Reduction in levels of 24S-hydroxycholesterol by statin treatment in patients with Alzheimer disease.
BACKGROUND
The statin treatment of dyslipidemia is associated with a reduced risk of development of Alzheimer disease (AD). The effect may be mediated by a reduction in cholesterol biosynthesis in the brain, by lowering levels of apolipoprotein E (apo E)-containing lipoproteins, or by pleitropic effects such as reduction in beta-amyloid production. In the brain, cholesterol from damaged or dying neurons is converted to 24S-hydroxycholesterol by cholesterol 24-hydroxylase (CYP46). The oxysterol is subsequently transferred across the blood-brain barrier, transported to the liver by low-density lipoproteins (LDLs), and excreted as bile acids. Most of plasma 24S-hydroxycholesterol is derived from brain cholesterol; consequently, plasma levels of the oxysterol reflect brain cholesterol catabolism.


OBJECTIVE
To examine the effect of 3 statins and a nonstatin hypolipidemic agent on plasma levels of 24S-hydroxycholesterol and apo E in patients with AD.


METHODS
The study had a sequential parallel design. It was open-labeled and involved lipoprotein and 24S-hydroxycholesterol evaluations at baseline and at 6 weeks of treatment with 40 mg of lovastatin, simvastatin, or pravastatin sodium per day, or 1 g of extended-release niacin per day. Blood samples were drawn after a 12-hour fast for measurement of plasma sterols, oxysterols, lipoprotein cholesterol, and levels of apo E, plasma transaminases, and glucose. Measurements were made at baseline and during treatment.


RESULTS
Statin treatment reduced levels of plasma lathosterol by 49.5%, 24S-hydroxycholesterol by 21.4%, LDL cholesterol by 34.9%, and total cholesterol by 25%. The ratios of lathosterol-campesterol and 24S-hydroxycholesterol-LDL cholesterol were reduced significantly, but the ratio of 24S-hydroxycholesterol-total cholesterol was unchanged. Extended-release niacin also significantly reduced levels of 24S-hydroxycholesterol by 10% and LDL cholesterol by 18.1%. None of the agents lowered plasma concentration of apo E.


CONCLUSIONS
Statins lowered levels of plasma 24S-hydroxycholesterol without affecting levels of apo E. The LDL lowering was more pronounced than 24S-hydroxycholesterol reductions. The effect of statins on LDL partially explains the reduction of plasma oxysterol level.
Vega
Gloria Lena
GL
Department of Clinical Nutrition, the Center for Human Nutrition, University of Texas Southwestern Medical Center and Nutrition and Metabolism Laboratory, Veterans Affairs Medical Center, Dallas 75390, USA. Gloria.Vega@utsouthwestern.edu
Weiner
Myron F
MF
Lipton
Anne M
AM
Von Bergmann
Klaus
K
Lutjohann
Dieter
D
Moore
Carol
C
Svetlik
Doris
D
D000368:Aged; D000544:Alzheimer Disease / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008148:Lovastatin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009525:Niacin / Q000627:therapeutic use; D017035:Pravastatin / Q000627:therapeutic use; D019821:Simvastatin / Q000627:therapeutic use; D013250:Steroid Hydroxylases / Q000187:drug effects / Q000378:metabolism*; D016896:Treatment Outcome
D006888:Hydroxycholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009525:Niacin; C044563:24-hydroxycholesterol; D008148:Lovastatin; D019821:Simvastatin; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase; D017035:Pravastatin