Treatment of Clinically Diagnosed Alzheimer’s Disease by External Counterpulsation A Randomized Clinical Trial

Abstract

Objective

To assess external counterpulsation (ECP) effects on cognitive and functional decline in early AD.

Methods

This 12-month, multicenter, blinded, randomized, sham-controlled trial enrolled 190 patients with early AD (MCI due to AD or mild AD per NIA-AA clinical criteria). Participants received either full-pressure ECP (150-300 mmHg) or sham (25 mmHg): 3-5 weekly one-hour sessions for 35 treatments, then twice-weekly through six months. Assessments occurred at baseline and weeks 6, 12, 18, 24, 36, and 52. Primary endpoints included ADCS-ADL, ADAS-cog-14, and VADAS-cog.

Results

Full-pressure ECP significantly improved ADCS-ADL scores versus sham (mean change 2.57 vs. -0.49; p=0.036) and VADAS-cog scores (9.95 vs. 5.22; p=0.005) at 12-24 weeks. Benefits persisted through 52 weeks despite treatment cessation at 6 months. No serious device-related adverse events occurred.

Conclusions

Full-pressure ECP therapy significantly improved cognition and ADL compared to sham treatment in early AD. ECP represents a novel therapeutic approach warranting further investigation.

Keywords

Alzheimer’s disease external counterpulsation mild cognitive impairment vascular therapy cognitive function activities of daily living

Introduction

The pathophysiology of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) is complex. Although research has focused on amyloid and tau protein buildup, these alone do not fully explain the clinical disease. More than simply a co-occurrence, multiple lines of evidence indicate that vascular disease, especially intra-cranial cerebrovascular disease, is intimately related to the epidemiology,^1-3 pathophysiology,^4-9 and clinical manifestation of MCI and AD.^10-12 This includes atherosclerotic vascular disease, cerebral amyloid angiopathy (CAA),^10,13 and importantly, functional changes in the neurovascular bundle and microvascular response (reactivity) to changes in demand.^6,14-18

External counterpulsation (ECP) is an impactful cardiovascular therapy used in treatment of refractory angina pectoris^19,20 and heart failure.²¹ The lower extremities are wrapped with pneumatic cuffs which are rapidly inflated, then deflated, during the diastolic period between each cardiac contraction (i.e., synchronized with the cardiac cycle). Each inflation transiently empties most blood from the legs, reversing flow in the lower aorta. Cuffs are deflated prior to the next cardiac contraction. Treatments, typically lasting an hour, dramatically increase endothelial shear stress in a manner analogous to physical exercise. This results in increased endothelial production of nitric oxide,²² improved vascular reactivity,²³ increased vascular compliance,²⁴ and increased endothelial production of various anti-inflammatory factors.^25,26 In cardiovascular disease, ECP has been shown to increase vascular collateralization.²⁷ These changes have been shown to persist for months to years after conclusion of treatment.²⁸

In addition to these generalized effects, ECP has been demonstrated to increase brain blood flow in healthy controls and in the setting of ischemic stroke.^29-31 Li et al³² found that ECP treatments improved cognition and brain perfusion in a small group of AD patients. Recently, Moriarty et al³³ found improvements in cognition and hippocampal blood flow in a pilot group of AD patients. The Renew Cerezen™ ECP device has recently been certified in the EU for treatment of mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s disease. Here, we investigate the impact of ECP on the course of patients with early AD.

Methods

It is difficult to design a placebo for ECP treatment since the physical compressions of the lower extremities are obvious to the patient. Therefore, we designed this trial as a randomized, single-blind, multi-site study evaluating the efficacy and safety of full-pressure, cardiac-cycle-synchronized treatment relative to a low-pressure, non-synchronized treatment. The study population consisted of participants aged 55-85 years with a clinical diagnosis of MCI or mild AD. Twelve study sites screened and enrolled 190 participants (Figure 2). Participants were prospectively randomized into two study arms (full-pressure ECP treatment versus low-pressure treatment) in a 1:1 ratio, stratified according to a) clinical diagnosis (MCI or AD as determined below) and b) cardiovascular risk (CVR) score³⁴ (grouped as low/medium vs. high/very high risk for future cardiac events). Randomization assignments were made using permuted blocks. Investigators received subject assignments from an Interactive Web Response System (IWRS).³⁵ Participants were not informed of their assigned treatment group.

