Statin Effects on Beta-Amyloid and Cerebral Perfusion in Adults at Risk for Alzheimer's Disease

Study Overview
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Brief Summary
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The purpose of the research is to see how simvastatin affects a substance in the body called beta-amyloid. Beta-amyloid is found in the brain and in the liquid around the brain and spinal cord. High amounts of beta-amyloid may be associated with a greater risk of getting Alzheimer's disease. This study will see if simvastatin can lower the amount of beta-amyloid in the spinal fluid. This study will also see if simvastatin affects memory and thinking, blood flow in the brain, and blood vessel function. The investigators hope that future studies show whether simvastatin might prevent memory loss and decrease the chance of developing Alzheimer's disease.

Detailed Description
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Studies show that some medicines that lower cholesterol may reduce the risk of developing Alzheimer's disease, but this has not yet been proven in humans. We are looking for individuals to participate in this study to see if a cholesterol-lowering medication, called simvastatin affects blood flow to the brain, blood vessel function and a substance in the spinal fluid related to the changes in Alzheimer's disease. The SHARP study included 88 adults ages 40-72 with parental history of documented Alzheimer's disease. The study had 9 visits over the course of 18 months. Participants had fasting blood tests collected, completed a medical history questionnaire and medication side effect review, underwent lumbar puncture procedure, completed memory testing, and had ultrasound and MRI procedures. Participants were randomly assigned to receive either simvastatin or a placebo each night for 18 months.

Official Title
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Statin Effects on Beta-Amyloid and Cerebral Perfusion in Adults at Risk for AD: Statins in Healthy, At-Risk Adults: Impact on Amyloid and Regional Perfusion (SHARP) Study

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Simvastatin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Parent diagnosed with Alzheimer's disease Age 40-72 Exclusion Criteria: Active liver disease History of adverse reaction to statins Contraindication to lumbar puncture Elevated creatine kinase and creatinine lab values Use of medications known to interact with statins History of dementia or mild cognitive impairment Currently pregnant or planning to become pregnant Use of large quantities of grapefruit juice (more than 1 quart per day) Contraindications to MRI (for MRI sub-study) Currently on cholesterol-lowering medication or use in past 4 months History of heart attack, heart problems, stroke and/or diabetes Drinking more than a quart of grapefruit juice per day Metal implants, or metal debris in body (MRI) List of medications that interact with simvastatin

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 72 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Simvastatin<br>40 mg. Simvastatin/day | Drug: Simvastatin<br>* 40 mg Simvastatin/day<br>|
| Placebo Comparator: Placebo<br>Matching Placebo | Drug: Placebo<br>* Matching Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Cerebrospinal Fluid (CSF) Beta-amyloid-42 Levels Compared to Baseline as Measured by xMAP | Change in CSF beta-amyloid-42 was defined as the ratio of 18-month levels to baseline levels. Beta-amyloid-42 is a substance found in the plaques in the brain of people with Alzheimer's disease and can be detected in CSF. There is no defined normal range yet for middle-aged adults. | Baseline and 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in CSF Beta-amyloid-40 Levels as Measured by xMAP (Multi-Analyte Profiling) ) | Change in CSF beta-amyloid-40 was defined as the ratio of 18-month levels to baseline levels. Beta amyloid-40 is a substance found in the brain vessels of individuals with Alzheimer's disease and has more potent cerebrovascular effects on individuals with Alzheimer's disease than any other form of beta amyloid. | Baseline and 18 months | 
| Changes in CSF Soluble Alpha Precursor Proteins (sAPP-alpha) and Soluble Beta Precursor Proteins (sAPP-beta) as Measured by Duplex | Changes in CSF sAPP-alpha and sAPP-beta were defined as the ratio of 18-month levels to baseline levels. sAPP-alpha and sAPP-beta are components of beta-amyloid that provide information on beta-amyloid breakdown. | Baseline and 18 months | 
| Changes in CSF Total Tau (T-tau) and Phosphorylated Tau (P-tau) as Measured by xMAP | Changes in CSF t-tau and p-tau were defined as the ratio of 18-month levels to baseline levels. T-tau and p-tau are substances found in the brain that can provide information on nerve cell health in the brain and tangle formation in nerve cells. | Baseline and 18 months |