Objective: To investigate the relationship between blood glycated hemoglobin (HbA1c) and cerebral cortical thickness (CT) and identify potential cellular mechanisms involved. Research design and methods: A cohort of 30,579 adults age 45 to 81 (mean +/- SD: 64 +/- 7.5) years with available data on brain MRI and blood HbA1c levels was analyzed. The relationship between HbA1c and CT was probed using independent spatial profiles of cell-specific gene expression. Lastly, a genome-wide association study was conducted on the shared variance between HbA1c and CT. Results: The HbA1c-CT association was noncontinuous, emerging negatively within the prediabetic range (39.6 mmol/mol). This association was strongest in brain regions with higher expression of genes specific to excitatory neurons and lower expression of genes specific to astrocytes and microglia. A significant locus implicated mitochondrial maintenance and ATP generation. Conclusions: Effective glycemia control at prediabetic levels is warranted to preserve brain health and prevent prediabetes-related neurobiologic perturbations.