ECP has been shown to improve glycemic control and vascular biology in participants with type 2 diabetes (T2D).³⁶ Given that AD is associated with T2D^37-40 and an increased level of cerebrovascular disease is seen in diabetic patients, the subgroup of patients with T2D was pre-specified for analysis. These results will be reported separately.

Oversight and Ethical Considerations

This 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. These criteria are presented in full in the Supplemental Data.

Key inclusion criteria.

• A clinical diagnosis consistent with published 2011 NIA-AA “core clinical criteria” guidelines for either:

i. The diagnosis of mild cognitive impairment due to Alzheimer’s disease⁴¹ or

ii. The diagnosis of dementia due to Alzheimer’s disease.⁴²

Key exclusion criteria:

• Any exclusion criterion from the NIA-AA core clinical criteria^41,42

• 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 the completion of the study.

• Active or history of cerebral hemorrhage, including subdural and subarachnoid or cerebral aneurysm.

Treatment Protocol

The study consisted of a 6-month treatment/maintenance period followed by 6-months of observation only (Supplemental Table 1). In the treatment period, participants in both low-pressure and full-pressure arms received 35 one-hour ECP treatments over 7-12 weeks, with 3-5 treatments weekly (target 5/week). No more than 7 days were permitted between treatments; no more than two treatments/day. After this treatment period, participants entered a twice-weekly-treatment maintenance period for a total treatment/maintenance period of 6 months. No study treatments were administered after this.

ECP treatments were performed in the supine position on a Renew Cerezen™ ECP unit (Figure 1). 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 subject, that pressure was used for all subsequent treatments. The average inflation pressure for the treatment group was 240 mmHg.

Figure 1.

The Renew Cerezen™ external counterpulsation (ECP) device. Pneumatic cuffs are wrapped around the calves, thighs and waist/buttocks. Using a single-channel ECG for synchronization, these cuffs are inflated and deflated between each heartbeat to expel and then readmit blood to the lower extremities. Cuffs deflate automatically if a premature contraction is detected. Inflation pressure is manually set with an available range of ∼25 to 300 mmHg. The Cerezen unit has a unique mechanism to prevent heating of the air inflating pressure cuffs, especially important for the fragile skin of elderly patients.

The low-pressure group always had a treatment pressure of ∼25 mmHg. To minimize potential counterpulsation effects, low-pressure group (only) treatments were performed without synchronization to the patient’s ECG. To make the patient experience as similar as possible between the groups, ECG leads were placed, but the ECP unit was controlled by a hidden ECG simulator with a fixed rate of 70 beats per minute. Asynchronous low-pressure compression has, however, been correlated with physiological effects on vascular function and blood flow, autonomic output, and even cellular/gene expression changes.^43-45 Thus, the low-pressure arm was not an inactive control.

Assessments

Efficacy and safety assessments were performed at baseline, 6, 12, 18 and 24 weeks, and 9 and 12 months, or upon termination of treatment as per Supplemental Table 1. Assessment visits generally occurred the day following a treatment session (maximum 2 days). 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 which we 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) which adds 3 scales emphasizing frontal lobe function.⁴⁶ This was used to optimize capture of vascular contributions to cognitive impairment in AD. Secondary outcomes, also measured as time-averaged outcomes as well as at individual time points, included the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale (ADCS-ADL), the ADAS-cog 14, the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale, and Trail Making B. The Mini-mental Status Exam (MMSE), second edition, was also performed at baseline and 6-, 9- and 12-month assessments. ADCS-ADL, ADCS-CGIC, Trail Making and Logical Memory assessments were performed by an independent 3^rd-party psychometrician.

Radiographic and Imaging Assessment

Magnetic resonance imaging (MRI) was conducted at screening to ensure there was no existing exclusionary brain pathology, including evidence of infection, infarction or other focal lesions. MRI was performed again at the 6-month and 1-year assessments. Details of MRI protocols are provided in the Supplemental data.

Blinding

Patients and caregivers were blinded to 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 PI were not blinded to treatment arm because it is not possible to administer the treatment without knowledge of the cuff inflation pressure. 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 homozygous for ϵ4 and ϵ4/ϵ3 heterozygotes were categorized as carriers; others were classified as a non-carrier.

