Similarly, levels of IRs, IGF-1R, IRS-1 and IRS-2 are reduced in AD brains [197], which suggests that reduced insulin and IGF-1 signaling may result in the hyperphosphorylation of Tau by mediating protein phosphatase-2A (PP2A) and glycogen synthase kinase 3β (GSK-3β) [193,196]. This evidence concerns the gene INS and Alzheimer disease.