Epidemiological studies demonstrate that hypercholesterolemia is a risk factor for Alzheimer's disease (AD). As the generation and accumulation of the b-amyloid peptide (Ab) in the brain appears to be significant for the initiation and progression of AD, it is possible that cholesterol levels regulate Ab formation and/or clearance. To test the effects of altering cholesterol on Ab formation, we incubated cells with or without lovastatin acid, the active metabolite of the HMG-CoA reductase inhibitor lovastatin, and measured the fraction of Ab formed from its precursor under each condition. We observed that treatment with lovastatin acid led to a profound decrease in the levels of Ab formed. This effect was observed at concentrations of 0.05-5 µM, ranges where this compound is effective at inhibiting HMG-CoA reductase. To examine the effects of lovastatin on Ab in vivo, human subjects who had elevated low-density lipoprotein cholesterol were treated during a double-blind, randomized study with 10-60-mg once-daily doses of a controlled-release formulation of lovastatin, or matching placebo. Serum Ab concentrations were measured before and after up to 3 months of treatment. Mean and median changes from baseline in serum Ab concentrations showed a significant (p < 0.0348), dose-dependent decrease. Differences between the 40- and 60-mg dose groups and placebo were statistically significant (Dunnett's p< 0.05). Our results suggest a mechanism by which hypercholesterolemia may increase risk for AD and indicate that lovastatin reduces Aß formation and may thereby be effective in delaying the onset and/or slowing the progression of AD.