Table of Contents
- Key Points
- Background: Why Blood Vessels Matter in Alzheimer's Disease
- What Is External Counterpulsation (ECP)?
- How the Study Was Conducted
- Who Participated in the Study
- The Treatment Protocol
- How Patients Were Assessed
- Key Findings: Detailed Results
- Special Finding: Patients with Type 2 Diabetes
- Brain Imaging Findings
- Safety Results
- What These Results Mean for Patients
- Limitations of the Study
- Recommendations and Next Steps
- Frequently Asked Questions
- Source Information
Key Points
- In a 12-month randomized trial of 190 patients with early Alzheimer's disease, full-pressure ECP improved thinking and daily functioning compared with a low-pressure sham treatment.
- The VADAS-cog cognitive score improved by 9.95 points on average with full-pressure ECP versus 5.22 points with sham (p=0.005).
- Daily-activity scores improved by 2.57 points with full-pressure ECP but declined by 0.49 points with sham (p=0.036).
- Benefits persisted through the full 52 weeks even though all treatment stopped at 6 months, and no serious device-related adverse events occurred.
- The study excluded people with a history of stroke, uncontrolled epilepsy, multiple sclerosis, Parkinson's disease, cerebral hemorrhage, or cerebral aneurysm.
Background: Why Blood Vessels Matter in Alzheimer's Disease
Alzheimer's disease (AD) and mild cognitive impairment (MCI) are complex conditions. For years, most research focused on the buildup of two proteins in the brain: amyloid and tau. However, these protein deposits alone do not fully explain the disease.
A growing body of evidence shows that vascular disease — problems with blood vessels — is closely tied to Alzheimer's disease. This is not simply a coincidence. Multiple studies indicate that vascular disease is intimately related to how common MCI and AD are. This is especially true for disease of the blood vessels inside the skull. Vascular disease is also related to how MCI and AD develop and how MCI and AD appear clinically.
This includes several specific types of blood vessel problems:
- Atherosclerotic vascular disease — hardening and narrowing of arteries due to fatty deposits
- Cerebral amyloid angiopathy (CAA) — a condition where amyloid protein builds up in the walls of blood vessels in the brain, making them fragile
- Functional changes in the neurovascular bundle — the close partnership between nerve cells and the blood vessels that supply them
- Impaired microvascular reactivity — the inability of tiny blood vessels to widen or narrow appropriately when the brain needs more blood flow
These findings suggest that improving blood vessel function could be a meaningful way to treat or slow Alzheimer's disease. That is the idea behind the treatment tested in this study.
What Is External Counterpulsation (ECP)?
External counterpulsation (ECP) is an established cardiovascular therapy. Doctors already use ECP to treat refractory angina pectoris (chest pain that does not respond to standard treatments) and heart failure.
Here is how ECP works. Pneumatic cuffs (inflatable pressure bands) are wrapped around the patient's calves, thighs, and waist or buttocks. These cuffs rapidly inflate and then deflate during the diastolic period — the brief pause between each heartbeat. The inflation is synchronized with the patient's cardiac cycle (heartbeat rhythm).
Each inflation briefly pushes most of the blood out of the legs and reverses blood flow in the lower aorta, the body's main artery. The cuffs then deflate just before the next heartbeat. A single treatment session typically lasts one hour.
This process dramatically increases endothelial shear stress — the frictional force of blood flowing along the inner lining of blood vessels. This effect is similar to what happens during physical exercise. The result is a cascade of beneficial changes:
- Increased production of nitric oxide by the endothelium (the inner lining of blood vessels). Nitric oxide helps blood vessels relax and widen.
- Improved vascular reactivity (blood vessels respond better to the body's signals)
- Increased vascular compliance (blood vessels become more flexible)
- Increased production of anti-inflammatory factors by the endothelium
In patients with cardiovascular disease, ECP has been shown to increase vascular collateralization — the growth of new small blood vessels that can bypass narrowed arteries. Importantly, these changes have been shown to persist for months to years after treatment ends.
