Abstract
Epidemiological studies demonstrate that hypercholesterolemia is a risk factor for Alzheimer's disease (AD). As the generation and accumulation of the beta-amyloid peptide (Abeta) in the brain appears to be significant for the initiation and progression of AD, it is possible that cholesterol levels regulate Abeta formation and/or clearance. To test the effects of altering cholesterol on Abeta formation, we incubated cells with or without lovastatin acid, the active metabolite of the HMG-CoA reductase inhibitor lovastatin, and measured the fraction of Abeta formed from its precursor under each condition. We observed that treatment with lovastatin acid led to a profound decrease in the levels of Abeta formed. This effect was observed at concentrations of 0.05-5 microM, ranges where this compound is effective at inhibiting HMG-CoA reductase. To examine the effects of lovastatin on Abeta 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 Abeta concentrations were measured before and after up to 3 months of treatment. Mean and median changes from b...Continue Reading
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