Brain health across the entire glycaemic spectrum: the UK Biobank.

AIMS: To understand the relationship between glycated haemoglobin (HbA1c ) and brain health, across the entire glycaemic spectrum. We hypothesised that individuals with increasingly higher HbA1c would be more likely to have worse brain health outcomes in comparison to normoglycaemic individuals. MATERIALS AND METHODS: We used data from the UK Biobank cohort, which recruited 500,000 individuals aged 40-69 years. HbA1c and diabetes diagnosis were used to define baseline glycaemic categories. Our outcomes included: incident all-cause dementia, vascular dementia (VD), Alzheimer's dementia (AD), hippocampal volume (HV), white matter hyperintensity (WMH) volume, cognitive function and decline. The reference group was normoglycaemic individuals (HbA1c 35-<42 mmol/mol). Our maximum analytical sample had 449,973 individuals with complete data. RESULTS: Pre- and known diabetes increased incident VD, (HR 1.54, 95%CI=1.04;2.28 and 2.97, 95%CI=2.26;3.90). Known diabetes increased all-cause and AD risk (HR 1.91, 95%CI=1.66;2.21 and HR 1.84, 95%CI=1.44;2.36, respectively). Pre- and known diabetes elevated risks of cognitive decline (OR 1.42, 1.48;2.96 and 1.39, 1.04;1.75). Pre-diabetes, undiagnosed and known diabetes conferred higher WMH volumes (3%, 22%, 7%,) and lower HV (36mm3 , 80mm3 , 82mm3 ), whereas low-normal HbA1c had 1% lower WMH volume and 12mm3 greater HV. CONCLUSION: Both pre-diabetes and known diabetes are harmful in terms of vascular dementia, cognitive decline and AD risks, as well as lower hippocampal volume. Associations appeared to be somewhat driven by antihypertensive medication, which implies that certain cardiovascular drugs may ameliorate some of the excess risk. Low-normal HbA1c levels, however, associate with more favourable brain health outcomes and warrant more in-depth investigation. This article is protected by copyright. All rights reserved.