Safety

Safety was assessed by ongoing review of adverse events, laboratory evaluations, and vital signs. The DMC 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 (Farmington Hills, MI, USA) to review any ethical or patient safety issues. A representative from Navitas Clinical Research (Rockville, MD, USA), 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. Efficacy analysis was performed, as pre-specified, on the averaged values of the 12-, 18- and 24-week assessments (which we define for convenience as the time-averaged outcomes) using both Bayesian and Frequentist statistics (further details in Supplemental Data). 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 above 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. Treatment of missing data is detailed in Supplemental Data. It should be noted that Bayesian PPS and Frequentist p-values have different meanings and are not expected to have identical values.⁴⁷ Broadly speaking, the p-value indicates the likelihood, given the null hypothesis, 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%

Results

Participants

Table 1 shows baseline characteristics of study participants. For all parameters other than ADCS-ADL, the baseline difference between full-pressure versus low-pressure groups was not statistically significant. The low-pressure group had slightly higher ADCS-ADL, p=0.035. Figure 2 shows subject screening, randomization and course through the study. The population was representative of the sex, racial and ethnic diversity of the U.S. (62% female, 14% Black, 18% Hispanic).

Table 1.

Baseline Characteristics of the Intention to Treat (ITT) Subjects

Characteristic	Full-pressure group (n = 95)	Low-pressure group (n = 95)
Age - Years	68.5 ± 7.7	68.1 ± 7.2
Sex - Number (%)
Female	56 (59%)	61 (64%)
Male	39 (41%)	34 (36%)
Race - Number (%)
Asian	4 (4%)	3 (3%)
Black	13 (14%)	13 (14%)
White	76 (80%)	78 (82%)
Other or Multiple	2 (2%)	1 (1%)
Hispanic Ethnicity - Number (%)	18 (19%)	17 (18%)
Cardiovascular Risk Score - Number (%)
Low to Medium Risk	62 (65%)	61 (64%)
High to Very High Risk	33 (35%)	34 (36%)
Disease Severity - Number (%)
Mild Cognitive Impairment due to Alzheimer’s Disease	69 (73%)	68 (72%)
Mild Alzheimer’s Disease	26 (27%)	27 (28%)
APOE status - Number (%)
ε4 carrier	37 (39%)	34 (36%)
Non-Carrier	58 (61%)	58 (61%)
Use of Cognition/Memory Medicationa - Number (%)	21 (22%)	21 (22%)
VADAS-cog Baseline Scoreb
Mean	41.5 ± 16.0	40.3 ± 13.6
Range	14 to 82.33	21.67 to 83.33
ADAS-Cog 14 Baseline Scorec
Mean	21.2 ± 12.7	20.6 ± 11.0
Range	1.33 to 55.33	5 to 55.33
ADAS-Cog 11 Baseline Scored
Mean	14 ± 9.4	13.8 ± 8.2
Range	1.33 to 41.33	2 to 40.33
ADCS-ADL Baseline Scoree
Mean	70.5 ± 6.9	72.4 ± 5.5
Range	52 to 78	57 to 78
Trail Making B Baseline Score^‡‡
Mean	159 ± 92.3	154.5 ± 88.7
Range	35 to 300	35 to 300
MMSE Baseline Score^††
Mean	24.5 ± 3.9	24.8 ± 3.9
Range	13 to 30	12 to 30

Plus-minus values are mean ± Standard Deviation. APOE means apolipoprotein E.

For all parameters other than ADCS-ADL, the baseline difference between full-pressure versus low-pressure groups was not statistically significant. For ADCS-ADL, p=0.035.

^aUse of Cognition/Memory Medication was based on patients' reported medication list.

^bThe Vascular Dementia Assessment Scale cognitive subscale (VADAS-cog) has scores that range from 0 to 120, with a higher number indicating greater impairment.

^cThe 14-subtest version of the Alzheimer’s Disease Assessment Scale-Cognitive subtest (ADAS-cog 14) has scores that range from 0 to 90, with a higher number indicating greater impairment.

^dThe 11-subtest version of the Alzheimer’s Disease Assessment Scale-Cognitive subtest (ADAS-cog 11) has scores that range from 0 to 70, with a higher number indicating greater impairment.

^eThe Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) has scores that range from 0 to 78, with a lower number indicating greater impairment.

‡‡The Trail Making B test has scores that range from 0 to 300, with a higher number indicating greater impairment.

††The Mini–Mental State Examination (MMSE) has scores that range from 0 to 30, with a lower number indicating greater impairment.

Figure 2.

