Alzheimer Disease
Conditions
Keywords
amyloid protein, apolipoprotein, cerebrospinal fluid, cerebrovascular circulation, inflammation, magnetic resonance imaging, prevention & control
Brief summary
The purpose of this study is to see how simvastatin, a cholesterol-lowering drug, affects processes related to the development of Alzheimer's disease, including: 1) levels of a substance called beta-amyloid-42 found in the spinal fluid surrounding the brain, 2) blood flow in the brain, 3) inflammation in the brain, and 4) cognitive function.
Detailed description
Some studies suggest that statin medications, which are a group of cholesterol-lowering medicines, may help prevent Alzheimer's disease. However, this has not been proven in humans. The purpose of this study is to see how simvastatin affects a substance in the spinal fluid around the brain called beta-amyloid-42 which is thought to contribute to Alzheimer's disease. This study also evaluates whether simvastatin improves regional brain blood flow (on magnetic resonance imaging \[MRI\]), reduces inflammation, and improves cognitive function. The ESPRIT study was a 9-month randomized, controlled clinical trial that randomized 100 middle-aged adults with a parental history of Alzheimer's disease. Participants were randomized to simvastatin 40 mg for one month then 80 mg daily or matching placebo tablets. Fifty of the ESPRIT subjects participated in the MRI sub-study. Participants had the following data collected: fasting blood tests (baseline and months 3 and 9), medical history and medication questionnaires (each visit), study medication side effect review (all visits), lumbar puncture procedure (baseline and month 9), memory testing (baseline and months 3 and 9), and MRI (baseline and month 9 in 50 sub-study participants).
Interventions
DRUGSimvastatin
40 mg tablet each night for one month, then 80 mg for 8 months
DRUGPlacebo
Matching tablet each night for 9 months
Sponsors
National Institute on Aging (NIA)
Paul Beeson Faculty Scholars Program
The John A. Hartford Foundation
The Atlantic Philanthropies
Starr Foundation
American Federation for Aging Research
Merck Sharp & Dohme LLC
University of Wisconsin, Madison
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to 69 Years
Healthy volunteers
Yes
Inclusion criteria
* Age 35 to 69 * Parent with Alzheimer's disease
Exclusion criteria
* Current use of cholesterol-lowering medication * Active liver disease * History of adverse reaction to statins * Contraindication to lumbar puncture * Elevated lab values (creatine kinase and creatinine) * Use of medications known to interact with statins * History of dementia * Currently pregnant or planning to become pregnant * Use of large quantities of grapefruit juice (more than 1 quart per day) * Current involvement in another investigational drug study * Contraindications to MRI (for MRI sub-study) * Ethical contraindication to placebo (persons with high vascular risk)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in Cerebrospinal Fluid (CSF) Beta-amyloid-42 | baseline and 9 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Regional Cerebral Blood Flow on MRI | baseline and 9 months | Mean changes noted in posterior cingulate cortex |
| Change in Inflammatory Markers | baseline and 9 months | Change noted in serum high-sensitivity c-reactive protein |
| Changes in Cognitive Performance | Baseline and 9 months | Change in Hopkins Verbal Learning Test Delayed Recall The Hopkins Verbal Learning Test Delayed Recall score is the raw number of words recalled at Trial 4, adjusted for years of education and age. This is a 12-item word list test. |
Countries
United States
Participant flow
Recruitment details
Middle-aged adults with parental history of Alzheimer's disease were recruited for this single-site trial (Madison, Wisconsin) from the Wisconsin Registry for Alzheimer's Prevention (WRAP) or the community through newsletters, websites, educational talks, health fairs, local clinics, and newspaper and magazine advertisements.
Pre-assignment details
103 participants enrolled in the trial and 100 were randomized to treatment (1 no longer met inclusion criteria, 2 declined participation).
