The expression of insulin signaling and N-methyl-D-aspartate receptor genes in areas of gray matter atrophy is associated with cognitive function in type 2 diabetes.

Type 2 diabetes (T2DM) is associated with brain abnormalities and cognitive dysfunction, including increased risk for Alzheimer's disease. However, the mechanisms of T2DM-related dementia remain poorly understood. We obtained retrospective data from the Mayo Clinic Study of Aging for 271 individuals with T2DM and 542 demographically matched non-diabetic controls (age 51-89, 62% male). We identified regions of significant gray matter atrophy in the T2DM group and then determined which genes were significantly expressed in these brain regions using imaging transcriptomics. We selected 15 candidate genes involved in insulin signaling, lipid metabolism, amyloid processing, N-methyl-D-aspartate-mediated neurotransmission, and calcium signaling. The T2DM group demonstrated significant gray matter atrophy in regions of the default mode, frontal-parietal, and sensorimotor networks (p < 0.05 cluster threshold corrected for false discovery rate, FDR). IRS1, AKT1, PPARG, PRKAG2, and GRIN2B genes were significantly expressed in these same regions (R2 > 0.10, p < 0.03, FDR corrected). Bayesian network analysis indicated significant directional paths among all 5 genes as well as the Clinical Dementia Rating score. Directional paths among genes were significantly altered in the T2DM group (Structural Hamming Distance = 12, p = 0.004), with PPARG expression becoming more important in the context of T2DM-related pathophysiology. Alterations of brain transcriptome patterns occurred in the absence of significant cognitive deficit or amyloid accumulation, potentially representing an early biomarker of T2DM-related dementia.