Patient enrollment, randomization and course

Enrollment, treatment and assessment spanned 11/2018 – 3/2021. During the treatment phase, both full- and low-pressure groups averaged 3.7 treatments/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.

Outcome Results

Figure 3 summarizes changes in key outcomes over the course of the study.

Blinded Outcomes

Activities of Daily Living (ADCS-ADL)

Each ADCS-ADL point indicates a change in ability or in level of caregiver assistance required. Higher scores indicate better function. Mean ADCS-ADL scores were similar at baseline in full- and low-pressure treatment groups (70.5 and 72.4, respectively). Time-averaged scores improved by 2.57 (95% CI: 0.82 – 4.31) in the full-pressure group but worsened by 0.49 in the low-pressure group (95% CI: -2.29 – +1.30). Full-pressure treatment was superior to low-pressure with PPS=99.7%, p=0.036 (Figure 3B). Improvement over baseline persisted through the 1-year assessment at which time gain from baseline in the full-pressure treatment participants was 1.6 (95% CI: 0.01 – 3.19) compared to the low-pressure group which had declined at -2.8 (95% CI: -5.59 – -0.01), p=0.007.

Figure 3.

Key Study Outcomes. All plots show the complete ITT population. Blue points represent the full-pressure group; orange represents low-pressure group. Whiskers show standard error of the mean. Values under plots indicate # patients assessed at each timepoint. Shaded area is time of treatment/maintenance. No treatment was given after this. For each plot, scores are plotted such that improved function is at the top, declining function at the bottom of the plot. (A) Change in VADAS-cog from baseline assessment. VADAS-cog is a superset of the ADAS-cog 14 with 3 added scales emphasizing frontal lobe function. Scores range 0-120, higher indicating greater impairment. Plot is oriented so improvement is at the top. (B) Change in ADCS-ADL from baseline. Scores can range from 0-78, with lower indicating greater impairment. A 1-point change indicates a change in the level of caregiver assistance required. (C) Change in ADAS-cog 14 from baseline assessment. Scores can range from 0-90, with higher indicating greater impairment. Plot is oriented so improvement is at the top. *Published lecanemab placebo and treatment group data are shown in green, as adapted from van Dyck et al.⁴⁸ Note that the lecanemab trial data were acquired in a different study and population and are solely for context. (D) Change in Trail Making B from baseline assessment. Scores can range from 0-300, with higher indicating greater impairment. Plot is oriented so improvement is at the top. (E) Change in MMSE from baseline assessment. Scores can range from 0-30, with lower indicating greater impairment

Clinicians’ Global Impression of Change (ADCS-CGIC)

As shown in Figure 4, the ADCS-CGIC odds ratio for improvement (full-pressure vs. low-pressure group) significantly (p<0.013) favored full-pressure treatment at 12-, 24-, 36- and 52-week assessments (OR 2.13 – 3.12) and approached significance at 18 weeks (OR 1.76, p=0.064).

Figure 4.

Clinician’s Global Impression of Change (ADCS-CGIC) Pre-specified logistic regression model for the common proportional odds ratio and significance tests for ADCS-CGIC. Overall, the odds ratios significantly favor full-pressure treatment

Trail Making Test B

Although the full-pressure group tended to improve relative to the low-pressure group in the time-averaged score (Figure 3D), the difference between the two groups was statistically significant only at the 12-month time point (p=0.020).

Unblinded Outcomes

VADAS-Cog

The full-pressure group improved (Figure 3A) the time-averaged score by 9.95 points (95% CI: 7.24 – 12.67). The low-pressure group had a lesser improvement of 5.22 (95% CI: 2.42 – 8.00). Full-pressure treatment was superior to low-pressure with PPS = 99.7% (p=0.005). Despite no ECP treatment being administered over the final 6 months, gain over baseline persisted through the 1-year assessment at which time improvement from baseline in the full-pressure treatment participants was 9.0 (95% CI: 6.20 – 11.80) compared to the low-pressure group which improved by 3.0 (95% CI: 0.29 – 5.71). This difference between treatment arms at 12 months was significant at p=0.002.

The difference between treatment arms was especially pronounced in the subgroup of participants with co-existing type 2 diabetes (n=39) with a time-averaged 10.7-point VADAS-cog improvement in the full-pressure group versus a >6-point deterioration in the low-pressure group (PPS=99.9%, p=0.003). Detailed results from this subgroup analysis will be reported separately.