Beyond these general cardiovascular effects, ECP has been shown to increase blood flow to the brain in healthy people. ECP has also been shown to increase blood flow to the brain in patients who have had an ischemic stroke. An ischemic stroke is a stroke caused by a blocked blood vessel.
Two earlier studies specifically pointed toward a potential benefit in Alzheimer's disease. Li and colleagues found that ECP treatments improved cognition and brain perfusion (blood flow) in a small group of AD patients. More recently, Moriarty and colleagues found improvements in cognition and hippocampal blood flow (blood flow to the memory center of the brain) in a pilot group of AD patients.
The Renew Cerezen™ ECP device has recently been certified in the European Union for the treatment of mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease. The current study was designed to investigate the impact of ECP on the course of patients with early AD in a larger, rigorously controlled trial.
How the Study Was Conducted
Designing a placebo for ECP treatment is difficult because the physical compressions of the lower extremities are obvious to the patient. To address this challenge, the researchers designed a randomized, single-blind, multi-site study. The trial evaluated the efficacy and safety of full-pressure, cardiac-cycle-synchronized treatment compared with a low-pressure, non-synchronized treatment.
The study population consisted of participants aged 55 to 85 years with a clinical diagnosis of MCI or mild AD. Twelve study sites screened and enrolled 190 participants.
Participants were prospectively randomized into two study arms in a 1:1 ratio:
- Full-pressure ECP treatment (active treatment)
- Low-pressure treatment (sham/control treatment)
Randomization was stratified (balanced) according to two factors:
- Clinical diagnosis (MCI or AD)
- Cardiovascular risk (CVR) score — grouped as low/medium risk versus high/very high risk for future cardiac events
Randomization assignments were made using permuted blocks, and investigators received subject assignments from an Interactive Web Response System (IWRS). Participants were not informed of their assigned treatment group.
The researchers also pre-specified a subgroup analysis for patients with type 2 diabetes (T2D). This is because ECP has been shown to improve glycemic control (blood sugar control) and vascular biology in people with T2D. Alzheimer's disease is associated with T2D, and diabetic patients tend to have more cerebrovascular disease. Results from this subgroup will be reported separately.
Oversight and Ethical Considerations
The study was carried out in accordance with the ethical principles of the Declaration of Helsinki and International Council for Harmonisation recommendations. The study was approved by the Advarra IRB (approval no. MOD00558904) on January 20, 2020.
Written informed consent was obtained from each patient, or from the patient's legal guardian or representative. Unblinded results and patient safety data were reviewed by an independent Data Monitoring Committee (DMC). Study performance and data collection were monitored and supervised by a third-party Contract Research Organization (Navitas Clinical Research, Rockville, Maryland, USA).
Eligibility Criteria
The study was open to all genders and minority groups. Participants were required to meet all inclusion criteria and to have none of the exclusion criteria.
Key inclusion criteria:
- A clinical diagnosis consistent with published 2011 NIA-AA "core clinical criteria" guidelines for either:
- Mild cognitive impairment due to Alzheimer's disease, or
- Dementia due to Alzheimer's disease
Key exclusion criteria:
- Any exclusion criterion from the NIA-AA core clinical criteria
- Major confounding neurodegenerative or psychiatric disorder unrelated to the condition under study, including:
- History of clinically evident stroke
- Current uncontrolled epileptic seizures or epilepsy
- Multiple sclerosis or Parkinson's disease
- Current clinically significant major psychiatric disorder that could impair completion of the study
- Active or history of cerebral hemorrhage (bleeding in the brain), including subdural and subarachnoid hemorrhage or cerebral aneurysm
Who Participated in the Study
The study enrolled 190 participants, with 95 in each treatment group. The population was representative of the sex, racial, and ethnic diversity of the United States: 62% female, 14% Black, and 18% Hispanic. Enrollment, treatment, and assessment spanned from November 2018 to March 2021.
