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

Aim: To investigate whether continuous HbA1c levels and HbA1c-polygenic risk scores (HbA1c-PRS) are significantly associated with worse brain health independent of type 2 diabetes (T2D) diagnosis (vs. not), by examining brain structure and cognitive test score phenotypes.

Methods: Using UK Biobank data (n = 39 283), we tested whether HbA1c levels and/or HbA1c-PRS were associated with cognitive test scores and brain imaging phenotypes. We adjusted for confounders of age, sex, Townsend deprivation score, level of education, genotyping chip, eight genetic principal components, smoking, alcohol intake frequency, cholesterol medication, body mass index, T2D and apolipoprotein (APOE) e4 dosage.

Results: We found an association between higher HbA1c levels and poorer performance on symbol digit substitution scores (standardized beta [β] = -0.022, P = .001) in the fully adjusted model. We also found an association between higher HbA1c levels and worse brain MRI phenotypes of grey matter (GM; fully-adjusted β = -0.026, P < .001), whole brain volume (β = -0.072, P = .0113) and a general factor of frontal lobe GM (β = -0.022, P < .001) in partially and fully adjusted models. HbA1c-PRS were significantly associated with GM volume in the fully adjusted model (β = -0.010, P = .0113); however, when adjusted for HbA1c levels, the association was not significant.

Conclusions: Our findings suggest that measured HbA1c is associated with poorer cognitive health, and that HbA1c-PRS do not add significant information to this.