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Do HMG CoA Reductase Inhibitors Affect Abeta Levels?

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ClinicalTrials.gov Identifier: NCT00303277
Recruitment Status : Completed
First Posted : March 16, 2006
Last Update Posted : April 13, 2010
Sponsor:
Information provided by:
Seattle Institute for Biomedical and Clinical Research

Study Description
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Brief Summary:
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 or disease Intervention/treatment Phase
Alzheimer's Disease Aging Drug: simvastatin Drug: pravastatin Phase 4

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 35 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Do HMG CoA Reductase Inhibitors Affect Abeta Levels?
Study Start Date : August 2002
Actual Primary Completion Date : April 2005
Actual Study Completion Date : April 2005

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: 1
simvastatin
 Drug: simvastatin
simvastatin 40 mg tablets once per day for 12 weeks
Other Name: Zocor
Active Comparator: 2
pravastatin
 Drug: pravastatin
pravastatin 80 mg tablets once per day for 12 weeks
Other Name: Lipitor


Outcome Measures
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Primary Outcome Measures :
  1. CSF abeta levels [ Time Frame: baseline and 12 weeks ]

Secondary Outcome Measures :
  1. CSF biomarkers [ Time Frame: baseline and 12 weeks ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00303277


Locations
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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
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Principal Investigator: Elaine R Peskind, MD University of Washington
More Information
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Publications of Results:

Other Publications:

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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    
Other Study ID Numbers: 21974
First Posted: March 16, 2006    Key Record Dates
Last Update Posted: April 13, 2010
Last Verified: April 2010
Keywords provided by Seattle Institute for Biomedical and Clinical Research:
Alzheimer's disease
beta-amyloid
statins
Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
 Simvastatin
Pravastatin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors