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Evidence That Simvastatin Affects Cholesterol Metabolism in the Human Brain

Sandra Locatelli, PhD; Dieter Lütjohann, PhD; Hartmut H.-J. Schmidt, MD; Carsten Otto, MD; Ulrike Beisiegel, PhD; Klaus von Bergmann, MD

Arch Neurol. 2002;59:213-216.

Background  Previous studies have shown that patients with early onset of Alzheimer disease and vascular dementia have higher levels of circulating brain-derived 24S-hydroxycholesterol (cerebrosterol).Two recent epidemiological studies indicated that treatment with inhibitors of cholesterol synthesis (statins) reduces the incidence of Alzheimer disease.

Objective  To test the hypothesis that treatment with high-dosage simvastatin reduces circulating levels of 24S-hydroxycholesterol.

Design  Prospective, 24-week treatment trial for lowering of cholesterol levels. We conducted assessments at baseline, week 6, and week 24.

Setting  An academic outpatient clinical study.

Patients  Eighteen patients who met the criteria for hypercholesterolemia.

Intervention  Treatment with 80 mg/d of simvastatin at night.

Main Outcome Measures  Plasma lipoprotein levels were measured enzymatically; lathosterol, by means of gas chromatography; and 24S-hydroxycholesterol, by means of gas chromatography–mass spectrometry.

Results  Simvastatin reduced total plasma cholesterol levels by 36% and 35% after 6 and 24 weeks, respectively (P<.001). Lathosterol levels were reduced by 74% and 72%, respectively, and the ratio of lathosterol to cholesterol, an indicator of whole-body cholesterol synthesis, was reduced by 60% and 61%, respectively (P<.001). Plasma 24S-hydroxycholesterol levels were lowered by 45% and 53%, respectively (P<.001). The ratio of 24S-hydroxycholesterol to cholesterol also decreased significantly (-12% [P= .01] and -23% [P<.002], respectively). The further reduction of 24S-hydroxycholesterol levels and its ratio to cholesterol from weeks 6 to 24 was also significant (P= .02 for both).

Conclusions  The greater reduction of plasma concentrations of 24S-hydroxycholesterol compared with cholesterol indicates that simvastatin in a dosage of 80 mg/d reduces cholesterol turnover in the brain. The present results might describe a possible mechanism of how long-term treatment with statins could reduce the incidence of Alzheimer disease.

From the Department of Clinical Pharmacology, University of Bonn, Bonn (Drs Locatelli, Lütjohann, and von Bergmann), the Medical Department, Charité, Berlin (Dr Schmidt), the Medical Department II, Klinikum University of Munich, Großhadern, Munich (Dr Otto), and Medical Clinic, University Hospital Hamburg, Hamburg (Dr Beisiegel), Germany.

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