Prediabetic HbA1c and cortical atrophy: underlying neurobiology

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 aged 45-81 years (mean [SD]=64 [7.5] years) with brain magnetic resonance imaging (MRI) and blood HbA1c levels were 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: HbA1c-CT association was non-continuous, emerging negatively within the prediabetic range (39.6 mmol/mol). This association was the 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 neurobiological perturbations.