{"product_id":"leg-cuff-therapy-improves-thinking-and-daily-function-in-early-alzheimers-disease-results-of-a-190-patient-randomized-trial","title":"Leg Cuff Therapy Improves Thinking and Daily Function in Early Alzheimer's Disease: Results of a 190-Patient Randomized Trial","description":"\u003cp\u003eIn a 12-month randomized trial, 190 patients with early Alzheimer's disease received treatment. Full-pressure external counterpulsation (ECP) is a device treatment that inflates cuffs on the legs in time with the heartbeat. Full-pressure ECP improved both thinking skills and daily functioning compared with a low-pressure sham treatment. Patients receiving full-pressure ECP improved their VADAS-cog cognitive score by 9.95 points on average. Patients receiving sham improved their VADAS-cog cognitive score by 5.22 points on average (p=0.005). Their daily-activity score improved by 2.57 points with full-pressure ECP. Their daily-activity score 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.\u003c\/p\u003e\n\n\u003ch1\u003eLeg Cuff Therapy Improves Thinking and Daily Function in Early Alzheimer's Disease: Results of a 190-Patient Randomized Trial\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why Blood Vessels Matter in Alzheimer's Disease\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#what-is-ecp\"\u003eWhat Is External Counterpulsation (ECP)?\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#study-methods\"\u003eHow the Study Was Conducted\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#who-participated\"\u003eWho Participated in the Study\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#treatment-protocol\"\u003eThe Treatment Protocol\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#assessments\"\u003eHow Patients Were Assessed\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#key-findings\"\u003eKey Findings: Detailed Results\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#diabetes-subgroup\"\u003eSpecial Finding: Patients with Type 2 Diabetes\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#mri\"\u003eBrain Imaging Findings\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#safety\"\u003eSafety Results\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#clinical-implications\"\u003eWhat These Results Mean for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of the Study\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations and Next Steps\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eIn 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.\u003c\/li\u003e\n\u003cli\u003eThe VADAS-cog cognitive score improved by 9.95 points on average with full-pressure ECP versus 5.22 points with sham (p=0.005).\u003c\/li\u003e\n\u003cli\u003eDaily-activity scores improved by 2.57 points with full-pressure ECP but declined by 0.49 points with sham (p=0.036).\u003c\/li\u003e\n\u003cli\u003eBenefits persisted through the full 52 weeks even though all treatment stopped at 6 months, and no serious device-related adverse events occurred.\u003c\/li\u003e\n\u003cli\u003eThe study excluded people with a history of stroke, uncontrolled epilepsy, multiple sclerosis, Parkinson's disease, cerebral hemorrhage, or cerebral aneurysm.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why Blood Vessels Matter in Alzheimer's Disease\u003c\/h2\u003e\n\n\u003cp\u003eAlzheimer'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.\u003c\/p\u003e\n\n\u003cp\u003eA 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.\u003c\/p\u003e\n\n\u003cp\u003eThis includes several specific types of blood vessel problems:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAtherosclerotic vascular disease\u003c\/strong\u003e — hardening and narrowing of arteries due to fatty deposits\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eCerebral amyloid angiopathy (CAA)\u003c\/strong\u003e — a condition where amyloid protein builds up in the walls of blood vessels in the brain, making them fragile\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eFunctional changes in the neurovascular bundle\u003c\/strong\u003e — the close partnership between nerve cells and the blood vessels that supply them\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eImpaired microvascular reactivity\u003c\/strong\u003e — the inability of tiny blood vessels to widen or narrow appropriately when the brain needs more blood flow\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThese 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.\u003c\/p\u003e\n\n\u003ch2 id=\"what-is-ecp\"\u003eWhat Is External Counterpulsation (ECP)?\u003c\/h2\u003e\n\n\u003cp\u003eExternal counterpulsation (ECP) is an established cardiovascular therapy. Doctors already use ECP to treat \u003cstrong\u003erefractory angina pectoris\u003c\/strong\u003e (chest pain that does not respond to standard treatments) and \u003cstrong\u003eheart failure\u003c\/strong\u003e.