ADAS-Cog 14

Full-pressure treatment was associated with improvement in ADAS-cog 14 time-averaged score as compared to the low-pressure group (6.16 points (95% CI: 4.07 – 8.22) vs 2.74 (95% CI: 0.52 – 4.88); PPS=99.6%; p<0.001). As with VADAS-cog, full-pressure treatment remained superior to low-pressure treatment at the 1-year assessment at which time improvement from baseline in the full-pressure treatment participants was 5.2 (95% CI: 3.15 – 7.25) compared to the low-pressure group which improved by 1.1 (95% CI: -1.02 – 3.22); difference between groups p=0.007 (Figure 3C).

Mini-Mental Status Exam

MMSE, an exploratory outcome, was assessed at baseline and at the 6, 9 and 12-month time-points (Figure 3E). Improvement from baseline score at 6 months was 1.68 points for the full-pressure group versus 0.19 for the low-pressure group (p=0.005). As with the other assessments reported above, 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 ADCS-ADL) are both important to patients. 63% of full-pressure vs. 44% of low-pressure participants (p=0.014) had improved or stable time-averaged scores in both tests (Supplemental table 4).

MRI Findings

Baseline imaging was conducted on all participants. A portion of the sample did not have MRI at both subsequent timepoints due to issues related to the COVID-19 pandemic, loss to follow-up, site upgrades or scan quality limitations. However, 98% (167/170) of subjects who completed the treatment/maintenance phase had either a 6-month and/or 1-year follow-up MRI. Relative to baseline MRI, no evidence of brain edema or hemorrhage was noted on the follow-up scans.

Other Factors

No significant influence of APOE ϵ4 carrier status, age, sex, race, or ethnicity was seen on ADCS-ADL, VADAS-cog or ADAS-cog 14 (see Supplemental Data).

Adverse events

The 190 study participants received a total of 10,644 treatments, averaging 56 treatments each, over the 6-month treatment/maintenance phase of the study. No treatments were administered during the second 6 months. Thirty adverse events (AEs) that were probably/suspected to be related to the device were experienced in 22 participants (11.6%), none of which were serious. The most common AE probably/suspected to be related to the device was mild skin irritation/injury, with 22 AEs in 16 participants. This occurred only in the full-pressure group, corresponding to an AE rate of 16.8% (16/95) per subject and 0.29% (16/5,453) per treatment. Due to the device mechanism of action and past clinical experience, skin AEs were anticipated and were resolved by minor adjustments (e.g., slight changes to the location of the compression cuffs). There were no study discontinuations or treatment withdrawals due to AEs. No safety signals were detected in the safety laboratory results, vitals, or physical findings related to the device.

Since amyloid is not a specific target of ECP, there was no expectation that ECP would promote amyloid-related imaging abnormalities (ARIA) as have been seen in trials using anti–amyloid beta (Aβ) immunotherapies for AD, thus this was not a specified outcome in this trial. It is noted that sequential MRI imaging identified no evidence of ARIA such as cerebral edema or new intra-cerebral hemorrhages or other new findings during the course of therapy. One patient in the low-pressure group developed a non-fatal intra-cerebral hemorrhage 1 month after their last ECP treatment. This was determined to not be treatment-related.

Discussion

An accumulating body of evidence indicates that vascular disease plays a meaningful role in the pathophysiology of AD and related dementias (ADRD) and represents a target for therapeutic intervention. The current study demonstrates that ECP, a vascular intervention, had notable and sustained effects on cognition and activities of daily living.

We evaluated the efficacy of two levels of ECP therapy, standard counterpulsation (full-pressure, cardiac-synchronized) versus low-pressure, unsynchronized pulsations, in patients with clinically diagnosed MCI and mild AD. The low-pressure treatments were designed so as to minimize vascular effects to the extent possible. Relative to the low-pressure group, the full-pressure group showed significant improvements in VADAS/ADAS-cog, ADCS-ADL, MMSE and CGIC. Both cognitive and functional improvements or stabilization (not just slowing of decline) were observed in most patients. In the full-pressure arm, 84% improved cognitive function (VADAS-cog) over baseline at the time-averaged efficacy assessment. This benefit persisted at one year, i.e., six months after the last ECP treatment, with 75% remaining improved over baseline. A benefit was also seen in activities of daily living where 58% of full-pressure patients improved time-averaged ADCS-ADL scores over baseline; 47% remained improved at 1-year. Further, at the 1-year assessment, 57% of full-pressure ECP patients had either improved over baseline or remained stable in both cognition and function (VADAS-cog and ADCS-ADL). Similarly, improvements were seen in CGIC, ADAS-cog 14, and MMSE. To our knowledge, this is the first demonstration of a therapy causing an actual improvement over baseline in cognitive and functional abilities in this population.

