Fortunately, future therapies can choose from a rich cGMP-modulating toolkit containing BBB-permeant PDE inhibitors (e.g., Sildenafil, Tadalafil), NO-GC stimulators (e.g., CYR119, CY6463), etc. The hypothesis-driven development of such therapeutics is, however, impossible without a clear understanding of the direction and the extent of the modulation of NO/cGMP/cGK signaling pathway in aging and AD and its cell type-specific interplay with the intracellular Ca2+ signaling. The gene discussed is PRKG1; the disease is Alzheimer disease.