Microvascular disease is seen as a consequence of diabetes and can also be found inAD brains, possibly contributing to the cognitive impairment and neurodegenerationseen in AD.5,62 Decreased blood flow and impairment of oxygen andnutrient delivery exacerbate the adverse effects of insulin/IGFresistance.63Consequently, there is an increase in oxidative stress and activation of signalingmechanisms which promote aberrant tau phosphorylation, AβPP cleavage,AβPP-Aβ deposition, and mitochondrial dysfunction.38,63. This evidence concerns the gene APP and Alzheimer disease.