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Gloria Lena Vega, PhD; Myron F. Weiner, MD; Anne M. Lipton, MD; Klaus von Bergmann, MD; Dieter Lütjohann, PhD; Carol Moore, MS; Doris Svetlik, RN, MS

Arch Neurol. 2003;60:510-515.

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 -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.

Study Design  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.

From the Departments of Clinical Nutrition (Dr Vega), Psychiatry (Drs Weiner and Lipton and Mss Moore and Svetlik), and Neurology (Dr Lipton), the Center for Human Nutrition (Dr Vega), and the Alzheimer's Disease Center (Drs Weiner and Lipton and Mss Moore and Svetlik), University of Texas Southwestern Medical Center, Dallas; Nutrition and Metabolism Laboratory, Metabolic Unit, Veterans Affairs Medical Center, Dallas (Dr Vega); and Department of Clinical Pharmacology, University of Bonn Medical Center, Bonn, Germany (Drs Bergmann and Lütjohann).

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