Baseline characteristics were well balanced between the two groups. The average age was 68.5 years in the full-pressure group and 68.1 years in the low-pressure group. For all parameters other than the ADCS-ADL (a daily activities scale), the baseline difference between groups was not statistically significant. The low-pressure group had slightly higher ADCS-ADL scores at baseline (p=0.035).
Key baseline characteristics included:
- Sex: 59% female in the full-pressure group, 64% female in the low-pressure group
- Race: 80% White, 14% Black, 4% Asian, 2% other/multiple in the full-pressure group; 82% White, 14% Black, 3% Asian, 1% other/multiple in the low-pressure group
- Hispanic ethnicity: 19% in the full-pressure group, 18% in the low-pressure group
- Cardiovascular risk: 65% low-to-medium risk and 35% high-to-very-high risk in the full-pressure group; 64% low-to-medium and 36% high-to-very-high in the low-pressure group
- Disease severity: 73% had MCI due to AD and 27% had mild AD in the full-pressure group; 72% had MCI and 28% had mild AD in the low-pressure group
- APOE ε4 carrier status: 39% carriers in the full-pressure group, 36% carriers in the low-pressure group
- Use of cognition/memory medication: 22% in each group
Baseline cognitive scores were similar between groups:
- VADAS-cog: mean 41.5 in the full-pressure group versus 40.3 in the low-pressure group
- ADAS-cog 14: mean 21.2 versus 20.6
- ADAS-cog 11: mean 14 versus 13.8
- ADCS-ADL: mean 70.5 versus 72.4
- Trail Making B: mean 159 versus 154.5
- MMSE: mean 24.5 versus 24.8
The Treatment Protocol
The study consisted of a 6-month treatment/maintenance period followed by 6 months of observation only.
During the treatment period, participants in both the low-pressure and full-pressure arms received 35 one-hour ECP treatments over 7 to 12 weeks, with 3 to 5 treatments weekly (target of 5 per week). No more than 7 days were permitted between treatments, and no more than two treatments per day were allowed.
After this initial treatment period, participants entered a twice-weekly maintenance period. The total treatment/maintenance period lasted 6 months. No study treatments were administered after this point.
ECP treatments were performed in the supine position (lying face up) on a Renew Cerezen™ ECP unit. For the full-pressure group, inflation pressure was gradually increased from zero over 5 minutes to the maximum comfortable pressure in the 150–300 mmHg range. Once the maximum comfortable pressure was determined for a given participant, that pressure was used for all subsequent treatments. The average inflation pressure for the treatment group was 240 mmHg.
The low-pressure group always had a treatment pressure of approximately 25 mmHg. To minimize potential counterpulsation effects, low-pressure group treatments were performed without synchronization to the patient's ECG (electrocardiogram, a recording of the heart's electrical activity). To make the patient experience as similar as possible between the groups, ECG leads were placed. However, the ECP unit was controlled by a hidden ECG simulator. The hidden ECG simulator had a fixed rate of 70 beats per minute.
The researchers noted an important caveat: asynchronous low-pressure compression has been correlated with physiological effects on vascular function and blood flow, autonomic output, and even cellular and gene expression changes. Therefore, the low-pressure arm was not a completely inactive control.
During the treatment phase, both groups averaged 3.7 treatments per week. Over the 6-month combined treatment/maintenance phase, participants averaged 2.58 treatments per week in the full-pressure group and 2.52 per week in the low-pressure group.
How Patients Were Assessed
Efficacy and safety assessments were performed at baseline, 6, 12, 18, and 24 weeks, and at 9 and 12 months. Assessment visits generally occurred the day following a treatment session (maximum 2 days after). A 9-month assessment was instituted partway through the study, so not all participants were assessed at 9 months.
The primary efficacy outcome was the time-averaged score of the VADAS-cog, defined as the mean of modeled values at weeks 12, 18, and 24. The VADAS-cog is a superset of the 14-item Alzheimer's Disease Assessment Scale (ADAS-cog 14) that adds 3 scales emphasizing frontal lobe function. This was used to optimize capture of vascular contributions to cognitive impairment in AD.