Potential Placebo or Practice Effect

The low-pressure treatment group also showed a treatment benefit by some, but not other, measures. This benefit was significantly less than that of the full-pressure treatment – both statistically and clinically. Although a component of placebo and/or practice effects in these data cannot be excluded, the significantly greater response in the full-pressure arm indicates a treatment benefit for at least those patients. If one considers cuff-inflation pressure as the treatment dose, the fact that a higher dose has a significantly greater effect than a lower dose is supportive of the therapeutic benefit of the treatment.

Role of Vascular Disease/Dysfunction and Cerebral Blood Flow in Alzheimer’s Disease

Vascular disease, especially intra-cranial cerebrovascular disease, is intimately related to the epidemiology, etiology and clinical manifestation of MCI due to AD and of AD.^11,17,49-51 Of patients with pathology-verified AD, nearly 80% have atherosclerotic cerebrovascular disease.^50,52 As many as 90% of AD patients also have cerebral amyloid angiopathy.⁵³ It has been demonstrated that concurrent vascular disease is a major determinant of the clinical manifestation of dementia in patients proven to have AD at autopsy. A given level of AD neurodegenerative pathology is associated with greater cognitive deficit if cerebrovascular disease is present than if it is absent.^12,50 This may not only worsen but also play a mechanistic role in the development of cognitive decline and dementia in patients with AD.⁹

Cerebral blood flow (CBF) has long been known to be reduced in AD.^2,54-57 Cerebrovascular resistance to blood flow is increased as much as 4 years before significant amyloid accumulation.⁵⁸ Regional cerebral blood flow may be reduced by as much as 50%,⁵⁸ well within the range known to impair mental function.^56,59 Key components of reduced CBF in AD are capillary vasoconstriction by pericytes (contractile cells surrounding brain capillaries) and impaired vascular reactivity to changes in metabolic demand.⁶ Arterial wall stiffness also plays a role.⁶⁰ Brain ischemia has been shown to produce Aβ^61-63 which in turn reduces perfusion.⁶⁴ Further, Aβ oligomers induce pericyte constriction of brain capillaries,⁶⁵ reducing perfusion and impeding clearance of Aβ from the interstitial fluid. Thus, small-vessel vascular disease and amyloid accumulation are intricately tied together in a vicious cycle, the so-called 2-hit phenomenon.^{8,16,17,66,67} Rabin et al⁶⁸ found that the vascular burden of CAA interacted with Aβ load to promote cognitive decline via tau deposition.

ECP has a well-documented impact on CBF. Many studies have demonstrated improved carotid and cerebral blood flow with ECP.^29-31,69-71 ECP increases shear stress at the carotid arteries^31,72 and likely at intra-cranial vessels. Importantly, Guluma et al³⁰ showed that even fairly low pressures of ECP increase CBF. ECP dramatically increases vascular endothelial shear stress in a manner analogous to physical exercise^31,72,73 leading to reduced intimal hyperplasia,⁷⁴ improved vascular reactivity^23,73,75-77 and improved tissue perfusion systemically.^24,27,28,78 ECP has been demonstrated to improve vascular compliance²⁴ and to increase endothelial nitric oxide synthase (eNOS) activity.^22,79,80 Nitric oxide, produced by eNOS, is an important mediator of vascular reactivity and protects neurons from tau phosphorylation.^81,82 In the setting of coronary atherosclerosis, ECP has been shown to increase vascular collateralization.²⁷ Inflammation likely plays an important role in AD⁸³ and ECP has been shown to reduce inflammatory cytokines^25,26,84

The reactivity of the cerebral microvasculature to changes in metabolic demand has emerged as an important pathophysiologic component of MCI⁸⁵ and AD.^6,14,86,87 Although not yet measured specifically in the brain, ECP has been demonstrated to improve vascular reactivity systemically^23,75,76 and to ameliorate the downregulation of eNOS associated with endothelial dysfunction.^22,73,79,80

With its demonstrated effects on vascular endothelial shear stress, compliance, reactivity and inflammation as well as atherosclerosis and T2D and the documented increases in cerebral blood flow, ECP addresses the pathophysiology of AD at multiple points. This study provides evidence that ECP can produce an improvement over baseline in cognitive and functional abilities in this population.

