Abstract
The thickness of the cerebral cortex decreases with ageing. Recent research suggests that obesity and type 2 diabetes mellitus may accelerate this cortical thinning, and that obesity-related insulin resistance may be a shared mechanistic pathway. Ageing of the cerebral cortex demonstrates sex-specific trajectories, with a gradual shift towards accelerated thinning beginning in midlife. Here, we investigated whether adiposity-related insulin resistance is associated with lower thickness of the human cerebral cortex in a community-based sample of middle-aged adults. We studied 533 adult participants (36-65 years) from the Saguenay Youth Study. Adiposity was assessed with bioimpedance, and insulin resistance was evaluated from a fasting blood sample with the homeostatic model assessment of insulin resistance (HOMA-IR). Associations between adiposity-related insulin resistance (adiposity/IR) and cortical thickness were assessed with linear models, separately in males and females younger or older than 50 years. Potential biological underpinnings were investigated with virtual histology. Adiposity/IR was associated with lower cortical thickness in females older than 50 years but not in males or younger females. The strength of the association varied across the cerebral cortex, with regions of the lateral frontal and parietal cortices and the superior temporal cortex demonstrating most pronounced thinning. Based on virtual histology, adiposity/IR-related cortical thinning may involve neurones, astrocytes, oligodendrocytes and ependymal cells acting so that they lower the cortical potential for synaptogenesis, formation of dendritic spines, production of extracellular matrix and myelination. Adiposity-related insulin resistance is associated with lower cortical thickness in middle-aged women older than 50 years. This aspect of thinning may involve neuronal and glial cells in a way that lowers the capacity of the cerebral cortex for neuronal plasticity and maintenance of myelination.