\u003c\/p\u003e\n\n\u003cp\u003eHere 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).\u003c\/p\u003e\n\n\u003cp\u003eEach 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.\u003c\/p\u003e\n\n\u003cp\u003eThis process dramatically increases \u003cstrong\u003eendothelial shear stress\u003c\/strong\u003e — 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:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eIncreased production of \u003cstrong\u003enitric oxide\u003c\/strong\u003e by the endothelium (the inner lining of blood vessels). Nitric oxide helps blood vessels relax and widen.\u003c\/li\u003e\n  \u003cli\u003eImproved vascular reactivity (blood vessels respond better to the body's signals)\u003c\/li\u003e\n  \u003cli\u003eIncreased vascular compliance (blood vessels become more flexible)\u003c\/li\u003e\n  \u003cli\u003eIncreased production of anti-inflammatory factors by the endothelium\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eIn patients with cardiovascular disease, ECP has been shown to increase \u003cstrong\u003evascular collateralization\u003c\/strong\u003e — 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.\u003c\/p\u003e\n\n\u003cp\u003eBeyond 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.\u003c\/p\u003e\n\n\u003cp\u003eTwo 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.\u003c\/p\u003e\n\n\u003cp\u003eThe 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.\u003c\/p\u003e\n\n\u003ch2 id=\"study-methods\"\u003eHow the Study Was Conducted\u003c\/h2\u003e\n\n\u003cp\u003eDesigning 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 \u003cstrong\u003erandomized, single-blind, multi-site study\u003c\/strong\u003e. The trial evaluated the efficacy and safety of full-pressure, cardiac-cycle-synchronized treatment compared with a low-pressure, non-synchronized treatment.\u003c\/p\u003e\n\n\u003cp\u003eThe 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.\u003c\/p\u003e\n\n\u003cp\u003eParticipants were prospectively randomized into two study arms in a 1:1 ratio:\u003c\/p\u003e\n\n\u003col\u003e\n  \u003cli\u003e\n\u003cstrong\u003eFull-pressure ECP treatment\u003c\/strong\u003e (active treatment)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLow-pressure treatment\u003c\/strong\u003e (sham\/control treatment)\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eRandomization was \u003cstrong\u003estratified\u003c\/strong\u003e (balanced) according to two factors:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eClinical diagnosis (MCI or AD)\u003c\/li\u003e\n  \u003cli\u003eCardiovascular risk (CVR) score — grouped as low\/medium risk versus high\/very high risk for future cardiac events\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eRandomization 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.\u003c\/p\u003e\n\n\u003cp\u003eThe 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.\u003c\/p\u003e\n\n\u003ch3\u003eOversight and Ethical Considerations\u003c\/h3\u003e\n\n\u003cp\u003eThe 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.\u003c\/p\u003e\n\n\u003cp\u003eWritten 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).\u003c\/p\u003e\n\n\u003ch3\u003eEligibility Criteria\u003c\/h3\u003e\n\n\u003cp\u003eThe 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.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eKey inclusion criteria:\u003c\/strong\u003e\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eA clinical diagnosis consistent with published 2011 NIA-AA \"core clinical criteria\" guidelines for either:\n    \u003cul\u003e\n      \u003cli\u003eMild cognitive impairment due to Alzheimer's disease, or\u003c\/li\u003e\n      \u003cli\u003eDementia due to Alzheimer's disease\u003c\/li\u003e\n    \u003c\/ul\u003e\n  \u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003e\u003cstrong\u003eKey exclusion criteria:\u003c\/strong\u003e\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eAny exclusion criterion from the NIA-AA core clinical criteria\u003c\/li\u003e\n  \u003cli\u003eMajor confounding neurodegenerative or psychiatric disorder unrelated to the condition under study, including:\n    \u003cul\u003e\n      \u003cli\u003eHistory of clinically evident stroke\u003c\/li\u003e\n      \u003cli\u003eCurrent uncontrolled epileptic seizures or epilepsy\u003c\/li\u003e\n      \u003cli\u003eMultiple sclerosis or Parkinson's disease\u003c\/li\u003e\n      \u003cli\u003eCurrent clinically significant major psychiatric disorder that could impair completion of the study\u003c\/li\u003e\n    \u003c\/ul\u003e\n  \u003c\/li\u003e\n  \u003cli\u003eActive or history of cerebral hemorrhage (bleeding in the brain), including subdural and subarachnoid hemorrhage or cerebral aneurysm\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"who-participated\"\u003eWho Participated in the Study\u003c\/h2\u003e\n\n\u003cp\u003eThe 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.