Potential Limitations of This Study

Patient Selection

In many recent AD drug trials, patients have been screened for amyloid pathology, typically with PET scans. Such screening is appropriate for therapies aimed at removing amyloid. The current study, however, evaluates a new type of treatment which is not targeted directly at amyloid. Although measurements of Aβ and other biomarkers improve the accuracy of diagnosing AD, these technologies are only starting to make their way into clinical practice. We chose to identify eligible participants for this study based on the NIA-AA core clinical criteria for AD⁴² or MCI due to AD,⁴¹ widely used in the community care setting. Based on current literature^88,89 it is likely that a fraction of our patients were amyloid-negative.

Impact of Patient Population on Study Relevance

The use of clinical criteria for diagnosis inevitably means that some study participants would not have elevated brain amyloid levels. Inclusion of potentially amyloid-negative patients yields a more heterogeneous patient group but does not reduce the clinical relevance of this study. Given the current limited access to amyloid PET and plasma biomarkers, there is a substantial population of clinically diagnosed early AD patients that will not have access to therapies that require evidence of amyloid pathology. A therapy such as ECP with a mechanism of action not dependent on clearing amyloid could substantially widen access to therapeutic options for many such patients. Amyloid-negative patients with Alzheimer’s phenotype may be an important group for future research.

Given that, as discussed above, at least 80% of AD patients have concurrent macrovascular disease and 80-90% have microvascular disease such as CAA, the great majority of all cases of sporadic AD can reasonably be considered “mixed dementia”. As discussed above, in addition to the presence of both macro- and microvascular disease, vascular reactivity and endothelial function have been consistently shown to be abnormal in AD. Sporadic AD without vascular disease or dysfunction, i.e., “pure AD”, is in fact relatively uncommon. From a mechanistic point of view, it is ideal for a study population to have a single, discrete pathology. However, from the perspective of a clinical therapeutic trial, it is important to clearly identify a patient population in a manner reproducible in the field and to demonstrate therapeutic efficacy in that group. This study has followed that approach. Although the exact percentage of this study population with “true” or “pure” AD is not known, the inclusion criteria for that population were explicitly stated and are consistent with community-based practice, thus allowing identification of comparable future patients.

Relevance of a Vascular Treatment to Alzheimer’s Disease

ECP is a vascular treatment. Is it possible that this study only demonstrates successful treatment of vascular dementia, not AD? As discussed above, the overwhelming majority of AD patients have macrovascular disease, small-vessel disease, impaired capillary vasodilatory response and reduced cerebral blood flow. The relative contribution of these factors to other known pathologies such as amyloid β and tau proteins is a matter of ongoing research. Whether vascular factors are causative, secondary or very common comorbidities, it is not unreasonable to suppose that treatment may influence cognition. This study does not attempt to break down either the specific mechanism of improvement in individual patients, nor to determine whether the treatment influenced the “essential nature” of AD or simply its overt clinical manifestations.

Impact of Patient Selection on Relevance to Community-Based Practice

The use of core clinical criteria for enrollment impacts the number of patients seen in a clinical setting for whom the results of this study would be applicable and who might, therefore, be considered eligible for ECP treatment. Applying the lecanemab pivotal trial’s inclusion/exclusion criteria⁴⁸ to the Mayo Study of Aging population of mild AD patients, Pittock et al⁹⁰ found that only 8% would have been eligible. Although the current study involved different patients, 69.6% of those screened qualified for ECP treatment. These are complicated issues, but ECP would likely be applicable to a much larger percentage of typical early AD patient populations than currently approved anti-amyloid therapies.

Blinding

ADCS-ADL, ADCS-CGIC and Trail Making Test B were performed by psychometricians blinded to treatment status and treatment arm. These tests showed substantial treatment benefit (Figure 3). VADAS-cog/ADAS-cog 14 and MMSE also showed treatment benefit but were conducted by site staff who were not necessarily blinded and thus were potentially susceptible to tester bias. There was, however, a good, although non-linear, correlation between ADL and VADAS-cog (See Supplemental Data Figure 1). Most important, the blinded and unblinded tests all showed similar findings, a clear improvement of the full-pressure group relative to baseline performance and superiority of full-pressure over low-pressure treatment. For most parameters, the low-pressure group also improved, but less so. This conclusion is the same if only the blinded tests are considered.

