Effect of statins on Alzheimer's disease biomarkers in cerebrospinal fluid

Article type: Research Article

Authors: Riekse, Robert G.^{a; f} | Li, Ge^{b; f; *} | Petrie, Eric C.^{b; f} | Leverenz, James B.^{b; c; f} | Vavrek, Darcy^f | Vuletic, Simona^e | Albers, John J.^e | Montine, Thomas J.^d | Lee, Virginia M.-Y.ⁱ | Lee, Michael^j | Seubert, Peter^j | Galasko, Douglas^k | Schellenberg, Gerard D.^{a; g} | Hazzard, William R.^{a; h} | Peskind, Elaine R.^{b; f}

Affiliations: [a] Department of Medicine, Division of Geriatric Medicine, University of Washington School of Medicine, WA, USA | [b] Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, WA, USA | [c] Department of Neurology, University of Washington School of Medicine, WA, USA | [d] Department of Pathology, Division of Neuropathology, University of Washington School of Medicine, WA, USA | [e] Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington School of Medicine, WA, USA | [f] Northwest Network VISN-20 Mental Illness Research, Education, and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, WA, USA | [g] Geriatric Research, Education, and Clinical Center (GRECC), VA Puget Sound Health Care System, Seattle, WA, USA | [h] Geriatrics and Extended Care, VA Puget Sound Health Care System, Seattle, WA, USA | [i] Department of Pathology, University of Pennsylvania, Philadelphia, PA, USA | [j] Elan Pharmaceuticals, South San Francisco, CA, USA | [k] Department of Neurology, University of California, San Diego, CA, USA

Correspondence: [*] Corresponding author: Ge Li, MD, PhD, VA Puget Sound Health Care System, S-116MIRECC, 1660 South Columbian Way, Seattle, WA 98108, USA. Tel.: +1 206 764 2485; Fax: +1 206 768 5456; E-mail: gli@u.washington.edu.

Abstract: Background: Treatment with HMG-CoA reductase inhibitors ("statins") has been variably associated with a reduced risk of Alzheimer's disease (AD) in epidemiologic studies and reduced amyloid-β (Aβ) deposition in animal models of AD. Putative neuroprotective effects of statins may vary in relation to their ability to penetrate into the central nervous system (CNS). Methods: We measured levels of cerebrospinal fluid (CSF) AD biomarkers following 14 weeks of treatment with simvastatin (a CNS permeant statin; n=10) at 40 mg/day or pravastatin (a CNS impermeant statin; n=13) at 80 mg/day in hypercholesterolemic subjects without dementia. Results: Simvastatin, but not pravastatin, reduced CSF levels of phospho-tau-181 (p-tau181) in all subjects. There were no differences in CSF levels of total tau, Aβ42, Aβ40, soluble amyloid β protein precursor (sAβPP) α or β, or F2-isoprostanes. Conclusions: Statins may modulate the phosphorylation of tau in humans and this effect may depend on the CNS availability of the statin. These results suggest another mechanism by which statins may act to reduce the risk of AD.

Keywords: Alzheimer's disease, statins, tau, clinical trial, CSF

DOI: 10.3233/JAD-2006-10408

Journal: Journal of Alzheimer's Disease, vol. 10, no. 4, pp. 399-406, 2006