Alzheimer's Disease, Hypertension
Conditions
Keywords
Alzheimer's Disease, Hypertension
Brief summary
Angiotensin converting enzyme inhibitors (ACE-I) are a group of blood pressure-lowering medicines. Some studies suggest that ACE-I, such as ramipril, may help prevent Alzheimer's disease (AD). The purpose of the research is to see how ramipril 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 ramipril can lower the amount of beta-amyloid in the spinal fluid. This study will also see if ramipril affects blood vessel function and memory and thinking. The investigators hope that future studies will show whether ramipril might prevent memory loss and decrease the chance of developing Alzheimer's disease.
Detailed description
High blood pressure (BP) in midlife is predictive of Alzheimer's disease (AD) in later life. Similarly, reductions in BP are associated with protection against AD. Treatment with antihypertensive medications, specifically angiotensin converting enzyme inhibitors (ACE-I) such as ramipril, is associated with up to a 55% reduction in the prevalence of AD, suggesting a potentially promising role for ACE-I in the prevention of AD. It is unknown however 1) whether ACE-Is will have the same effect on Cerebrospinal fluid (CSF) Aβ levels in humans as in animal models 2) whether ACE-Is induce changes associated with vascular function (i.e. levels of CSF angiotensin converting enzyme (ACE) and peripheral endothelial function) and 3) whether there are interactions between ACE-I-induced changes in CSF Aβ, CSF ACE and indices of vascular function. One mechanism by which antihypertensives may protect against AD is via Aβ neuropathology. In order to better understand the mechanisms through which ACE-I may modify CSF Aβ and possibly AD risk, we propose a randomized, double-blind, placebo-controlled pilot clinical trial, enrolling 20 middle-aged (age range 40 - 65 years), mildly hypertensive (between 130 - 160 mmHg mean systolic and between 85 - 100 mmHg mean diastolic) participants, who are adult children of an individual with AD. The main objective of this trial is to examine the effects of the ACE-I, ramipril, on 1) CSF Aβ levels 2) CSF ACE levels and 3) peripheral endothelial function as measured by brachial artery flow-mediated vasodilation (FMD) and aortic augmentation index (AAIx), in middle-aged adults with mildly elevated BP, who are at increased risk of developing AD.
Interventions
DRUGRamipril
Ramipril 5 mg/day
DRUGPlacebo
Matching Placebo
Sponsors
University of Wisconsin, Madison
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Between the ages of 40 and 65 * Mean resting blood pressure between 130-160 systolic and 85-100 diastolic * Parent with Alzheimer's Disease
Exclusion criteria
* Current involvement in another investigational drug trial. * Potassium \> 5.0 * Dementia based on DSMIV criteria * Mini-Mental State Exam (MMSE) score \< 27 * Current blood pressure medication (\< 4 months from screening) * Weight loss medication * Contraindications for LP * Know diagnosis or history of hospitalization due to congestive heart failure * Elevated creatinine (females \> 1.3 mg/dL or males \> 1.4 mg/dL at baseline) * Diabetes Type I and II * Know adverse reaction to an ACE-I or an angiotensin receptor blocker * Pregnant of nursing women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cerebrospinal Fluid (CSF) Amyloid Beta-42 (Aβ42) Levels Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | Baseline to 4 months | CSF Aβ42 levels will be measured from the cerebrospinal fluid taken from subjects on ramipril or placebo at the baseline visit and month 4 and will be measured by Dr. Henrik Zetterberg's laboratory. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in CSF Angiotensin Converting Enzyme (ACE) Levels Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | Baseline to 4 months | CSF ACE levels will be measured from the cerebrospinal fluid taken from subjects on Ramipril or placebo at the baseline visit and month 4 and will be measured by ARUP® laboratories by spectrophotometric enzymatic assay. |
| Change in Flow-mediated Vasodilation (FMD) Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | Baseline to 4 months | FMD is calculated as the ratio of brachial artery diameter after reactive hyperemia to baseline diameter, expressed as percentage change. FMD for each subject (ramipril v placebo) will be measured at baseline and month 4, observing any differences. |
