Brain insulin resistance deteriorates cognition by altering the topological features of brain networks.

Insulin resistance represents one of the mechanisms underlying the link between type 2 diabetes (T2D) and Alzheimer's disease (AD), and we explored its in vivo neurobiology related to cognition based on a pathway-based genetic association analyses. Eighty-seven mild cognitive impairment (MCIs) subjects and 135 matched controls (HCs) were employed at baseline, and they underwent functional MRI scans, clinical evaluations and exon sequencings of 20 genes related to brain insulin resistance. A longitudinal study for an average of 35 months was performed to assess their cognitive decline over time. By using cognition as the phenotype, we detected genes that modified cognitive impairments, including AKT2, PIK3CB, IGF1R, PIK3CD, MTOR, IDE, AKT1S1 and AKT1. Based on these loci, the mass univariate modeling was utilized to construct the functional network. The MCIs showed disconnections mainly in the cerebellum-frontal-temporal regions, while compensations may occur in frontal-parietal regions to maintain the overall network efficiency. Moreover, the behavioral significance of the network was highlighted, as topological characteristics of the medial temporal lobe and the prefrontal cortex partially determine longitudinal cognitive decline. Our results suggested that the restoration of insulin activity represents a promising therapeutic target for alleviating cognitive decline associated with T2D and AD.