PGC and Alzheimer disease: It could be argued that PDE9 is not an optimal target because it controls periplasmic levels of cGMP generated by the natriuretic peptide/pGC system, which seems to be upregulated in AD, but not the cytoplasmic cGMP fueled by the NO-stimulated sGC, which is involved in memory formation and is compromised in AD [40,84].