These findings from a randomised controlled clinical study using soy isoflavones (100 mg/day) revealed important factors related to the feasibility of conducting similar studies enrolling older participants. Unlike previous investigations of isoflavone's cognitive effects, our study sample was markedly older and included both men and women. Plasma genistein and daidzein levels in our study were elevated with daily administration of the dietary supplement. However, confirming earlier reports [13
], there was substantial variability in levels achieved even with chronic use of a stable dose, and standardised time for blood collection (4 h post-dosing). While there may be quantification differences between laboratories [26
], genistein levels achieved in our study (170–180 nmol/l) were noticeably lower than those obtained in the only other investigation of cognitive effects [12
] (615.1 nmol/l) that measured plasma isoflavone levels. Data from this study highlight the need to clarify factors affecting the bioavailability of these compounds as we attempt to understand their cognitive efficacy in older adults.
Another important finding was that none of our older subjects could be characterised as equol producers. This is unexpected based on estimates that 20–25% of adult Westerners are so-called equol producers [25
], but in-line with reports that the proportion of equol producers decreases with age [15
]. It has been proposed that equol production in adults is associated with greater effectiveness of soy [27
], and that differences in the proportion of equol producers enrolled in various studies could partly explain disparate findings [28
]. Our healthy older adults appear less likely to convert daidzein into equol, perhaps due to alterations in gut motility, absorption or kidney clearance. Overall, these findings suggest that older adults using common over-the-counter soy supplements are less likely to demonstrate equol-associated benefits.
Interestingly, our data suggested that the isoflavones, genistein and daidzein, may offer a combination of cognitive effects for older men and women with improvements in the areas of visual-spatial memory, construction, category fluency, speeded dexterity and motor planning. A number of small intervention studies also indicated that administration of isoflavones enhanced cognition [5–10
]. In particular, these studies described improvements in cognitive abilities characterised as frontal lobe functions, such as verbal fluency, planning and cognitive flexibility, and on tasks such as mental rotation and other visuospatial skills. Our data partially supported these findings, such that isoflavone-treated subjects showed improvement on a visual construction and memory test, verbal fluency and mazes, an executive function task assessing planning and working memory. Unexpectedly, our data suggested the placebo-treated subjects improved to a greater extent than isoflavone-treated subjects on speeded tests of divided and selective attention. These surprising findings need further clarification. Lastly, our cognitive data were consistent with previous reports finding no enhancement of verbal memory [8
In contrast to studies suggesting beneficial cognitive effects, three investigations did not find cognitive improvements associated with either soy isoflavone supplementation [12
] or soy milk intervention [30
]. Differences in participants’ characteristics and background diet could contribute to discrepant findings from various studies. The present study differs from previous research on cognitive effects of soy isoflavones in its inclusion of older participants of both sexes. Trials examining the cognitive effects of soy isoflavones have primarily enrolled postmenopausal women in their 50s or 60s. The highly limited data related to age and sex differences in response to soy isoflavone treatment suggest that these exist [9, 10
], such that isoflavones may act as phyto-selective oestrogen receptor modulators (phytoSERMs) with both oestrogen-agonist and antagonist actions [31
]. Moreover, background diet of all but one of our participants included little or no isoflavones. The individual and combined effect of these factors may affect outcomes by influencing metabolism of an isoflavone intervention. Unfortunately, most studies did not measure plasma levels of isoflavones. Given inter-individual differences in isoflavone metabolism, it is imperative to examine cognitive change in association with estimates of biological exposure to isoflavones.
There are limitations inherent in our small sample size. Consequently, the study was not powered to examine the effect of subject characteristics such as sex and background diet. Rather, these data offer preliminary support for future investigations of this well-tolerated nutritional supplement's influence on cognitive function in older adults. The selection of isolated glycoside isoflavone tablets, as opposed to a whole food intervention, may also be a limitation of the study. The use of an isolate may fail to adequately mimic isoflavones found in whole foods, and thus fail to achieve biologically relevant levels of metabolites. However, considering the feasibility of a dietary intervention in an elderly population, newer aglycon supplement formulations may offer reasonable alternatives to whole foods.
These novel data describe the feasibility of a soy isoflavone supplement targeting cognitive outcomes, obtained exclusively from older adults, a growing population likely interested in cognition-enhancing supplements. Our findings revealed that soy isoflavone administration elevated plasma genistein and daidzein, but not equol levels in our older population. Further, our data revealed the necessity of measuring plasma isoflavone levels when conducting intervention trials with older adults, given the variability in genistein and daidzein plasma levels observed with stable dosing. Our data also emphasise the need to clarify factors affecting isoflavone metabolism and equol production in older adults and influencing cognitive efficacy of isoflavones, such as age and gender.