\u003c\/p\u003e\n\n\u003cp\u003eBaseline 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).\u003c\/p\u003e\n\n\u003cp\u003eKey baseline characteristics included:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eSex:\u003c\/strong\u003e 59% female in the full-pressure group, 64% female in the low-pressure group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eRace:\u003c\/strong\u003e 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\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eHispanic ethnicity:\u003c\/strong\u003e 19% in the full-pressure group, 18% in the low-pressure group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eCardiovascular risk:\u003c\/strong\u003e 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\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eDisease severity:\u003c\/strong\u003e 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\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAPOE ε4 carrier status:\u003c\/strong\u003e 39% carriers in the full-pressure group, 36% carriers in the low-pressure group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eUse of cognition\/memory medication:\u003c\/strong\u003e 22% in each group\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eBaseline cognitive scores were similar between groups:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eVADAS-cog:\u003c\/strong\u003e mean 41.5 in the full-pressure group versus 40.3 in the low-pressure group\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eADAS-cog 14:\u003c\/strong\u003e mean 21.2 versus 20.6\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eADAS-cog 11:\u003c\/strong\u003e mean 14 versus 13.8\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eADCS-ADL:\u003c\/strong\u003e mean 70.5 versus 72.4\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eTrail Making B:\u003c\/strong\u003e mean 159 versus 154.5\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMMSE:\u003c\/strong\u003e mean 24.5 versus 24.8\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"treatment-protocol\"\u003eThe Treatment Protocol\u003c\/h2\u003e\n\n\u003cp\u003eThe study consisted of a 6-month treatment\/maintenance period followed by 6 months of observation only.\u003c\/p\u003e\n\n\u003cp\u003eDuring 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.\u003c\/p\u003e\n\n\u003cp\u003eAfter 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.\u003c\/p\u003e\n\n\u003cp\u003eECP 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.\u003c\/p\u003e\n\n\u003cp\u003eThe 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.\u003c\/p\u003e\n\n\u003cp\u003eThe 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.\u003c\/p\u003e\n\n\u003cp\u003eDuring 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.\u003c\/p\u003e\n\n\u003ch2 id=\"assessments\"\u003eHow Patients Were Assessed\u003c\/h2\u003e\n\n\u003cp\u003eEfficacy 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.\u003c\/p\u003e\n\n\u003cp\u003eThe \u003cstrong\u003eprimary efficacy outcome\u003c\/strong\u003e 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.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eSecondary outcomes\u003c\/strong\u003e, also measured as time-averaged outcomes and at individual time points, included:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003eAlzheimer's Disease Cooperative Study–Activities of Daily Living Scale (ADCS-ADL)\u003c\/li\u003e\n  \u003cli\u003eADAS-cog 14\u003c\/li\u003e\n  \u003cli\u003eAlzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale\u003c\/li\u003e\n  \u003cli\u003eTrail Making B test\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe 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).\u003c\/p\u003e\n\n\u003ch3\u003eBrain Imaging\u003c\/h3\u003e\n\n\u003cp\u003eMagnetic 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.\u003c\/p\u003e\n\n\u003ch3\u003eBlinding\u003c\/h3\u003e\n\n\u003cp\u003ePatients 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.\u003c\/p\u003e\n\n\u003ch3\u003eAPOE ε4 Carrier Status\u003c\/h3\u003e\n\n\u003cp\u003eAPOE 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.\u003c\/p\u003e\n\n\u003ch3\u003eSafety Monitoring\u003c\/h3\u003e\n\n\u003cp\u003eSafety 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.\u003c\/p\u003e\n\n\u003ch3\u003eStatistical Analysis\u003c\/h3\u003e\n\n\u003cp\u003eAnalysis of study outcomes was performed on an \u003cstrong\u003eintention-to-treat (ITT)\u003c\/strong\u003e 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.\u003c\/p\u003e\n\n\u003cp\u003eBayesian 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.\u003c\/p\u003e\n\n\u003cp\u003eThe 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%.\u003c\/p\u003e\n\n\u003ch2 id=\"key-findings\"\u003eKey Findings: Detailed Results\u003c\/h2\u003e\n\n\u003cp\u003eFull-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.