Here, we report that mirodenafil exerts neuroprotective effects against cognitive dysfunction and AD pathophysiology through multiple mechanisms of action involving (1) the reduction of Aβ and phosphorylated tau burdens, (2) enhanced neuronal survival through the activation of the cGMP/PKG/CREB pathway and its downstream effectors and (3) the inactivation of GR transcriptional activity and the activation of the Wnt/β-catenin signaling pathway (Additional file 1: Fig. S4). This evidence concerns the gene PRKG1 and Alzheimer disease.