The relationship between glycaemia, cognitive function, structural brain outcomes and dementia: A Mendelian randomization study in the UK Biobank

Aims: To investigate the relationship between glycaemia and cognitive function, brain structure and incident dementia using bidirectional Mendelian randomisation (MR). Methods: UK Biobank (n~500,000) individuals, aged 40-69 years at baseline. Our exposures were genetic instruments for type-2 diabetes (163 variants) and HbA1c (52 variants) and our outcomes were reaction time (RT - milliseconds), visual memory (number of incorrect responses), hippocampal and white matter hyperintensity volumes (both mm3), Alzheimer's disease (AD). To study potential bidirectional effects, we then investigated the associations between genetic variants for RT (43 variants) and clinical type-2 diabetes and measured HbA1c. We used conventional inverse-variance weighted (IVW) MR, alongside standard MR sensitivity analyses. Results: Using IVW, genetic liability to type-2 diabetes was not associated with reaction time (exponentiated{beta}=1.00, 95%CI=1.00; 1.00), visual memory (exp{beta}=1.00, 95%CI=0.99; 1.00), white matter hyperintensity volume (exp{beta}=0.98, 95%CI=0.93; 1.03), hippocampal volume (coefficient mm3=0.00, 95%CI=-0.01; 0.01) or risk of AD (OR 0.97, 95%CI=0.89; 1.06). HbA1c was not associated with reaction time (exp{beta}=1.01, 95%CI=1.00; 1.01), white matter hyperintensity volume (exp{beta}=0.88, 95%CI=0.73; 1.07), hippocampal volume (coefficient=-0.02, 95%CI=-0.10; 0.06), risk of AD (OR 0.94, 95%CI=0.47; 1.86), but HbA1c was associated with visual memory (exp{beta}=1.06, 95%CI=1.05; 1.07) using a weighted median approach. IVW showed no evidence that reaction time was associated with diabetes (OR 0.96, 95%CI=0.63; 1.46) or HbA1c (coefficient=-0.08, 95%CI=-0.57; 0.42). MR-Egger intercept p-values indicated no major issues with unbalanced horizontal pleiotropy (all p>0.05). Conclusions: Overall, we observed little evidence of causal associations between glycaemia and cognition, structural brain and dementia phenotypes.