\u003c\/p\u003e\n\n\u003ch3\u003eActivities of Daily Living (ADCS-ADL)\u003c\/h3\u003e\n\n\u003cp\u003eEach ADCS-ADL point indicates a change in ability or in the level of caregiver assistance required. Higher scores indicate better function.\u003c\/p\u003e\n\n\u003cp\u003eMean 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).\u003c\/p\u003e\n\n\u003cp\u003eFull-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.\u003c\/p\u003e\n\n\u003cp\u003eImprovement 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.\u003c\/p\u003e\n\n\u003ch3\u003eClinicians' Global Impression of Change (ADCS-CGIC)\u003c\/h3\u003e\n\n\u003cp\u003eThe 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\u0026lt;0.013). The difference approached significance at 18 weeks (odds ratio 1.76, p=0.064).\u003c\/p\u003e\n\n\u003cp\u003eAn 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.\u003c\/p\u003e\n\n\u003ch3\u003eTrail Making Test B\u003c\/h3\u003e\n\n\u003cp\u003eThe 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).\u003c\/p\u003e\n\n\u003ch3\u003eVADAS-cog (Cognitive Function)\u003c\/h3\u003e\n\n\u003cp\u003eThe 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).\u003c\/p\u003e\n\n\u003cp\u003eDespite 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.\u003c\/p\u003e\n\n\u003ch3\u003eADAS-cog 14 (Cognitive Function)\u003c\/h3\u003e\n\n\u003cp\u003eFull-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\u0026lt;0.001.\u003c\/p\u003e\n\n\u003cp\u003eAs 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.\u003c\/p\u003e\n\n\u003ch3\u003eMini-Mental Status Exam (MMSE)\u003c\/h3\u003e\n\n\u003cp\u003eThe 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).\u003c\/p\u003e\n\n\u003ch3\u003eImpact on Both Cognition and Function\u003c\/h3\u003e\n\n\u003cp\u003eCognitive 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).\u003c\/p\u003e\n\n\u003ch2 id=\"diabetes-subgroup\"\u003eSpecial Finding: Patients with Type 2 Diabetes\u003c\/h2\u003e\n\n\u003cp\u003eThe 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).\u003c\/p\u003e\n\n\u003cp\u003eDetailed results from this subgroup analysis will be reported separately.\u003c\/p\u003e\n\n\u003ch2 id=\"mri\"\u003eBrain Imaging Findings\u003c\/h2\u003e\n\n\u003cp\u003eBaseline 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.\u003c\/p\u003e\n\n\u003ch2 id=\"safety\"\u003eSafety Results\u003c\/h2\u003e\n\n\u003cp\u003eNo 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.\u003c\/p\u003e\n\n\u003cp\u003eThe 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.\u003c\/p\u003e\n\n\u003ch2 id=\"clinical-implications\"\u003eWhat These Results Mean for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThis 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.\u003c\/p\u003e\n\n\u003cp\u003eSeveral aspects of these results are particularly noteworthy for patients and families:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eBenefits persisted after treatment stopped.\u003c\/strong\u003e 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.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eBoth cognition and function improved.\u003c\/strong\u003e The treatment helped not only with memory and thinking tests but also with everyday activities like managing medications, preparing meals, and handling finances.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eClinicians noticed the difference.\u003c\/strong\u003e 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.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eThe treatment was safe.\u003c\/strong\u003e No serious device-related adverse events occurred.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePatients with type 2 diabetes showed particularly strong responses.\u003c\/strong\u003e 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.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe researchers concluded that ECP represents a novel therapeutic approach warranting further investigation.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of the Study\u003c\/h2\u003e\n\n\u003cp\u003eSeveral important limitations should be considered when interpreting these results:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eThe low-pressure arm was not a completely inactive control.\u003c\/strong\u003e 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.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eNot all assessments were blinded.\u003c\/strong\u003e 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.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMRI data were incomplete.\u003c\/strong\u003e 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.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eThe 9-month assessment was added partway through the study.\u003c\/strong\u003e Not all participants were assessed at 9 months.