Risk of Alzheimer disease is increased in patients with diabetes. Insulin resistance is identified as a pathogenic mechanism of impaired cognitive dysfunction. Amyloid beta oligomers cause impaired insulin signaling at IRS-1 via mechanisms of TNFalpha and JNK activation. Attenuation of PI-3 kinase pathway is also involved in the hyper-phosphorylation of Tau. Impairment of orexin function is connected to the age related insulin resistance and shortening of life expectancy. Synapse deterioration and loss via these mechanisms underlying defective brain insulin signaling result in cognitive dysfunction. Stimulation of insulin signaling is a developing therapeutic approach in Alzheimer disease. Nasal insulin administration, thiazolidinedione, and GLP-1 receptor agonist possess neuronal protective effects in the treatment of mild cognitive dysfunction. Further identification of the pathogenic mechanism connecting between Alzheimer disease and insulin resistance contributes to development of novel therapeutics in Alzheimer disease.