Pharmacological concentrations of the HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer beta-amyloid peptide in vitro and in patients.
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 baseline in serum Abeta 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 Abeta formation and may thereby be effective in delaying the onset and/or slowing the progression of AD.
Buxbaum
Joseph D
JD
Laboratory of Molecular Neuropsychiatry, Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. buxbaj01@doc.mssm.edu
Cullen
Edward I
EI
Friedhoff
Lawrence T
LT
D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000188:drug therapy; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism
D016229:Amyloid beta-Peptides; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010446:Peptide Fragments; D002784:Cholesterol; D008148:Lovastatin