It has been demonstrated that animals bred on a life-long soy-based nutrition will stay more alert than animals never exposed to soy. Discontinuation of soy deteriorates the cognitive functions of the previously supplemented animals (Lund et al. 2001). The positive results of Lund et al. (2001) seemed to be restricted to female animals. However, other research groups found corresponding effects also in male animals: a 16-week supplementation of isoflavones led to an improvement of the visual memory of elderly male rats (Lee et al. 2004).
The findings from experimental studies point towards protective effects of the isoflavones on functions of the central nervous system (CNS). In addition to the improvement of cognitive functions, isoflavones were shown to protect from ischemic tissue lesions in apoplexy – an effect which has not only been related to the activation of the estrogen receptor beta (ER-β), but also to the inhibition of the enzyme tyrosine kinase by isoflavones. Isoflavones possess – experimentally confirmed – antioxidative and neuroprotective effects, they improve microcirculation and have a regulatory influence on different neurotransmitter systems (Lee et al. 2005).
The relationship with ER-β
The effects demonstrated with isoflavones are related to the hormonal protective system activated via ER-β. ER-β has been evidenced in various regions of the CNS, and it obviously plays an important role in the regulation of cognitive functions. E.g., ER-β is particularly abundant in the hippocampus, and thus in a brain region related to verbal memory (Duffy et al. 2003; Kritz-Silverstein et al. 2003; Thorp et al. 2009). ER-β is also expressed in brain areas held responsible for cognitive processes and mood.
Whereas formerly it was thought that the ER-α system has nerve-protecting effects (Nilsen et al. 2000), there is today ample evidence demonstrating that it is not ER-α, but ER-β which plays a paramount role in the protection of neural cells from degenerative disorders (Carswell et al. 2004; Sampei et al. 2000). Estrogen still improves the cognitive functions in ER-α knock-out animals still producing ER-β receptors. The contrary, however, is not observed: the cognitive functions of animals possessing ER-α, but not ER-β, are not positively influenced by estrogen (Fugger et al. 1998; Fugger et al. 2000; Rissman et al. 2002). In addition, the same protection by activation of ER-β can also be achieved with the isoflavone genistein – a known ER-β-selective natural compound (Linford and Dorsa 2002).
Zhao et al. (2009) performed a range of comparative analyses of the estrogen receptor alpha/beta binding profile, and in vitro to in vivo estrogenic activities in neural and uterine tissues induced by clinically relevant phyto-estrogens: genistein, daidzein, equol, and IBSO03569, when used alone or in combination. The combination of genistein plus daidzein plus equol resulted in the greatest binding selectivity for ER-β and an overall improved efficacy/safety profile when compared with single or other combined formulations, including:
- An approximate 30% increase in ER-β-binding selectivity (83-fold over ER-α);
- A greater effect on neuronal survival against the impact of neurotoxins;
- An enhanced activity in promoting defense mechanisms against neurodegeneration, including mitochondrial function and beta-amyloid degradation; and
- No effect on uterine growth.
Zhao et al. (2009) suggest that such observations speak in favour of a therapeutic potential of combined isoflavones as an alternative approach to conventional estrogen therapy for long-term safe use to reduce the increased risk of cognitive decline and neurodegenerative disease associated with menopause in women (Zhao et al. 2009).
Clinical studies and observations
Observations of an improvement of mental abilities of humans under the impact of soy are seemingly contradictory. In fact, however, there are obvious reasons for negative study outcomes when the study designs are more closely examined.
E.g, one of the first epidemiologic studies on soy and mental performance stated that soy does not act positively in males – it would rather act quite negatively on memory functions: high consumption of tofu correlated with a lower brain mass and a worse memory (White et al. 2000). By taking a closer look at the study details this conclusion becomes, however, quite questionable. E.g., the information of tofu consumption of the spouses did not come from the wives themselves, but from their husbands, and the indications were taken from a questionnaire dating back 20 years, which assessed the nutritional habits or the previous years. Under such circumstances valid data on soy consumption cannot be assembled.
