Do HMG CoA Reductase Inhibitors Affect Abeta Levels? - Full Text View

Purpose

Recent evidence suggests that there is a significant overlap between AD and cerebrovascular disease. In fact, AD and cerebrovascular disease may share some of the same risk factors, including hypercholesterolemia. In addition, studies have suggested that the HMG Co-A reductase inhibitor lipid-lowering agents, known as "statins," decrease the risk of AD by up to 70%; however, effects differed by specific statin use. This study will compare two statins, simvastatin (which crosses the blood brain barrier) and pravastatin (which does not), with respect to their ability to alter blood and cerebrospinal fluid (CSF) levels of AD and inflammatory markers. The primary aim of the proposed study is to determine whether there is a reduction in Abeta with statins and whether the ability of the statin to cross the blood-brain barrier will affect its ability to decrease Abeta. If it can be demonstrated that statins alter AD-associated biomarkers, this would have broad implications for the treatment and prevention of AD.

Condition	Intervention	Phase
Alzheimer's Disease Aging	Drug: simvastatin Drug: pravastatin	Phase 4

Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Prevention
Official Title:	Do HMG CoA Reductase Inhibitors Affect Abeta Levels?

Resource links provided by NLM:

Genetics Home Reference related topics: Alzheimer disease

MedlinePlus related topics: Alzheimer's Disease Statins

Drug Information available for: Simvastatin Pravastatin Pravastatin sodium

U.S. FDA Resources

Further study details as provided by Seattle Institute for Biomedical and Clinical Research:

Primary Outcome Measures:

CSF abeta levels [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

CSF biomarkers [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]

Enrollment:	35
Study Start Date:	August 2002
Study Completion Date:	April 2005
Primary Completion Date:	April 2005 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: 1 simvastatin	Drug: simvastatin simvastatin 40 mg tablets once per day for 12 weeks Other Names: simvastatin Zocor
Active Comparator: 2 pravastatin	Drug: pravastatin pravastatin 80 mg tablets once per day for 12 weeks Other Names: pravastatin Lipitor

Detailed Description:

Recent evidence suggests that there is a significant overlap between AD and cerebrovascular disease. In fact, AD and cerebrovascular disease may share some of the same risk factors, including hypercholesterolemia. In addition, studies have suggested that the HMG Co-A reductase inhibitor lipid-lowering agents, known as "statins," decrease the risk of AD by up to 70%; however, effects differed by specific statin use. This study will compare two statins, simvastatin (which crosses the blood brain barrier) and pravastatin (which does not), with respect to their ability to alter blood and cerebrospinal fluid (CSF) levels of AD and inflammatory markers. The primary aim of the proposed study is to determine whether there is a reduction in Abeta with statins and whether the lipophilicity of the statin will affect its ability to decrease Abeta. In addition, the proposal will determine statin effects on both peripheral and central inflammation and whether the lipophilicity of the statin will affect its ability to decrease inflammation. If it can be demonstrated that statins alter AD-associated biomarkers, this would have broad implications for the treatment and prevention of AD.

This study will be performed in 60 cognitively normal middle-aged and older persons with hypercholesterolemia (total cholesterol >200 and/or LDL>130), presumably persons that have a lipid-related increased risk of AD and in whom alterations of CSF Abeta can be interpreted.The differential effects of the two statins will be evaluated in a 12-week randomized treatment trial with 30 subjects in each group.

Prior to randomization and following 12 weeks of treatment with simvastatin or pravastatin, subjects will undergo CSF and blood collection. In the CSF, concentrations of Abeta 1-40, Abeta 1-42, soluble APP, tau, 24S-hydroxycholesterol, apoE, total cholesterol, F2-isoprostanes, glucose, protein, and cell count will be measured. In the blood, concentrations of total cholesterol, HDL, LDL, triglyceride, phospholipids, fatty acids, 24S-hydroxycholesterol, apoE, apoB, apoA1, Abeta 1-40, Abeta 1-42, F2-isoprostanes, C-reactive protein, fibrinogen, iron, homocysteine, and albumin will be measured. Plasma simvastatin and pravastatin concentrations will be measured at study completion. APOE genotyping will be performed.

Eligibility

Ages Eligible for Study:	18 Years to 90 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Total cholesterol > 200, and/or LDL > 130
No cognitive impairment
Statin-naive for at least one year
Women must not be pregnant, nursing, or planning to become pregnant

Exclusion Criteria:

Back ailments which would hinder LP procedure
Neurological disease, including stroke, Parkinson's disease, Multiple Sclerosis, uncontrolled epilepsy, history of severe head trauma
Hepatic disease
Renal insufficiency
Unstable medical disease
Severe pulmonary disease
Severe cardiac disease
Uncontrolled hypertension (greater than 160/90)
Uncontrolled hyper/hypothyroidism
History of blood clotting abnormalities or platelet abnormalities
History of chronic major psychiatric disorders or presence of current major depressive disorder (by DSM-IV criteria)
History of substance abuse within the past year
Taking exclusionary medications

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00303277

Locations

United States, Washington
VA Puget Sound Health Care System
Seattle, Washington, United States, 98108

Sponsors and Collaborators

Seattle Institute for Biomedical and Clinical Research

Investigators

Principal Investigator:

Elaine R Peskind, MD

University of Washington

More Information

Publications:

Riekse RG, Li G, Petrie EC, Leverenz JB, Vavrek D, Vuletic S, Albers JJ, Montine TJ, Lee VM, Lee M, Seubert P, Galasko D, Schellenberg GD, Hazzard WR, Peskind ER. Effect of statins on Alzheimer's disease biomarkers in cerebrospinal fluid. J Alzheimers Dis. 2006 Dec;10(4):399-406.

Li G, Larson EB, Sonnen JA, Shofer JB, Petrie EC, Schantz A, Peskind ER, Raskind MA, Breitner JC, Montine TJ. Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease. Neurology. 2007 Aug 28;69(9):878-85.

Li G, Higdon R, Kukull WA, Peskind E, Van Valen Moore K, Tsuang D, van Belle G, McCormick W, Bowen JD, Teri L, Schellenberg GD, Larson EB. Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study. Neurology. 2004 Nov 9;63(9):1624-8.

Responsible Party:	Elaine R. Peskind, MD, Professor, Director of Clinical Research, Mental Health Service, VA Puget Sound Health Care System/University of Washington School of Medicine
ClinicalTrials.gov Identifier:	NCT00303277 History of Changes
Other Study ID Numbers:	21974
Study First Received:	March 14, 2006
Last Updated:	April 12, 2010
Health Authority:	United States: Institutional Review Board

Keywords provided by Seattle Institute for Biomedical and Clinical Research:

Alzheimer's disease
beta-amyloid
statins

Additional relevant MeSH terms:

Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Simvastatin

Pravastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Lipid Regulating Agents
Therapeutic Uses
Anticholesteremic Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on May 23, 2013