Secondary outcomes, also measured as time-averaged outcomes and at individual time points, included:
- Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale (ADCS-ADL)
- ADAS-cog 14
- Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale
- Trail Making B test
The Mini-Mental Status Exam (MMSE), second edition, was also performed at baseline and at 6-, 9-, and 12-month assessments. The ADCS-ADL, ADCS-CGIC, Trail Making, and Logical Memory assessments were performed by an independent third-party psychometrician (a specialist trained to administer and score cognitive tests).
Brain Imaging
Magnetic resonance imaging (MRI) was conducted at screening. The MRI ensured there was no existing exclusionary brain pathology. Exclusionary brain pathology included evidence of infection, infarction, or other focal lesions. Infarction is tissue death due to lack of blood supply. MRI was performed again at the 6-month and 1-year assessments.
Blinding
Patients and caregivers were blinded to the treatment arm, as was the independent psychometrician administering the ADL, CGIC, Trail Making, and Logical Memory assessments. The ECP operator, site study coordinator, and site principal investigator were not blinded to the treatment arm. This is because it is not possible to administer the treatment without knowing the cuff inflation pressure. The VADAS-cog, ADAS-cog 14, and MMSE assessments were therefore conducted by site staff who were not guaranteed to be blinded.
APOE ε4 Carrier Status
APOE genotype was assessed at baseline. Participants who were homozygous for ε4 (having two copies of the ε4 version of the gene) and ε4/ε3 heterozygotes (having one copy each of the ε4 and ε3 versions) were categorized as carriers. All others were classified as non-carriers.
Safety Monitoring
Safety was assessed by ongoing review of adverse events, laboratory evaluations, and vital signs. The Data Monitoring Committee reviewed safety data from the study on a biannual basis. Ad hoc meetings of the DMC could be called at any time by the DMC Chairperson or by Renew Research to review any ethical or patient safety issues. A representative from Navitas Clinical Research, independent from study operations, served as the DMC Executive Secretary.
Statistical Analysis
Analysis of study outcomes was performed on an intention-to-treat (ITT) basis, meaning all participants were analyzed according to their assigned group regardless of whether they completed the treatment. Efficacy analysis was performed, as pre-specified, on the averaged values of the 12-, 18-, and 24-week assessments (defined as the time-averaged outcomes) using both Bayesian and Frequentist statistics.
Bayesian analysis with imputation of missing data was used for the VADAS-cog, ADAS-cog 14, and ADL data to generate posterior probabilities of superiority (PPS) of full-pressure over low-pressure arms. All assessments were multiply imputed, if necessary, for missing data. For frequentist analysis of continuous outcomes with multiple time points, a mixed model repeated measures (MMRM) analysis of covariance (ANCOVA) model was used.
The researchers noted that Bayesian PPS and Frequentist p-values have different meanings and are not expected to have identical values. Broadly speaking, the p-value indicates the likelihood, given the null hypothesis (the assumption that there is no real difference between groups), that a study would randomly produce the observed data. The posterior probability is the likelihood that a study hypothesis is true given the observed data. The primary endpoint was considered met if PPS exceeded the 97.9% required for an overall one-sided Type 1 error rate of 2.5%.
Key Findings: Detailed Results
Full-pressure ECP treatment significantly improved both cognition and daily functioning compared with low-pressure sham treatment. These benefits persisted through the full 52-week assessment period, even though all treatment stopped at 6 months.
Activities of Daily Living (ADCS-ADL)
Each ADCS-ADL point indicates a change in ability or in the level of caregiver assistance required. Higher scores indicate better function.
Mean ADCS-ADL scores were similar at baseline in the full-pressure and low-pressure treatment groups (70.5 and 72.4, respectively). Time-averaged scores improved by 2.57 points (95% CI: 0.82 – 4.31) in the full-pressure group but worsened by 0.49 points in the low-pressure group (95% CI: -2.29 – +1.30).
Full-pressure treatment was superior to low-pressure treatment with a posterior probability of superiority (PPS) of 99.7% and p=0.036. This means there is less than a 4% chance that this difference was due to random chance.