In contrast to the findings of White et al. (2000), other authors observed an improved cognitive performance in women and in men. In a case-control study 27 students were given 100 mg of isoflavones for 10 weeks. Improvements were found for short and long term memory, and for mental flexibility (File et al. 2001). This improvement came unexpected, as all study participants were young and mentally healthy. The same phenomenon was also observed in postmenopausal healthy women in the “SOPHIA” study. These women took 110 mg isoflavones daily for six months. As compared with controls without soy intake , the supplementation of isoflavones improved the verbal memory (Kritz-Silverstein et al. 2003). An improvement of the visual memory and the ability to plan ahead was found when soy isoflavones were supplemented to postmenopausal women in a double-blind trial conducted with 35 women receiving either a soy preparation with 60 mg isoflavones daily or placebo for the duration of 12 weeks (Duffy et al. 2003).
Another double-blind study could not confirm these results: In this placebo-controlled trial, 202 healthy post-menopausal women received either soy protein with 99 mg isoflavones daily or milk protein. After one year of supplementation no group difference was found regarding cognitive functions (Kreijkamp-Kaspers et al. 2004). The authors speculated that treatment duration might have been too short to induce a statistically significant difference in regenerative effects due to the relative high age of the patients (65 years and older).
A double-blind trial in cross-over design with placebo-control was performed in 2006. Each patient subsequently received both treatments, soy isoflavones and placebo, for the duration of six months each, in random order. In the 78 supplemented postmenopausal women the dose of 60 mg of isoflavones improved the mood and cognitive performance (Casini et al. 2006).
Fournier et al. (2007) investigated whether soy isoflavones (soy milk and supplement) could improve cognitive functioning in healthy, postmenopausal women. A total of 79 postmenopausal women, 48-65 years of age, completed a double-blind, placebo-controlled trial in which they were randomly assigned to one of three experimental groups: cow's milk and a placebo supplement (control); soy milk and placebo supplement (soy milk, 72 mg isoflavones/day); or cow's milk and isoflavone supplement (isoflavone supplement, 70 mg isoflavones/day). In this study, soy isoflavones ingested over a 16-week period did not improve or appreciably affect cognitive functioning in healthy, postmenopausal women (Fournier et al. 2007).
Similar results were obtained in a 6-month double-blind, randomized, placebo-controlled, parallel group trial examining the effects of 80 mg of soy isoflavones on cognitive performance and quality of life in 176 Chinese postmenopausal women. No difference between groups was found (Ho et al. 2007). However, the study was performed in a population which already had life-long exposure to soy isoflavones, which is not normally the case in European populations.
A paradoxical result was presented in a study in 719 Javanese and Sundanese elderly, where high tofu consumption was associated with worse memory (p < 0.01; 95% CI = -0.34 to -0.06), whereas tempeh consumption was related to better memory (p < 0.05, 95% CI = 0.00-0.28), particularly in participants over 68 years of age (Hogervorst et al. 2008). The authors speculate that the high folate levels in tempeh might have had protective effects, whereas the isoflavones would act like estrogen, and therefore have a negative impact on memory. This latter hypothesis has, however, long since been disproved.
The opposite hypothesis is used by another study: Here, the authors link estrogen to an improvement of memory, and hypothesize on similar effects of isoflavones as “phyto-estrogens”. In a trial in 28 young women supplemented with dietary isoflavones an improvement of cognitive functions was observed. The women were tested on three different occasions: Once during a menses and thus in a low-estrogenic situation, one during a luteal phase (high estrogenic situation), and once during a menses after a three-day supplementation phase with a soy preparation. During the high estrogen-phase verbal, but not working memory was improved when compared to the low-estrogen phase. As isoflavones improved both, working and verbal memory, the authors postulate estrogen-independent mechanisms of action (Islam et al. 2008).
A double-blind, randomised, placebo-controlled, 12-week trial was performed in 84 healthy postmenopausal women. Participants were randomly assigned to receive 20 g of soy protein containing 160 mg of total isoflavones (n = 38) vs. milk protein (n = 46), both provided in the form of a powder to be mixed with beverages. Whereas there was a significant improvement in quality of life scales (vasomotor, psychosexual, physical, and sexual) among the women taking isoflavones (but not with placebo), no significant changes in cognition were observed (Basaria et al. 2009).
