not associated with diabetes risk (OR 0.96, 95%CI=0.63; 1.46) or with HbA1c (s coefficient mmol/mol=-0.08, 95%CI=-0.57; 0.42). Overall, we observed little evidence of causal association between genetic instruments for T2D or peripheral glycaemia and some measures of cognition and brain structure in midlife.