Cleavage of the amyloid precursor protein (APP) by - and -secretases results in generation of the amyloid- protein (A), which is characteristically deposited in the brain of Alzheimer’s disease patients. Inhibitors of 3-hydroxy-3-methyl-glutaryl (HMG) -CoA reductase (the statins) reduce levels of cholesterol and isoprenoids such as geranylgeranyl pyrophosphate (GGPP). Previous studies have demonstrated that cholesterol increases and statins reduce A levels mostly by regulating -secretase activity. In this study, we focused on the role of geranylgeranyl isoprenoids GGPP and geranylgeraniol (GGOH) in regulating A production. Our data show that the inhibition of GGPP synthesis by statins plays an important role in statin-mediated reduction of A secretion. Consistent with this finding, the geranylgeranyl isoprenoids preferentially increase the yield of A of 42 residues (A42) in a dose-dependent manner. Our studies further demonstrated that geranylgeranyl isoprenoids increase the yield of APP-CTF (a.k.a. AICD) as well as A by stimulating -secretase-mediated cleavage of APP-CTF and APP-CTF in vitro. Furthermore, GGOH increases the levels of the active -secretase complex in the detergent-insoluble membrane fraction along with its substrates, APP-CTF and APP-CTF. Our results indicate that geranylgeranyl isoprenoids may be an important physiological facilitator of -secretase activity that can foster production of the pathologically important A42.—Zhou, Y., Suram, A., Venugopal, C., Prakasam, A., Lin, S., Su, Y., Li, B., Paul, S. M., Sambamurti, K. Geranylgeranyl pyrophosphate stimulates -secretase to increase the generation of A and APP-CTF.