Improvement over baseline persisted through the 1-year assessment. At that time, the gain from baseline in the full-pressure treatment participants was 1.6 points (95% CI: 0.01 – 3.19), compared with the low-pressure group, which had declined by 2.8 points (95% CI: -5.59 – -0.01), p=0.007.
Clinicians' Global Impression of Change (ADCS-CGIC)
The ADCS-CGIC odds ratio for improvement (full-pressure versus low-pressure group) significantly favored full-pressure treatment at the 12-, 24-, 36-, and 52-week assessments (odds ratio 2.13 to 3.12, p<0.013). The difference approached significance at 18 weeks (odds ratio 1.76, p=0.064).
An odds ratio of 2.13 to 3.12 means that clinicians rated patients in the full-pressure group as showing improvement 2 to 3 times more often than patients in the low-pressure group.
Trail Making Test B
The full-pressure group tended to improve relative to the low-pressure group in the time-averaged score. However, the difference between the two groups was statistically significant only at the 12-month time point (p=0.020).
VADAS-cog (Cognitive Function)
The full-pressure group improved the time-averaged VADAS-cog score by 9.95 points (95% CI: 7.24 – 12.67). The low-pressure group had a lesser improvement of 5.22 points (95% CI: 2.42 – 8.00). Full-pressure treatment was superior to low-pressure treatment with PPS = 99.7% (p=0.005).
Despite no ECP treatment being administered over the final 6 months, the gain over baseline persisted through the 1-year assessment. At that time, improvement from baseline in the full-pressure treatment participants was 9.0 points (95% CI: 6.20 – 11.80), compared with the low-pressure group, which improved by 3.0 points (95% CI: 0.29 – 5.71). This difference between treatment arms at 12 months was significant at p=0.002.
ADAS-cog 14 (Cognitive Function)
Full-pressure treatment was associated with improvement in the ADAS-cog 14 time-averaged score compared with the low-pressure group: 6.16 points (95% CI: 4.07 – 8.22) versus 2.74 points (95% CI: 0.52 – 4.88); PPS=99.6%; p<0.001.
As with the VADAS-cog, full-pressure treatment remained superior to low-pressure treatment at the 1-year assessment. At that time, improvement from baseline in the full-pressure treatment participants was 5.2 points (95% CI: 3.15 – 7.25), compared with the low-pressure group, which improved by 1.1 points (95% CI: -1.02 – 3.22). The difference between groups was p=0.007.
Mini-Mental Status Exam (MMSE)
The MMSE, an exploratory outcome, was assessed at baseline and at the 6-, 9-, and 12-month time points. Improvement from baseline score at 6 months was 1.68 points for the full-pressure group versus 0.19 points for the low-pressure group (p=0.005). As with the other assessments, a treatment benefit persisted through the 1-year time point (p=0.025).
Impact on Both Cognition and Function
Cognitive abilities (as reflected by the VADAS-cog) and functional ability (as reflected by the ADCS-ADL) are both important to patients. In the full-pressure group, 63% of participants had improved or stable time-averaged scores on both tests, compared with 44% of low-pressure participants (p=0.014).
Special Finding: Patients with Type 2 Diabetes
The difference between treatment arms was especially pronounced in the subgroup of participants with co-existing type 2 diabetes (n=39). In this subgroup, the full-pressure group showed a time-averaged 10.7-point VADAS-cog improvement, while the low-pressure group showed a deterioration of more than 6 points (PPS=99.9%, p=0.003).
Detailed results from this subgroup analysis will be reported separately.
Brain Imaging Findings
Baseline imaging was conducted on all participants. A portion of the sample did not have MRI at both subsequent time points due to issues related to the COVID-19 pandemic, loss to follow-up, site upgrades, or scan quality. The article notes that MRI was performed at the 6-month and 1-year assessments, but detailed imaging results were not fully reported in the main text of this article.
Safety Results
No serious device-related adverse events occurred during the study. Safety was assessed through ongoing review of adverse events, laboratory evaluations, and vital signs. The independent Data Monitoring Committee reviewed safety data on a biannual basis throughout the study.
