Arterial Stiffness, Cognition, and Equol (ACE)

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Project Summary/Abstract This application, “Arterial stiffness, Cognition and Equol (ACE),” is an early stage randomized controlled trial (RCT) designed to test the effect of a 24-month intervention of 10 mg/day equol supplementation on cognitive decline, arterial stiffness, and white matter lesions (WMLs) among 400 individuals aged 70+ without dementia. Recent studies in Japan reported that a diet high in soy and soy isoflavones (ISFs) is inversely associated with incident cognitive impairment and dementia. The Women’s Isoflavone Soy Health (WISH) in the US, an RCT of ISFs, however, showed no significant effect of ISFs on cognition. We posit that the discrepant result is due to the difference in equol-producing capability. Equol, a metabolite of an ISF daidzein transformed by the gut microbiome, is most bioactive among all ISFs and their metabolites. 50-70% of Japanese convert daidzein to equol in contrast to 20-30% of Americans. The subgroup analysis of WISH showed that equol producers had better cognition than the control group, suggesting that equol may slow cognitive decline. In addition, 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. Finally, 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. Serum equol levels were measured using samples collected and stored 6-9 years before the imaging study; 50% were non-equol producers and equol producers were divided into two groups (high and low). Non-equol producers had >100% greater WML% than high producers, suggesting that supplementation of equol may slow the progression of WMLs. No previous study has tested the effect of equol supplementation on cognitive decline, arterial stiffness or WMLs in older adults. We hypothesize that supplementation of 10 mg/day equol will significantly slows both cognitive decline (primary outcome), and the progression of arterial stiffness and WML% (secondary outcomes). The overall impact of our trial will be to determine the role of equol supplementation in improving cognitive and cerebrovascular outcomes in older adults. Should a positive signal be identified in this early-stage trial, it would not only lead to a phase 3 trial to test a hypothesis that equol supplementation reduces risk for cognitive impairment and dementia but also to an RCT of a diet rich in ISFs between equol producers and non-producers, moving toward a precision health strategy.