A 12-week double-blind, placebo-controlled cross-over trial was conducted in thirty-four healthy men to investigate the effect of isoflavone supplementation on cognitive function. Volunteers were randomised to take four capsules/d containing soy isoflavones (116 mg/d: 68 mg daidzein, 12 mg genistein, 36 mg glycitein) or placebo for 6 weeks, and the alternate treatment during the following 6 weeks. Assessments of memory (verbal episodic, auditory and working), executive function (planning, attention, and mental flexibility) and visual-spatial processing were performed at baseline and after each treatment period. Isoflavone supplementation significantly improved spatial working memory (p = 0.01). Isoflavones did not affect auditory and episodic memory or visual-spatial processing. Isoflavone supplementation in healthy males may enhance cognitive processes which appear dependent on estrogen activation (Thorp et al. 2009).
In a randomised, placebo-controlled, double-blind pilot study, non-demented elderly subjects ingested either 100 mg/day soy isoflavones (glycoside weight) or matching placebo tablets for 6 months. Plasma levels of genistein and daidzein (p < 0.001), but not the levels of equol, increased with isoflavone administration. While similar at baseline, the two groups differed across 6 months of treatment on 8 of 11 cognitive tests administered. The data support the potential cognitive effects of soy isoflavones in older adults (Gleason et al. 2009).
Conclusions
Although the results from the clinical trials were mixed, the overall data point to potential moderate benefits of a regular dietary intake of isoflavones for memory and cognitive functions – benefits which add to other favourable effects such as an improvement of menopausal complaints or bone-mineral density. The study results are supported by mechanistic studies in vitro and in vivo.
References
Basaria, S., Wisniewski, A., Dupree, K., Bruno, T., Song, M. Y., Yao, F., Ojumu, A., John, M., and Dobs, A. S. (2009). Effect of high-dose isoflavones on cognition, quality of life, androgens, and lipoprotein in post-menopausal women. J. Endocrinol. Invest 32 (2): 150-155.
Carswell, H. V., Macrae, I. M., Gallagher, L., Harrop, E., and Horsburgh, K. J. (2004). Neuroprotection by a selective estrogen receptor beta agonist in a mouse model of global ischemia. Am J. Physiol Heart Circ. Physiol 287 (4): H1501-H1504.
Casini, M. L., Marelli, G., Papaleo, E., Ferrari, A., D'Ambrosio, F., and Unfer, V. (2006). Psychological assessment of the effects of treatment with phytoestrogens on postmenopausal women: a randomized, double-blind, crossover, placebo-controlled study. Fertil. Steril. 85 (4): 972-978.
Duffy, R., Wiseman, H., and File, S. E. (2003). Improved cognitive function in postmenopausal women after 12 weeks of consumption of a soya extract containing isoflavones. Pharmacol. Biochem. Behav. 75 (3): 721-729.
File, S. E., Jarrett, N., Fluck, E., Duffy, R., Casey, K., and Wiseman, H. (2001). Eating soya improves human memory. Psychopharmacology (Berl) 157 (4): 430-436.
Fournier, L. R., Ryan Borchers, T. A., Robison, L. M., Wiediger, M., Park, J. S., Chew, B. P., McGuire, M. K., Sclar, D. A., Skaer, T. L., and Beerman, K. A. (2007). The effects of soy milk and isoflavone supplements on cognitive performance in healthy, postmenopausal women. J. Nutr. Health Aging 11 (2): 155-164.
Fugger, H. N., Cunningham, S. G., Rissman, E. F., and Foster, T. C. (1998). Sex differences in the activational effect of ERalpha on spatial learning. Horm. Behav. 34 (2): 163-170.
Fugger, H. N., Foster, T. C., Gustafsson, J., and Rissman, E. F. (2000). Novel effects of estradiol and estrogen receptor alpha and beta on cognitive function. Brain Res. 883 (2): 258-264.
Gleason, C. E., Carlsson, C. M., Barnet, J. H., Meade, S. A., Setchell, K. D., Atwood, C. S., Johnson, S. C., Ries, M. L., and Asthana, S. (2009). A preliminary study of the safety, feasibility and cognitive efficacy of soy isoflavone supplements in older men and women. Age Ageing 38 (1): 86-93.
