There has been considerable interest in the association between cholesterol, its upstream isoprenoid family members (FPP and GGPP) and Alzheimers disease (AD).However, the HMG-CoA reductase inhibitors, statins, have had mixed effects in preventing or treating AD.One explanation for those disappointing results is that statins are targeting the wrong protein.We have recently found that FPP and GGPP levels and gene expression of FPP synthase and GGPP synthase were significantly elevated in brain tissue of Alzheimer disease patients as compared with normal neurological controls;cholesterol levels and HMG-CoA reductase gene expression were unchanged.FPP is a precursor of both cholesterol and GGPP.Stimulation of FPP synthase gene expression can occur with the binding of the transcription factor sterol regulatory element binding protein-2 (SREBP-2).Activation of the SREBP-2 pathway is induced by low cholesterol levels.What is not known is if SREBP-2 can be activated by changes in FPP levels when cholesterol levels are unaltered as in the case of AD.To begin to understand FPP and GGPP regulation in brain, effects of inhibition of the FPP synthase protein by a direct inhibitor (alendronate) and inhibition of HMG-CoA reductase by a statin on translocation of SREBP-2 into the nucleus were examined in mouse primary neurons and SH-SY5Y neuroblastoma cells.Simvastatin-induced inhibition of HMG-CoA reductase significantly increased SREBP-2 abundance in the nuclear fraction of cells.In contrast, inhibition of FPP synthase which reduced FPP levels but not cholesterol levels did not stimulate movement of SREBP-2 into the nucleus but did stimulate FPP synthase gene expression.SREBP-2 may not be driving the increases in FPP synthase gene expression and FPP levels in AD brain which raises the novel possibility that FPP synthase gene expression may involve other mechanisms besides SREBP-2.A consequence of the increase in FPP and GGPP levels in brain tissue of AD patients could be an over-abundance ofprenylated proteins (e.g., Rho, Racl, CDC42) resulting in cell dysfunction.Drugs which directly inhibit FPP synthase may be better candidates than statins for treating AD.Supported by grants from the National Institutes of Health AG-23524, AG18357, Hanna Bragard-Apfel Foundation and the Department of Veterans Affairs.