Previously, the bi-directional relationship between BDNF and CREB was described, and in AD, accumulation of Aβ and hyperactivation of GSK3β were reported to decrease the phosphorylation and activation of CREB in brain tissue collected from patients with AD, as well as in in vitro and in vivo models of AD, and thus we speculate that this may be a potential mechanism by which BDNF is downregulated [68,151,152,153]. This evidence concerns the gene CREB1 and Alzheimer disease.