The researchers noted that the Renew Cerezen™ ECP unit has a unique mechanism to prevent heating of the air inflating pressure cuffs. This feature is especially important for the fragile skin of elderly patients.
What These Results Mean for Patients
This study found that full-pressure ECP therapy significantly improved cognition and activities of daily living compared with sham treatment in early Alzheimer's disease. The benefits were seen across multiple measures of thinking and daily function.
Several aspects of these results are particularly noteworthy for patients and families:
- Benefits persisted after treatment stopped. Even though all ECP treatment ended at 6 months, improvements in cognition and daily function were still present at the 1-year assessment. This suggests that ECP may produce lasting changes in brain blood flow or vascular health.
- Both cognition and function improved. The treatment helped not only with memory and thinking tests but also with everyday activities like managing medications, preparing meals, and handling finances.
- Clinicians noticed the difference. The ADCS-CGIC results show that clinicians rated patients receiving full-pressure treatment as improved 2 to 3 times more often than those receiving sham treatment.
- The treatment was safe. No serious device-related adverse events occurred.
- Patients with type 2 diabetes showed particularly strong responses. This subgroup had a 10.7-point improvement in cognitive scores with full-pressure treatment versus a more than 6-point decline with sham treatment.
The researchers concluded that ECP represents a novel therapeutic approach warranting further investigation.
Limitations of the Study
Several important limitations should be considered when interpreting these results:
- The low-pressure arm was not a completely inactive control. The researchers acknowledged that asynchronous low-pressure compression has been correlated with physiological effects on vascular function, blood flow, autonomic output, and even cellular and gene expression changes. This means the comparison may underestimate the true effect of full-pressure ECP.
- Not all assessments were blinded. The ECP operator, site study coordinator, and site principal investigator knew which treatment each patient received. The VADAS-cog, ADAS-cog 14, and MMSE assessments were conducted by site staff who were not guaranteed to be blinded. This could potentially influence results.
- MRI data were incomplete. A portion of the sample did not have MRI at both follow-up time points due to COVID-19 pandemic issues, loss to follow-up, site upgrades, or scan quality problems.
- The 9-month assessment was added partway through the study. Not all participants were assessed at 9 months.
- The study population had specific characteristics. Participants were aged 55 to 85 with a clinical diagnosis of MCI or mild AD. Results may not apply to patients with moderate or severe Alzheimer's disease or to other types of dementia.
- Treatment required frequent clinic visits. The protocol involved 35 treatments over 7 to 12 weeks, followed by twice-weekly maintenance treatments for a total of 6 months. This is a significant time commitment for patients and caregivers.
Recommendations and Next Steps
Based on these results, the researchers recommend further investigation of ECP as a treatment for early Alzheimer's disease. The Renew Cerezen™ ECP device has already been certified in the European Union for the treatment of mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease.
For patients and families considering ECP therapy, several points are important:
- Discuss with your doctor. ECP is not yet approved for Alzheimer's disease in all countries. Ask your neurologist or geriatrician whether ECP might be appropriate for your specific situation.
- Understand the treatment commitment. ECP treatment requires frequent clinic visits — typically 3 to 5 sessions per week for 7 to 12 weeks, followed by twice-weekly maintenance sessions for a total of 6 months.
- Know the eligibility criteria. The study excluded patients with a history of stroke, uncontrolled epilepsy, multiple sclerosis, Parkinson's disease, cerebral hemorrhage, or cerebral aneurysm. These conditions may also affect eligibility for ECP in clinical practice.
- Ask about the specific device. The study used the Renew Cerezen™ ECP device. Other ECP devices may have different specifications and may not produce the same results.
- Monitor for benefits. If you do receive ECP treatment, your doctor may use cognitive tests and daily activity assessments to track whether the treatment is helping.
The researchers emphasize that ECP represents a novel therapeutic approach that warrants further investigation. Larger and longer studies will be needed to confirm these findings and to determine the optimal treatment protocol.
