Effects of Simvastatin on Cerebrospinal Fluid Biomarkers and Cognition in Middle-Aged Adults at Risk for Alzheimer's Disease

Article type: Research Article

Authors: Carlsson, Cynthia M.^{a; e; *} | Gleason, Carey E.^{a; e} | Hess, Timothy M.^b | Moreland, Kimberly A.^a | Blazel, Hanna M.^a | Koscik, Rebecca L.^b | Schreiber, Nathan T.N.^a | Johnson, Sterling C.^{a; e} | Atwood, Craig S.^{a; e} | Puglielli, Luigi^{a; e} | Hermann, Bruce P.^c | McBride, Patrick E.^d | Stein, James H.^d | Sager, Mark A.^a | Asthana, Sanjay^{a; e}

Affiliations: [a] Department of Medicine, Section of Geriatrics and Gerontology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA | [b] Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA | [c] Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA | [d] Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA | [e] Department of Veterans Affairs (VA) Geriatric Research, Education and Clinical Center (GRECC), Madison, WI, USA

Correspondence: [*] Corresponding author: Cynthia M. Carlsson, MD, MS, Assistant Professor of Medicine, Section of Geriatrics and Gerontology, University of Wisconsin School of Medicine and Public Health, William S. Middleton Memorial Veterans Hospital Geriatric Research, Education and Clinical Center (GRECC) (11G), 2500 Overlook Terrace, Madison, WI 53705, USA. Tel.: +1 608 280 7000; Fax: +1 608 280 7165; E-mail: cmc@medicine.wisc.edu.

Abstract: Background:Statins reduce amyloid-β (Aβ) levels in the brain and cerebrospinal fluid (CSF) in animals and may thereby favorably alter the pathobiology of AD. It is unclear if statins modify Aβ metabolism or improve cognition in asymptomatic middle-aged adults at increased risk for AD. Methods:In a 4-month randomized, double-blind, controlled study, we evaluated the effects of simvastatin 40 mg daily vs. placebo on CSF Aβ42 levels and cognition in 57 asymptomatic middle-aged adult children of persons with AD. Results:Compared to placebo, individuals randomized to simvastatin for 4 months had similar changes in CSF Aβ42 (p=0.344) and total tau levels (p=0.226), yet greater improvements in some measures of verbal fluency (p=0.024) and working memory (p=0.015). APOE4 genotype, gender, and vascular risk factors were associated with CSF biomarker levels, but did not modify treatment effects. Conclusion:In asymptomatic middle-aged adults at increased risk for AD, simvastatin use improved selected measures of cognitive function without significantly changing CSF Aβ42 or total tau levels. Further studies are needed to clarify the impact of higher dose and/or longer duration statin therapy on not only Aβ metabolism, but also other preclinical processes related to the development of AD.

Keywords: Alzheimer's disease, amyloid β-protein, biological markers, cerebrospinal fluid, genetic predisposition to disease, hydroxymethylglutaryl-CoA reductase inhibitors, neuropsychological tests, simvastatin, tau proteins

DOI: 10.3233/JAD-2008-13209

Journal: Journal of Alzheimer's Disease, vol. 13, no. 2, pp. 187-197, 2008