A Phase 2 interventional study of S-equol and Placebo in Arterial Stiffness, White Matter Lesions and Cognitive Decline, sponsored by Akira Sekikawa. Active, not recruiting at 3 sites in United States. Open to participants aged 65 Years to 85 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-08-20.
Sponsored by Akira Sekikawa · Phase 2, Interventional, and Prevention
The ACE Trial, funded by the National Institute on Ageing/National Institutes of Health (NIH), is a multicenter clinical trial. The ACE Trial will determine if taking the dietary supplement Equol could slow the progression of stiffening of the arteries, small blood vessel disease in the brain and memory decline. Equol is a soy-based supplement that has plant estrogen-like compounds in it.
Equol is a metabolite of soy isoflavone. Our studies in Japan and other studies suggest that Equol may slow mechanisms related to memory decline. No previous studies in the United States have tested the effect of Equol on these mechanisms or memory decline. Supplementation of Equol in the ACE Trial is approved by the Food and Drug Administration (FDA).
Researchers at the University of Pittsburgh, Pittsburgh, Pennsylvania, Wake Forest University, Winston-Salem, North Carolina, and Emory University, Atlanta, Georgia, are recruiting participants.
The ACE Trial will ask participants to complete 7 clinic visits over a two-year period. The participants are asked to take Equol tablets daily for 24 months. Clinic procedures include Pulse Wave Velocity (to measure arterial stiffness), Magnetic Resonance Imaging (MRI) of the brain and tests of awareness and thinking.
The ACE trial is an early-stage multi-center randomized controlled trial (RCT) designed to test the effect of a 24-month intervention of 10 mg/day equol supplementation on arterial stiffness, white matter lesions (WMLs) in the brain and cognitive decline among 400 individuals aged 65 and 85 without dementia. Recent studies in Japan reported that a diet high in soy and soy isoflavones is inversely associated with incident cognitive impairment and dementia. The Women's Isoflavone Soy Health (WISH) in the US, an RCT of soy isoflavones, however, showed no significant effect on cognition. We posit that the discrepant result is due to the difference in equol-producing capability. Equol, a metabolite of soy isoflavone daidzein transformed by the gut microbiome, is the most bioactive among all soy isoflavones and their metabolites. 50-70% of Japanese convert daidzein to equol in contrast to 20-30% of Americans. Arterial stiffness, a significant predictor of cognitive decline, is significantly improved in a short-duration RCT of 10 mg/day equol supplementation in middle-aged subjects. WMLs are a risk factor for age-related cognitive decline and dementia. We reported a longitudinal association of equol-producing status with WML% (WML volume normalized to total brain volume) in cognitively normal elderly in Japan. The subgroup analysis of WISH showed that equol producers had better cognition than the control group, suggesting that equol may slow cognitive decline. No previous study has tested the effect of equol supplementation on arterial stiffness, WMLs or cognitive decline in older adults.
3,843 studies on the registry are indexed under Cognitive Dysfunction; 1,100 are open to participants now.
This study's enrollment of 369 is above the median of 65 across 2,808 interventional studies indexed under Cognitive Dysfunction.
Browse Cognitive Dysfunction studies →This is the only study on the registry with Akira Sekikawa as lead sponsor.
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Inclusion Criteria:
Men and women age between 65 and 85 at entry of European Americans or African Americans
Inclusion criteria via screening visit:
Exclusion Criteria:
Exclusion criteria via initial screening by phone
Exclusion criteria via screening visit
In addition, individuals with the following condition will be excluded because these conditions do not allow subjects to undergo examinations the investigators proposed in the project:
Exclusion criteria at structural brain MRI Any other conditions which, in the opinion of the investigator, might pose a risk to the participant or make participation in the study not in the participant's best interest
*1 Few studies have investigated the association of equol, a metabolite of soy isoflavone daidzein, with breast cancer. These studies reported no significant association of serum or urine equol with the risk of breast cancer. Dietary intake of soy and soy isoflavones is generally considered to have benefits for menopausal symptoms, cardiovascular health, bone health, and cancers of the breast and prostate. Observational studies show that soy consumption is associated with a reduced risk of many cancers including breast cancer. Moreover, a prospective cohort study of 6,000+ North American women with breast cancer showed that dietary intake of soy and isoflavones was associated with reduced all-cause mortality. However, there is little evidence to support that the use of supplements containing soy isoflavones or soy protein powder to reduce cancer risk. A recent large prospective cohort study in France reported that supplementation of soy isoflavones increased the risk of estrogen receptor-negative breast cancer, especially among women who had a history of breast cancer in first-degree relatives.
Exclusion criteria at the baseline visit
The investigators recruit subjects without dementia. Thus, at the initial screening by phone, the investigators exclude individuals whose score for the Telephone Interview for Cognitive Status is 22 and below. Then, at the screening visit, investigators will exclude individuals with a Quick Dementia Rating System score ≥ 6.0.
