Background: Evidence from observational studies and short-duration randomized controlled trials (RCTs) suggests that equol, a gut-derived metabolite of soy isoflavone daidzein, may confer cognitive benefits through efficient blood-brain barrier permeability, high selective affinity to the estrogen receptor-beta, and anti-atherogenic properties. Only 20-30% of Westerners possess the ability to convert daidzein to equol as compared to 50-70% of East Asians. Cross-sectional studies conducted in Japan reported that equol producers exhibit fewer white matter lesions (WMLs) and better cognition. However, it is unclear whether equol or the equol producer phenotype as a surrogate for certain microbiome composition or both may protect against dementia. Objective: To delineate the effect of equol and equol producers by testing whether equol producers have fewer WMLs and better cognitive function than non-producers in an older population with very low soy consumption. Methods: The Arterial Stiffness, Equol, and Cognition (ACE) trial (NCT05741060) recruited dementia-free infrequent soy consumers aged 65-85 to test whether equol supplementation can slow the progression of arterial stiffness, WMLs, and cognitive impairment. This analysis included 362 ACE participants (mean age 72.0 ± 4.7 years; 52% female; 21% African American) who underwent brain magnetic resonance imaging (MRI) scans and NIH Toolbox Cognitive Battery assessments. Equol producer phenotype was defined as the urinary equol-to-daidzein ratio (log10 ≥ -1.75) after a three-day soy challenge. Associations of equol producer phenotype with WMLs normalized to total intracranial volume (WML%) and cognitive tests were assessed using gamma-distributed generalized linear regression and linear regression adjusting for demographics, APOE-e4 status, and cardiovascular risk factors. Results: 30% of the participants were equol producers (Table 1). There is no statistically significant difference in WML% (Table 2) or cognitive performance (Table 3) between equol producers and non-producers. Conclusions: Among infrequent soy consumers, equol producer phenotype is not associated with WMLs or cognitive performance. Without soy intake, equol producers do not show a similar cognitive advantage as observed in East Asians. The results suggest that equol is critical for the cognitive benefits.
Li et al. (Tue,) studied this question.