Testing for associations between HbA1c levels, polygenic risk, and brain health in UK Biobank (N=39,283)

Objective: Type-2 diabetes (T2D) has been associated with poorer brain health, and glycated haemoglobin (HbA1c) levels is a diagnostic test for diabetes. The aim of this study was to investigate whether continuous HbA1c levels, and HbA1c polygenic risk scores (HbA1c-PRS) significantly associate with worse brain health independent of T2D diagnosis (vs. not), by examining brain structure and cognitive test scores phenotypes.Methods: Using cross-sectional UK Biobank data (n=39,283), we tested whether HbA1c and/or HbA1c-PRS were significantly associated with multiple cognitive test scores. We also assessed associations with brain imaging phenotypes including grey matter (GM), white matter (WM), whole brain volume, hippocampal volume, white matter hyperintensity (WMH) volumes, white matter tract integrity and frontal lobe GM. We adjusted for potential confounders of age (at MRI), sex, deprivation, education, genotyping chip, 8 genetic principal components for population stratification, smoking, alcohol intake, cholesterol medication, body mass index (BMI), T2D, and APOE e4 dosage. Results: We found an association between higher HbA1c levels and poorer performance on symbol digit substitution scores (standardised beta [β] = -0.022 p = 0.001) in the fully adjusted model. We also found an association between higher HbA1c levels and worse brain MRI phenotypes of GM (β = -0.026, p < 0.001), whole brain volume (β = -0.072, p = 0.0113), and general factor for frontal lobe of GM (β = -0.022, p < 0.001) in fully adjusted models. HbA1c-PRS score was significantly associated with GM volume in the fully adjusted model (β = -0.010, p = 0.0113), however when adjusted for HbA1c levels the association was not significant.Conclusion: Our findings suggest that measured HbA1c correlates to some extent with poorer cognitive and structural brain health, and HbA1c-PRS does not add significant information to this, however further studies in diverse populations are needed to confirm these results.