Reduction of plasma 24S-hydroxycholesterol (cerebrosterol) levels using high-dosage simvastatin in patients with hypercholesterolemia: evidence that simvastatin affects cholesterol metabolism in the human brain.

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.