Frequently Asked Questions
What is external counterpulsation (ECP) and how is it given?
ECP is an established cardiovascular therapy. Inflatable cuffs are wrapped around the calves, thighs, and waist or buttocks. They inflate and deflate in time with the heartbeat, briefly pushing blood out of the legs. A session typically lasts one hour, and patients lie face up during treatment.
Who was eligible to take part in the ECP trial?
Participants were aged 55 to 85 with a clinical diagnosis of mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease. People were excluded if they had a history of stroke, uncontrolled epilepsy, multiple sclerosis, Parkinson's disease, cerebral hemorrhage, or cerebral aneurysm, or a major unrelated psychiatric or neurodegenerative disorder.
Did the benefits last after ECP treatment stopped?
Yes. All treatment stopped at 6 months, but improvements in cognition and daily functioning were still present at the 1-year assessment. At that point, the full-pressure group's VADAS-cog gain from baseline was 9.0 points, compared with 3.0 points in the low-pressure group, a difference significant at p=0.002.
What were the side effects or safety concerns with ECP?
No serious device-related adverse events occurred during the study. Safety was assessed through ongoing review of adverse events, laboratory evaluations, and vital signs, and an independent Data Monitoring Committee reviewed safety data twice a year. The device also has a mechanism to prevent heating of the air in the pressure cuffs.
How often are ECP treatments given, and for how long?
The protocol involved 35 one-hour treatments over 7 to 12 weeks, with 3 to 5 sessions weekly, followed by twice-weekly maintenance sessions. The total treatment and maintenance period lasted 6 months, after which no study treatments were given. This is a significant time commitment for patients and caregivers.
Is ECP approved for Alzheimer's disease, and should I ask my doctor?
ECP is not yet approved for Alzheimer's disease in all countries. The Renew Cerezen ECP device has been certified in the European Union for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease. Ask your neurologist or geriatrician whether ECP might be appropriate for your situation.
I have early Alzheimer's disease — when should I seek a second opinion about external counterpulsation (ECP) leg cuff therapy?
Seek a second opinion when ECP is proposed for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease, or when you are weighing it against your current plan. In a 190-patient randomized trial, full-pressure ECP improved VADAS-cog scores by 9.95 points versus 5.22 with sham, and daily-activity scores by 2.57 points versus a 0.49-point decline, with benefits persisting through 52 weeks. ECP is not approved for Alzheimer's disease in all countries, and the trial excluded people with prior stroke, uncontrolled epilepsy, multiple sclerosis, Parkinson's disease, cerebral hemorrhage, or cerebral aneurysm. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
Original article title: Treatment of Clinically Diagnosed Alzheimer's Disease by External Counterpulsation A Randomized Clinical Trial.
Authors: Jack E. Juni, MD; Jeffrey M. Burns, MD, MS; David H. Salat, PhD; Drew Hill, MSE; Steven Tally, PhD; Jeffrey S. Martin, PhD; Michael D. Devous, PhD; and Patrick M. Moriarty, MD
Publication: American Journal of Alzheimer's Disease & Other Dementias®, Volume 41: 1–16, © The Author(s) 2026
DOI: 10.1177/15333175261451918
Article history: Received December 30, 2025; Revised April 23, 2026; Accepted May 4, 2026
Author affiliations: Renew Research, LLC, Farmington Hills, MI, USA; University of Kansas Alzheimer's Disease Center, Kansas City, KS, USA; MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA; Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, CA, USA; Department of Basic Medical Sciences, Lincoln Memorial University, Knoxville, TN, USA; MDD Enterprises, Nogal, New Mexico, USA; University of Kansas Medical Center, Kansas City, KS, USA
Corresponding author: Jack E. Juni, MD, Medical Device Development, Renew Research, 26800 Haggerty Road, Farmington Hills, MI 48331, USA. Email: juni@stage2innovations.com
Funding and disclosures: Data Availability Statement included at the end of the original article. The article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License.
This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes only and does not constitute medical advice. Patients should consult their healthcare providers about any treatment decisions.
