Background: Observational studies in Asia show that dietary intake of soy isoflavones
had a significant inverse association with coronary heart disease (CHD). A recent randomized controlled
trial (RCT) of soy isoflavones on atherosclerosis in the US, however, failed to show their
benefit. The discrepancy may be due to the much lower prevalence of S-equol producers in Westerners:
Only 20-30% of Westerners produce S-equol in contrast to 50-70% in Asians. S-equol is a
metabolite of dietary soy isoflavone daidzein by gut microbiome and possesses the most antiatherogenic
properties among all isoflavones. Several short-duration RCTs documented that soy
isoflavones improves arterial stiffness. Accumulating evidence shows that both atherosclerosis and
arterial stiffness are positively associated with cognitive decline/dementia. Therefore, potentially,
soy isoflavones, especially S-equol, are protective against cognitive decline/dementia.
Methods/Results: This narrative review of clinical and epidemiological studies provides an overview
of the health benefits of soy isoflavones and introduces S-equol. Second, we review recent
evidence on the association of soy isoflavones and S-equol with CHD, atherosclerosis, and arterial
stiffness as well as the association of atherosclerosis and arterial stiffness with cognitive decline/
dementia. Third, we highlight recent studies that report the association of soy isoflavones and
S-equol with cognitive decline/dementia. Lastly, we discuss the future directions of clinical and
epidemiological research on the relationship of S-equol and CHD and dementia.
Conclusions: Evidence from observational studies and short-term RCTs suggests that S-equol is
anti-atherogenic and improves arterial stiffness and may prevent CHD and cognitive impairment/
dementia. Well-designed long-term (≥ 2years) RCTs should be pursued.