Disentangling the relationship between glucose, insulin and brain health: A UK Biobank study

Abstract Background Glycaemic traits are associated with poorer brain health and dementia risk. Recent advances in genetic instruments for specific glycaemic markers enable an in‐depth investigation of the likely nature of associations and underlying mechanisms between diabetes‐related mechanisms and brain health and dementia. Methods We used two‐sample Mendelian randomisation (MR) in the UK Biobank (UKB) (maximum N = 357 883 White British, mean age 56.9 years, 54% female) applying inverse‐variance weighted MR as our main estimator alongside MR‐Egger, weighted median estimator (WME) and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR‐PRESSO) as sensitivity tests. Instruments were 53 insulin resistance, 109 fasting glucose, 48 fasting insulin and 15 2‐h post‐load glucose genetic variants with variant–outcome effects estimated adjusting for 10 PCs. We checked core MR assumptions and sought to replicate results in an independent Alzheimer's dementia genome‐wide association study (GWAS). Results In UKB, higher 2‐h post‐load glucose was associated with a 69% increased Alzheimer's dementia risk (odds ratio 1.69 [95% confidence interval 1.38–2.07]), though this did not replicate in an independent GWAS. Fasting insulin, fasting glucose and postprandial glucose did not influence total brain, hippocampal or white‐matter hyperintensity volumes. Discussion The association between elevated 2‐h post‐load glucose and increased Alzheimer's risk supports a potential role for postprandial hyperglycaemia in dementia. The lack of associations between fasting or postprandial glucose and hippocampal, total‐brain or white matter hyperintensity volumes suggests this risk may operate independently of gross structural atrophy. Conclusion Genetically proxied postprandial hyperglycaemia contributes to increased Alzheimer's risk in mid‐life, warranting replication in other populations and ancestries to confirm and clarify underlying mechanisms.