Ho, S. C., Chan, A. S., Ho, Y. P., So, E. K., Sham, A., Zee, B., and Woo, J. L. (2007). Effects of soy isoflavone supplementation on cognitive function in Chinese postmenopausal women: a double-blind, randomized, controlled trial. Menopause 14 (3 Pt 1): 489-499.
Hogervorst, E., Sadjimim, T., Yesufu, A., Kreager, P., and Rahardjo, T. B. (2008). High Tofu Intake Is Associated with Worse Memory in Elderly Indonesian Men and Women. Dement. Geriatr. Cogn Disord. 26 (1): 50-57.
Islam, F., Sparkes, C., Roodenrys, S., and Astheimer, L. (2008). Short-term changes in endogenous estrogen levels and consumption of soy isoflavones affect working and verbal memory in young adult females. Nutr. Neurosci. 11 (6): 251-262.
Kreijkamp-Kaspers, S., Kok, L., Grobbee, D. E., de Haan, E. H., Aleman, A., Lampe, J. W., and van der Schouw, Y. T. (2004). Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized controlled trial. JAMA 292 (1): 65-74.
Kritz-Silverstein, D., Von Muhlen, D., Barrett-Connor, E., and Bressel, M. A. (2003). Isoflavones and cognitive function in older women: the SOy and Postmenopausal Health In Aging (SOPHIA) Study. Menopause 10 (3): 196-202.
Lee, Y. B., Lee, H. J., and Sohn, H. S. (2005). Soy isoflavones and cognitive function. J. Nutr. Biochem. 16 (11): 641-649.
Lee, Y. B., Lee, H. J., Won, M. H., Hwang, I. K., Kang, T. C., Lee, J. Y., Nam, S. Y., Kim, K. S., Kim, E., Cheon, S. H., and Sohn, H. S. (2004). Soy isoflavones improve spatial delayed matching-to-place performance and reduce cholinergic neuron loss in elderly male rats. J. Nutr. 134 (7): 1827-1831.
Linford, N. J. and Dorsa, D. M. (2002). 17beta-Estradiol and the phytoestrogen genistein attenuate neuronal apoptosis induced by the endoplasmic reticulum calcium-ATPase inhibitor thapsigargin. Steroids 67 (13-14): 1029-1040.
Lund, T. D., West, T. W., Tian, L. Y., Bu, L. H., Simmons, D. L., Setchell, K. D., Adlercreutz, H., and Lephart, E. D. (2001). Visual spatial memory is enhanced in female rats (but inhibited in males) by dietary soy phytoestrogens. BMC Neurosci. 2: 20
Nilsen, J., Mor, G., and Naftolin, F. (2000). Estrogen-regulated developmental neuronal apoptosis is determined by estrogen receptor subtype and the Fas/Fas ligand system. J. Neurobiol. 43 (1): 64-78.
Rissman, E. F., Heck, A. L., Leonard, J. E., Shupnik, M. A., and Gustafsson, J. A. (2002). Disruption of estrogen receptor beta gene impairs spatial learning in female mice. Proc Natl. Acad. Sci. U. S A 99 (6): 3996-4001.
Sampei, K., Goto, S., Alkayed, N. J., Crain, B. J., Korach, K. S., Traystman, R. J., Demas, G. E., Nelson, R. J., and Hurn, P. D. (2000). Stroke in estrogen receptor-alpha-deficient mice. Stroke 31 (3): 738-743.
Thorp, A. A., Sinn, N., Buckley, J. D., Coates, A. M., and Howe, P. R. (2009). Soya isoflavone supplementation enhances spatial working memory in men. Br. J. Nutr. 1-7.
White, L. R., Petrovitch, H., Ross, G. W., Masaki, K., Hardman, J., Nelson, J., Davis, D., and Markesbery, W. (2000). Brain aging and midlife tofu consumption. J. Am Coll. Nutr. 19 (2): 242-255.
Zhao, L., Mao, Z., and Brinton, R. D. (2009). A select combination of clinically relevant phytoestrogens enhances estrogen receptor beta-binding selectivity and neuroprotective activities in vitro and in vivo. Endocrinology 150 (2): 770-783
Clinical effects 