INS and Alzheimer disease: The attractiveness of the metabolic/brain insulin resistance hypothesis is that the impairments in brain insulin and IGF signaling caused by insulin/IGF resistance, together with the eventual depletion of trophic factors, could account for nearly all other abnormalities that occur in AD, including increased oxidative stress and ROS generation, mitochondrial dysfunction, cell death, loss of synaptic plasticity, deficits in cholinergic homeostasis, increase expression of AβPP, hyper-phosphorylation of tau, compromised myelin maintenance, and neuroinflammation.