[Frontiers in Bioscience 7, a50-59, April 1, 2002]

PHARMACOLOGICAL CONCENTRATIONS OF THE HMG-CoA REDUCTASE INHIBITOR LOVASTATIN DECREASE THE FORMATION OF THE ALZHEIMER b-AMYLOID PEPTIDE IN VITRO AND IN PATIENTS

Joseph D. Buxbaum1, Edward I. Cullen2 and Lawrence T. Friedhoff2

1Laboratory of Molecular Neuropsychiatry, Departments of Psychiatry and Neurobiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, and 2Andrx Laboratories, a division of Andrx Corporation, 401 Hackensack Avenue, Hackensack, NJ 07601

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Materials and methods
3.1. Materials
3.2. Cells
3.3. Assay of APP Processing
3.4. Filipin staining
3.5. Study subjects
3.6. Serum Ab assays
3.7. Statistical analyses
4. Results
4.1. Lovastatin acid decreases Ab formation in cultured cells
4.2. Lovastatin decreases Ab levels in patients
5. Discussion
5.1. The central role for Ab in the biology of AD
5.2. Summary of the findings from our studies
5.3. Other studies on cholesterol lowering agents, cholesterol and Ab
5.4. Potential mechanisms for the effects of cholesterol lowering agents on Ab
5.5. Future directions
6. Acknowledgements
7. References

1. ABSTRACT

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 ÁM, 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.