| Change in Augmentation Index (%) Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | Baseline to 4 months | Pulse wave velocity was measured using an AtCor SphymoCor Px tonometry system. A small pressure transducer was placed on the skin at the point the arterial pulsation of the right common carotid and right radial arteries. A Millar micromanometer is in the tip of the probe. Using a generalized transfer function, the distance between these pressure points, and the peripheral arterial waveforms, a central aortic pressure signal is derived, from which aortic augmentation index is determined. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the Wisconsin Alzheimer's Disease Research Center (ADRC) registry and from the community for the clinical trial, Studying the Effects of Antihypertensives in Individuals at Risk for Alzheimer's (SEAIRA).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching Placebo
Placebo: Matching Placebo | 6 |
| Active Ramipril 5mg/day
Ramipril: Ramipril 5 mg/day | 8 |
| Total | 14 |
Baseline characteristics
| Characteristic | Active | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 6 Participants | 14 Participants |
| Age, Continuous | 56.3 years STANDARD_DEVIATION 6.1 | 52.0 years STANDARD_DEVIATION 6.7 | 54.2 years STANDARD_DEVIATION 6.4 |
| Region of Enrollment United States | 8 participants | 6 participants | 14 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 6 | 0 / 8 |
| serious Total, serious adverse events | 0 / 6 | 0 / 8 |
Outcome results
Primary
Change in Cerebrospinal Fluid (CSF) Amyloid Beta-42 (Aβ42) Levels Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo
CSF Aβ42 levels will be measured from the cerebrospinal fluid taken from subjects on ramipril or placebo at the baseline visit and month 4 and will be measured by Dr. Henrik Zetterberg's laboratory.
Time frame: Baseline to 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Cerebrospinal Fluid (CSF) Amyloid Beta-42 (Aβ42) Levels Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | -22.5 pg/ml | Standard Deviation 78.7 |
| Active | Change in Cerebrospinal Fluid (CSF) Amyloid Beta-42 (Aβ42) Levels Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | -31.71 pg/ml | Standard Deviation 90.6 |
p-value: 0.836Wilcoxon (Mann-Whitney)
p-value: 0.836Wilcoxon (Mann-Whitney)
Secondary
Change in Augmentation Index (%) Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo
Pulse wave velocity was measured using an AtCor SphymoCor Px tonometry system. A small pressure transducer was placed on the skin at the point the arterial pulsation of the right common carotid and right radial arteries. A Millar micromanometer is in the tip of the probe. Using a generalized transfer function, the distance between these pressure points, and the peripheral arterial waveforms, a central aortic pressure signal is derived, from which aortic augmentation index is determined.
Time frame: Baseline to 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Augmentation Index (%) Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | 1.7 Percentage change | Standard Deviation 8.9 |
| Active | Change in Augmentation Index (%) Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | -1.8 Percentage change | Standard Deviation 2.2 |
p-value: 0.491Wilcoxon (Mann-Whitney)
p-value: 0.491Wilcoxon (Mann-Whitney)
Secondary
Change in CSF Angiotensin Converting Enzyme (ACE) Levels Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo
CSF ACE levels will be measured from the cerebrospinal fluid taken from subjects on Ramipril or placebo at the baseline visit and month 4 and will be measured by ARUP® laboratories by spectrophotometric enzymatic assay.
Time frame: Baseline to 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in CSF Angiotensin Converting Enzyme (ACE) Levels Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | -0.10 U/L | Standard Deviation 0.21 |
| Active | Change in CSF Angiotensin Converting Enzyme (ACE) Levels Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | -0.63 U/L | Standard Deviation 0.32 |
p-value: 0.009Wilcoxon (Mann-Whitney)
p-value: 0.009Wilcoxon (Mann-Whitney)
Secondary
Change in Flow-mediated Vasodilation (FMD) Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo
FMD is calculated as the ratio of brachial artery diameter after reactive hyperemia to baseline diameter, expressed as percentage change. FMD for each subject (ramipril v placebo) will be measured at baseline and month 4, observing any differences.
Time frame: Baseline to 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Flow-mediated Vasodilation (FMD) Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | -0.70 Percentage change | Standard Deviation 1.56 |
| Active | Change in Flow-mediated Vasodilation (FMD) Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | -0.29 Percentage change | Standard Deviation 1.23 |
p-value: 0.755Wilcoxon (Mann-Whitney)
p-value: 0.755Wilcoxon (Mann-Whitney)