Practice Effect

Some authors^91,92 have noted a practice or learning effect in ADAS-cog scores measured repeatedly in AD patients, although the magnitude of the observed effect differs between studies. While a practice effect cannot be excluded in the current study, the full-pressure group showed significantly better outcomes than the low-pressure group, despite the same exposure to study testing.

Conclusion

This study evaluated ECP treatment in a clinically diagnosed population. Compared to each individual’s baseline, external counterpulsation significantly improved multiple measures of cognition (VADAS, ADAS-cog 14, MMSE), activities of daily living (ADCS-ADL) and overall clinical assessment (CGIC) with minimal adverse events. For the majority of patients, the observed changes represented improvements over baseline rather than simply a slowing of the rate of decline. Treatment response was evident to at least one year (6 months after last ECP treatment). The benefit/risk profile is highly favorable, particularly compared to that of presently approved Alzheimer’s disease therapies. The success of this treatment emphasizes the important role of the vascular system in clinical AD. ECP is a promising treatment for this otherwise devastating disease. It might also be explored as a potential complement to anti-amyloid treatments.

Supplemental Material

Supplemental Material - Treatment of Clinically Diagnosed Alzheimer’s Disease by External Counterpulsation A Randomized Clinical Trial

Supplemental Material for Treatment of Clinically Diagnosed Alzheimer’s Disease by External Counterpulsation A Randomized Clinical Trial by Jack E. Juni, Jeffrey M. Burns, David H. Salat, Drew Hill, Steven Tally, Jeffrey S. Martin, Michael D. Devous and Patrick M. Moriarty in American Journal of Alzheimer’s Disease & Other Dementias®.

Supplemental Material

Supplemental Material - Treatment of Clinically Diagnosed Alzheimer’s Disease by External Counterpulsation A Randomized Clinical Trial

Footnotes

Acknowledgements

We thank the study participants, their families and caregivers – without them, this study would not have been possible. Thanks are extended to the clinical site coordinators. Thanks are also extended to team at Navitas Clinical Research for contributions at many levels. Special thanks are given to Jonathan Helfgott for his work in managing the clinical phase of the study and Thomas Moreno for initial data analysis.

ORCID iD

Jeffrey S. Martin

Author Contributions

Dr. Juni had full access to the study data and takes responsibility for the integrity of the data and accuracy of the data analysis. Drs. Moriarty, Burns and Juni contributed to the study conceptualization. Dr. Juni prepared the original draft manuscript. All authors made substantial contributions to the methodology, acquisition, analysis and/or interpretation of the data, critically reviewed and edited the manuscript for intellectual content, approved the final version to be published, and are accountable for all aspects of the work.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for this study was provided by Renew Research.

Declaration of Conflicting Interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Juni is an employee of Renew Research. Dr. Moriarty reports research support or consulting relationships with Regeneron, Amgen, Esperion, Kaneka, Novartis, Vascular Health Foundation, Ionis, FH Foundation, Aegerion, Merck and Renew Research. Dr. Burns has received research support from the NIH, research support to conduct clinical trials (paid to institution) from Eli Lilly, Amylyx, Biogen, AbbVie, Astra-Zeneca, and Roche, and has served as a consultant for Renew Research, Eisai, Eli Lilly, Labcorp, Renew Biotechnologies, and New Amsterdam Pharma. Dr. Salat reports Support from Niji Corporation. Mr. Hill is an employee of Renew Research. Dr. Tally is part of a group (UC San Diego Health Services Research Center) that conducts sponsor-initiated research for Renew Research but receives no personal funding for consulting or other activities. Dr. Martin was a paid consultant for Renew Research at the initiation of the trial, but currently holds no interest in the company and was not compensated for contributions to the manuscript. Dr. Devous was a paid consultant for Renew Research after the conclusion of the trial. He has or has had consulting relationships with Eli Lilly, Cognoptix, Life Molecular Imaging, Novoic and Positrigo. He was not involved in the collection or initial analyses of the data.

Data Availability Statement

The data supporting the findings of this study are available within the article and/or its supplemental material.*

Article information

This study was registered at ClinicalTrials.gov (NCT03721705).

Group Information

The study investigators are listed in the Supplemental Data.

Role of the Funder/Sponsor

Renew Research was responsible for design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.

Supplemental Material

Supplemental material for this article is available online.

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