Increased cGMP levels have been detected in the brain after the administration of tadalafil and sildenafil, confirming that both drugs cross the BBB and reach the brain at a sufficient concentration to inhibit PDE5 [3, 11], the stimulation of the cGMP/PKG pathway and the restoration of CREB signaling may underlie the therapeutic effect of PDE5 inhibitors in AD. The gene discussed is CREB1; the disease is Alzheimer disease.