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STATINS AND PLASMA LEVELS OF AMYLOID

The following points are made by K. Höglund et al (Arch Neurol. 2004;61:333-337):

1) Previous studies support the theory that the formation and aggregation of beta-amyloid (beta-A), the major constituent of senile plaques in brain and blood vessels, is critical for the initiation of Alzheimer disease (AD). The beta-A peptide is produced in two major forms, beta-A40 and beta-A42, during the processing of the integral plasma membrane protein, amyloid precursor protein (APP). Secreted soluble beta-A is a product of normal cell metabolism,(1) and is found in various body fluids, including cerebrospinal fluid (CSF) and plasma.(2-3)

2) Several studies have suggested an association between AD, beta-A, and cholesterol metabolism. Clinical studies have revealed that patients with AD have elevated levels of cholesterol in the plasma(4) and that the plasma level of apolipoprotein E, the main lipid transporter protein in the brain, is related to AD.(5) Longitudinal studies have suggested that an elevated midlife level of cholesterol is a risk factor for AD, and recent retrospective clinical studies have indicated that patients treated with statins have a reduced prevalence of AD.

3) Statins reduce de novo cholesterol synthesis by inhibiting the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, which leads to a decrease in low-density lipoprotein cholesterol level in human plasma. In vitro studies have shown that cholesterol modulates the processing of APP. The hypothesis that lowering cholesterol levels favors the nonamyloidogenic pathway has further been supported by animal studies. However, there are also two prospective studies that do not support the connection between statin treatment and reduced prevalence of AD.

4) It is believed that cholesterol in the brain mainly results from de novo synthesis of cholesterol in the cells. The efflux of cholesterol is in the form of 24S-hydroxycholesterol. Two recent studies have demonstrated that patients with early-onset AD and vascular dementia have elevated concentrations of 24S-hydroxycholesterol in their plasma, indicating an overproduction of cholesterol in the brain. Support for this hypothesis has been given in two studies showing that cholesterol metabolism in the human brain was affected by treatment with statins and effects were seen after 6 weeks of treatment.

6) The authors conclude: The origin of beta-A in plasma is still unclear. No correlation between CSF and plasma levels of beta-A has been seen, nor is there a correlation between CSF, beta-A42, and blood-brain barrier deficits, which suggests that plasma beta-A42 is not derived from the brain but is secreted peripherally. Despite a marked reduction in cholesterol levels, the authors did not observe any change in plasma levels of beta-A. It is possible that statins may affect beta-A metabolism in the brain, but not peripherally. However, several studies have found no change in CSF levels or only minor effects in mild AD cases after statin treatment. In conclusion, further studies are needed to examine the mechanism by which statins may reduce the risk of developing AD.

5) The authors report a prospective, randomized, dose-finding 36-week treatment trial with statins. Plasma samples were taken at baseline (week 0) and at weeks 6, 12, and 36. The setting was an outpatient clinical study at a university hospital. The subjects were 39 patients who met the criteria for hypercholesterolemia.

References (abridged):

1. Seubert P, Vigo-Pelfrey C, Esch F, et al. Isolation and quantification of soluble Alzheimer's -peptide from biological fluids. Nature. 1992;359:325-327

2. Galasko D, Chang L, Motter R, et al. High cerebrospinal fluid tau and low amyloid 42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol. 1998;55:937-945

3. Mayeux R, Tang MX, Jacobs DM, et al. Plasma amyloid -peptide 1-42 and incipient Alzheimer's disease. Ann Neurol. 1999;46:412-416

4. Giubilei F, D'Antona R, Antonini R, et al. Serum lipoprotein pattern variations in dementia and ischemic stroke. Acta Neurol Scand. 1990;81:84-86

5. Jarvik GP, Wijsman EM, Kukull WA, et al. Interactions of apolipoprotein E genotype, total cholesterol level, age, and sex in prediction of Alzheimer's disease: a case-control study. Neurology. 1995;45:1092-1096

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