Alzheimer's Disease
Conditions
Brief summary
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
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.
Interventions
DRUGSimvastatin
40 mg Simvastatin/day
DRUGPlacebo
Matching Placebo
Sponsors
National Institute on Aging (NIA)
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
40 Years to 72 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Cerebrospinal Fluid (CSF) Beta-amyloid-42 Levels Compared to Baseline as Measured by xMAP | Baseline and 18 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in CSF Beta-amyloid-40 Levels as Measured by xMAP (Multi-Analyte Profiling) ) | Baseline and 18 months | 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. |
| Changes in CSF Soluble Alpha Precursor Proteins (sAPP-alpha) and Soluble Beta Precursor Proteins (sAPP-beta) as Measured by Duplex | Baseline and 18 months | 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. |
| Changes in CSF Total Tau (T-tau) and Phosphorylated Tau (P-tau) as Measured by xMAP | Baseline and 18 months | 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. |
Countries
United States
Participant flow
Recruitment details
Asymptomatic middle-aged adults (ages 40-72 years) with parental history of AD were recruited from the community through local memory clinics, newsletters, educational talks, booths at health fairs, and newspaper and magazine advertisements.
Pre-assignment details
Screened individuals were not randomized to drug or placebo if they withdrew consent, were unable to complete baseline procedures or no longer met inclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Simvastatin 40 mg. Simvastatin/day
Simvastatin: 40 mg Simvastatin/day | 44 |
| Placebo Matching Placebo
Placebo: Matching Placebo | 44 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Mental health issues | 0 | 2 |
| Overall Study | withdrew from study due to busy schedule | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | Simvastatin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 3 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 38 Participants | 41 Participants | 79 Participants |
| Age, Continuous | 54.4 years STANDARD_DEVIATION 7.8 | 55.95 years STANDARD_DEVIATION 6.2 | 55.21 years STANDARD_DEVIATION 6.99 |
| Region of Enrollment United States | 44 participants | 44 participants | 88 participants |
| Sex: Female, Male Female | 32 Participants | 31 Participants | 63 Participants |
| Sex: Female, Male Male | 12 Participants | 13 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 44 |
| other Total, other adverse events | 0 / 44 | 0 / 44 |
| serious Total, serious adverse events | 0 / 44 | 0 / 44 |
Outcome results
Primary
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.
Time frame: Baseline and 18 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Simvastatin | Changes in Cerebrospinal Fluid (CSF) Beta-amyloid-42 Levels Compared to Baseline as Measured by xMAP | 1.01 ratio |
| Placebo | Changes in Cerebrospinal Fluid (CSF) Beta-amyloid-42 Levels Compared to Baseline as Measured by xMAP | 0.98 ratio |
Secondary
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.
Time frame: Baseline and 18 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Simvastatin | Changes in CSF Beta-amyloid-40 Levels as Measured by xMAP (Multi-Analyte Profiling) ) | 1.03 ratio |
| Placebo | Changes in CSF Beta-amyloid-40 Levels as Measured by xMAP (Multi-Analyte Profiling) ) | 0.98 ratio |
Secondary
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.
Time frame: Baseline and 18 months
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Simvastatin | Changes in CSF Soluble Alpha Precursor Proteins (sAPP-alpha) and Soluble Beta Precursor Proteins (sAPP-beta) as Measured by Duplex | sAPP-alpha | 0.96 ratio |
| Simvastatin | Changes in CSF Soluble Alpha Precursor Proteins (sAPP-alpha) and Soluble Beta Precursor Proteins (sAPP-beta) as Measured by Duplex | sAPP-beta | 0.98 ratio |
| Placebo | Changes in CSF Soluble Alpha Precursor Proteins (sAPP-alpha) and Soluble Beta Precursor Proteins (sAPP-beta) as Measured by Duplex | sAPP-alpha | 1.03 ratio |
| Placebo | Changes in CSF Soluble Alpha Precursor Proteins (sAPP-alpha) and Soluble Beta Precursor Proteins (sAPP-beta) as Measured by Duplex | sAPP-beta | 1.00 ratio |
Secondary
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.
Time frame: Baseline and 18 months
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Simvastatin | Changes in CSF Total Tau (T-tau) and Phosphorylated Tau (P-tau) as Measured by xMAP | Total tau | 1.01 ratio |
| Simvastatin | Changes in CSF Total Tau (T-tau) and Phosphorylated Tau (P-tau) as Measured by xMAP | Phosphorylated tau | 1.16 ratio |
| Placebo | Changes in CSF Total Tau (T-tau) and Phosphorylated Tau (P-tau) as Measured by xMAP | Total tau | 1.01 ratio |
| Placebo | Changes in CSF Total Tau (T-tau) and Phosphorylated Tau (P-tau) as Measured by xMAP | Phosphorylated tau | 1.15 ratio |