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eThe study population had specific characteristics.\u003c\/strong\u003e 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.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eTreatment required frequent clinic visits.\u003c\/strong\u003e 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.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations and Next Steps\u003c\/h2\u003e\n\n\u003cp\u003eBased 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.\u003c\/p\u003e\n\n\u003cp\u003eFor patients and families considering ECP therapy, several points are important:\u003c\/p\u003e\n\n\u003col\u003e\n  \u003cli\u003e\n\u003cstrong\u003eDiscuss with your doctor.\u003c\/strong\u003e 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.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eUnderstand the treatment commitment.\u003c\/strong\u003e 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.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eKnow the eligibility criteria.\u003c\/strong\u003e 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.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAsk about the specific device.\u003c\/strong\u003e The study used the Renew Cerezen™ ECP device. Other ECP devices may have different specifications and may not produce the same results.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMonitor for benefits.\u003c\/strong\u003e If you do receive ECP treatment, your doctor may use cognitive tests and daily activity assessments to track whether the treatment is helping.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThe 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.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is external counterpulsation (ECP) and how is it given?\u003c\/h3\u003e\n\u003cp\u003eECP 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.\u003c\/p\u003e\n\u003ch3\u003eWho was eligible to take part in the ECP trial?\u003c\/h3\u003e\n\u003cp\u003eParticipants 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.\u003c\/p\u003e\n\u003ch3\u003eDid the benefits last after ECP treatment stopped?\u003c\/h3\u003e\n\u003cp\u003eYes. 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.\u003c\/p\u003e\n\u003ch3\u003eWhat were the side effects or safety concerns with ECP?\u003c\/h3\u003e\n\u003cp\u003eNo 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.\u003c\/p\u003e\n\u003ch3\u003eHow often are ECP treatments given, and for how long?\u003c\/h3\u003e\n\u003cp\u003eThe 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.\u003c\/p\u003e\n\u003ch3\u003eIs ECP approved for Alzheimer's disease, and should I ask my doctor?\u003c\/h3\u003e\n\u003cp\u003eECP 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.\u003c\/p\u003e\n\u003ch3\u003eI have early Alzheimer's disease — when should I seek a second opinion about external counterpulsation (ECP) leg cuff therapy?\u003c\/h3\u003e\n\u003cp\u003eSeek 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.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Treatment of Clinically Diagnosed Alzheimer's Disease by External Counterpulsation A Randomized Clinical Trial.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e 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\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e American Journal of Alzheimer's Disease \u0026amp; Other Dementias®, Volume 41: 1–16, © The Author(s) 2026\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e 10.1177\/15333175261451918\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eArticle history:\u003c\/strong\u003e Received December 30, 2025; Revised April 23, 2026; Accepted May 4, 2026\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor affiliations:\u003c\/strong\u003e 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\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eCorresponding author:\u003c\/strong\u003e Jack E. Juni, MD, Medical Device Development, Renew Research, 26800 Haggerty Road, Farmington Hills, MI 48331, USA. Email: juni@stage2innovations.com\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding and disclosures:\u003c\/strong\u003e 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.\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis 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.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47807385862300,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/0599\/5449\/5644\/files\/ddn-medical-article-leg-cuff-therapy-improves-thinking-and-daily-function-in-early-alzheimers-disease-results-of-a-190-patient-randomized-tr-hero.png?v=1792819307","url":"https:\/\/diagnosticdetectives.com\/de\/products\/leg-cuff-therapy-improves-thinking-and-daily-function-in-early-alzheimers-disease-results-of-a-190-patient-randomized-trial","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}