S-equol - 10 mg per day tablet for 24 months.
Drug: S-equol
10 mg per day for 24 months of tablets that will be of the same size/shape/color as the experimental tablet.
Drug: Placebo
Experimental drug
Also known as: Equelle
Placebo - 10 mg per day for 24 months of tablets that will be the same size/shape/color as the s-equol tablets.
Change in arterial stiffness
Arterial stiffness describes the rigidity of the arterial wall and is a significant predictor of cognitive decline. Arterial stiffness will be measured by pulse wave velocity (m/s) with a SphygmoCor device (Sydney, Australia). The range of pulse wave velocity is from 5 to 20 m/s.
Time frame: Change from baseline in arterial stiffness at 12 months
Change in arterial stiffness
Arterial stiffness describes the rigidity of the arterial wall and is a significant predictor of cognitive decline. Arterial stiffness will be measured by pulse wave velocity (m/s) with a SphygmoCor device (Sydney, Australia). The range of pulse wave velocity is from 5 to 20 m/s.
Time frame: Change from baseline in arterial stiffness at 24 months
Change in white matter lesion (WML) volume percent
WMLs are a significant predictor of cognitive decline. WMLs will be measured using an automated brain magnetic resonance imaging method. WML volume percent will be calculated by dividing WML volume by total brain volume as a percentage. The range of WML volume percent is from 0 to 4.2%.
Time frame: Change from baseline in WML volume percent at 24 months
Change in cognitive score measured by the Preclinical Alzheimer's Cognitive Composite-5 (PACC-5) score
The PACC-5 is a composite neuropsychological measure optimized to detect subtle changes over time in cognitively unimpaired older adults. The range of PACC-5 score is from -3 to 3.
Time frame: Change from baseline in cognitive score measured by the PACC-5 at 12 months
Change in cognitive score measured by the Preclinical Alzheimer's Cognitive Composite-5 (PACC-5) score.
The PACC-5 is a composite neuropsychological measure optimized to detect subtle changes over time in cognitively unimpaired older adults. The range of PACC-5 score is from -3 to 3 where 3 represents better cognition.
Time frame: Change from baseline in cognitive score measured by the PACC-5 at 24 months
Change in NIH Toolbox (NIH-TB) cognition battery score
NIH-TB Cognition battery, comprised of computerized tests of fluid and crystallized cognitive abilities, via proctored iPad administration.
Time frame: Change from baseline in NIH-TB cognition battery score at 12 months
Change in NIH Toolbox (NIH-TB) cognition battery score
NIH-TB Cognition battery, comprised of computerized tests of fluid and crystallized cognitive abilities, via proctored iPad administration.
Time frame: Change from baseline in NIH-TB cognition battery score at 24 months
Changes in select brain markers other than white matter lesion (WML) volume percent
Brain markers other than WML volume percent will be measured using MRI, including cerebral blood flow, venous oxygenation, white matter organization lacunar infarct and cortical thickness.
Time frame: Change from baseline in brain markers other than WML volume percent at 24 months
Change in ultrasound measurements of carotid artery
Ultrasound measurements of carotid artery include carotid plaque and intima-media thickness. Investigators will use a high-resolution ultrasound system equipped with a variable frequency transducer (NextGen LOGIQ\*e R7).
Time frame: Change from baseline in ultrasound measurements of carotid artery at 24 months
Change in select plasma biomarkers
Plasma biomarkers of inflammation and endothelial function (C-reactive protein, intracellular adhesion molecule, vascular cell adhesion molecule, glial fibrillary acidic protein, neurofilament light) as well as amyloid-β40, amyloid-β42 and phosphorylated tau 181 will be measured.
Time frame: Change from baseline in select plasma biomarkers at 24 months
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — The Center for Clinical Trial \& Data Coordination (CCDC), University of Pittsburgh, has rich experience as the Data Core (DC) for other NIH-funded studies, in reporting to and providing final datasets for an NIH Central Data Repository. The final dataset(s) will include demographic and clinical data at baseline, study arm assignment, and all primary and secondary outcomes for the ACE trial. The final dataset(s) will be completely de-identified. These data will be released to an NIH Central Data Repository no later than 1 year after the end of the clinical activity (final patient follow-up, etc.) or immediately after the main paper of the trial has been published, whichever comes first. The files available will include original copies of the case report forms, a detailed codebook of variable names, value labels, formats, missing data reports, and linkage files for samples. The analytic dataset may also include derived variables that were created during the analytic process.
Supporting information: Study protocol, Sap, Icf
This study is active, not recruiting, as verified in Aug 2026. You cannot join it, but the record below documents what was studied.
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