Participants by arm
| Arm | Count |
|---|---|
| Simvastatin Simvastatin 40 mg tablet nightly for 1 month then 80 mg tablet nightly for 8 months | 51 |
| Placebo Matching placebo tablet nightly for 9 months | 49 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Simvastatin | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 7 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 49 Participants | 42 Participants | 91 Participants |
| Age, Continuous | 53.3 years STANDARD_DEVIATION 7.4 | 52.4 years STANDARD_DEVIATION 8.5 | 52.8 years STANDARD_DEVIATION 8 |
| Apolipoprotein E4 carrier | 21 participants | 17 participants | 38 participants |
| Cerebrospinal fluid beta-amyloid-42 | 345.6 ng/L STANDARD_DEVIATION 77.1 | 331.0 ng/L STANDARD_DEVIATION 83.7 | 338.7 ng/L STANDARD_DEVIATION 80.2 |
| Cognitive Function | 29.5 points STANDARD_DEVIATION 0.8 | 29.6 points STANDARD_DEVIATION 0.6 | 29.5 points STANDARD_DEVIATION 0.7 |
| Education | 16.1 years | 16.3 years STANDARD_DEVIATION 3.2 | 16.2 years STANDARD_DEVIATION 2.9 |
| High-sensitivity c-reactive protein | 2.59 mg/L STANDARD_DEVIATION 3.71 | 2.03 mg/L STANDARD_DEVIATION 2.21 | 2.32 mg/L STANDARD_DEVIATION 3.06 |
| Region of Enrollment United States | 51 participants | 49 participants | 100 participants |
| Sex: Female, Male Female | 35 Participants | 35 Participants | 70 Participants |
| Sex: Female, Male Male | 16 Participants | 14 Participants | 30 Participants |
| Total cholesterol | 192.8 mg/dL STANDARD_DEVIATION 36.4 | 187.6 mg/dL STANDARD_DEVIATION 27.7 | 190.3 mg/dL STANDARD_DEVIATION 32.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 51 | 1 / 49 |
| serious Total, serious adverse events | 0 / 51 | 0 / 49 |
Outcome results
Primary
Change in Cerebrospinal Fluid (CSF) Beta-amyloid-42
Time frame: baseline and 9 months
Population: 1 participant declined follow up CSF collection in simvastatin arm; CSF could not be accessed at month 9 in 1 participant in placebo arm
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin | Change in Cerebrospinal Fluid (CSF) Beta-amyloid-42 | -5.2 ng/L | Standard Deviation 44.1 |
| Placebo | Change in Cerebrospinal Fluid (CSF) Beta-amyloid-42 | -3.1 ng/L | Standard Deviation 38.2 |
p-value: 0.966Kruskal-Wallis
Secondary
Change in Inflammatory Markers
Change noted in serum high-sensitivity c-reactive protein
Time frame: baseline and 9 months
Population: 2 participants in the simvastatin arm and 3 participants in the placebo arm had incomplete hs-CRP results
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin | Change in Inflammatory Markers | -1.16 mg/L | Standard Deviation 3.55 |
| Placebo | Change in Inflammatory Markers | -0.31 mg/L | Standard Deviation 1.83 |
p-value: 0.113Kruskal-Wallis
Secondary
Changes in Cognitive Performance
Change in Hopkins Verbal Learning Test Delayed Recall The Hopkins Verbal Learning Test Delayed Recall score is the raw number of words recalled at Trial 4, adjusted for years of education and age. This is a 12-item word list test.
Time frame: Baseline and 9 months
Population: 1 participant in simvastatin arm with missing data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin | Changes in Cognitive Performance | 0.40 adjusted words recalled | Standard Deviation 1.38 |
| Placebo | Changes in Cognitive Performance | 0.26 adjusted words recalled | Standard Deviation 1.54 |
p-value: 0.21Kruskal-Wallis
Secondary
Changes in Regional Cerebral Blood Flow on MRI
Mean changes noted in posterior cingulate cortex
Time frame: baseline and 9 months
Population: Number of participants analyzed represent participants in MRI substudy with readable MRI scans at both baseline and 9 months; 24 and 17 readable MRI scans in simvastatin and placebo arms, respectively. Unusable MRI scans resulted from poor quality images due to technical problems.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin | Changes in Regional Cerebral Blood Flow on MRI | 4.09 mL/100 g/min | Standard Deviation 6.69 |
| Placebo | Changes in Regional Cerebral Blood Flow on MRI | -5.08 mL/100 g/min | Standard Deviation 8.28 |
p-value: 0.015ANCOVA