Phytoestrogen consumption and risk for cognitive decline and dementia: With consideration of thyroid status and other possible mediators

Accepted Manuscript Title: Phytoestrogen consumption and risk for cognitive decline and dementia: With consideration of thyroid status and other possible mediators Author: M. Soni L.R. White A. Kridawati S. Bandelow E. Hogervorst PII: DOI: Reference:

S0960-0760(15)30125-4 http://dx.doi.org/doi:10.1016/j.jsbmb.2015.10.024 SBMB 4559

To appear in:

Journal of Steroid Biochemistry & Molecular Biology

Received date: Revised date: Accepted date:

20-5-2015 7-9-2015 29-10-2015

Please cite this article as: M.Soni, L.R.White, A.Kridawati, S.Bandelow, E.Hogervorst, Phytoestrogen consumption and risk for cognitive decline and dementia: With consideration of thyroid status and other possible mediators, Journal of Steroid Biochemistry and Molecular Biology http://dx.doi.org/10.1016/j.jsbmb.2015.10.024 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

PHYTOESTROGEN CONSUMPTION AND RISK FOR COGNITIVE DECLINE AND DEMENTIA: WITH CONSIDERATION OF THYROID STATUS AND OTHER POSSIBLE MEDIATORS Soni, M.1 [email protected], White, L. R.2 [email protected], Kridawati, A.3 [email protected], Bandelow, S.3 [email protected], Hogervorst, E1* [email protected] 1 School of Sport Exercise and Health Sciences, National Centre for Sports and Exercise Medicine, Loughborough University, Loughborough, Leicestershire, LE11 3TU, United Kingdom. 2 Pacific Health Research and Education Institute, Kuakini Physicians Tower, 405 N. Juakini St., Ste. 1111, Honolulu, HI 96817, USA. 3 Department of Public Health, Respati University Yogyakarta, Indonesia. *Corresponding author.

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HIGHLIGHTS  Type of soy product and aglycone composition may affect cognitive outcome  Thyroid dysfunction, old age and equol deficiency are associated with negative cognitive outcomes  Cognitive tasks that recruit the prefrontal cortex may be most sensitive to phytoestrogens  Optimal phytoestrogen dosage and intake in diet are yet to be determined

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ABSTRACT

It is predicted that around 20% of the worlds population will be age 60 or above by 2050. Prevalence of cognitive decline and dementia is high in older adults and modifiable dietary factors may be able to reduce risk for these conditions.

Phytoestrogens are

bioactive plant chemicals found in soy, which have a similarity in structure to natural estradiol (the most abundant circulating estrogen). This structural likeness enables phytoestrogens to interact with estrogen receptors in the brain, potentially affecting cognition. However, findings in this domain are largely inconsistent, with approximately 50% of studies showing positive effects of phytoestrogens on cognition and the other half resulting in null/negative findings. This paper provides an updated review of the relationship between consumption of phytoestrogens and risk for cognitive decline and/or dementia. In particular, possible mediators were identified to explain discrepant findings and for consideration in future research. A case can be made for a link between phytoestrogen consumption, thyroid status and cognition in older age, although current findings in this area are very limited. Evidence suggests that inter-individual variants that can affect phytoestrogen bioavailability (and thus cognitive outcome) include age and ability to breakdown ingested phytoestrogens into their bioactive metabolites. Factors of the study design that must be taken into account are type of soy product, dosage, frequency of dietary intake and type of cognitive test used. Guidelines regarding optimal phytoestrogen dosage and frequency of intake are yet to be determined.

ABBREVIATIONS Alzheimer‟s Disease (AD) Estrogen Receptor (ER) Estrogen Receptor Alpha Subtype (ERα) Estrogen Receptor Beta Subtype (ERβ) Honolulu Aging Asia Study (HAAS) Messenger Ribonucleic Acid (mRNA) Randomised controlled trials (RCTs) Soy and Postmenopausal Health in Aging Study (SOPHIA) United States of America (USA)

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United Kingdom (UK) Women‟s Isoflavone Soy Health (WISH)

KEYWORDS: Phytoestrogen; Soy; Memory; Cognition; Dementia; Thyroid

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1. INTRODUCTION

Proportion of elderly adults (aged 60 and above) is predicted to rise to around one fifth of the global population by 2050 [1]. A particular issue associated with aging is cognitive decline and risk for dementia. Severity of cognitive impairment can lie on a spectrum ranging from mild cognitive impairment (MCI) to dementia, although definitions of these terms can vary. MCI describes a memory impairment, which cannot be explained by neurological or psychiatric factors [2]. Other cognitive functions usually remain intact and the impairment does not significantly interfere with daily life. Cognitive decline no dementia (CIND) refers not only to isolated memory deficits but global impairments across a number of cognitive domains. MCI and CIND indicate individuals whose cognitive ability is worse than what would be expected based on age and educational levels [2]. Prevalence of CIND is thought to be nearly one-fifth in Americans aged over 71 years of age and large proportion of these individuals can also be categorised as having MCI [3]. MCI is thought to be a precursor for dementia. Approximately 10-15% of individuals with MCI go on to develop dementia [4], although reversal to the unimpaired state is also possible. Dementia is a neurodegenerative disease resulting in a marked decline in memory and other cognitive functions. The most common pathologies are Alzheimer‟s disease and vascular dementia, accounting for around 60% and 20% of cases respectively [5]. Currently, dementia is one of the leasing causes of disability and dependence globally [6]. Worldwide prevalence rates for dementia in 2010 were estimated to be around 4.7% in those above the age of 60 and without significant public health intervention this figure is expected to double within 20 years [6]. Understanding modifiable lifestyle factors (e.g. diet) could therefore provide a cost-effective measure to delay and even potentially prevent disease onset. This is important given evidence that delaying disease onset and progression by a year could potentially lower prevalence by over nine million cases in the next three decades [7].

Further to findings from our earlier review [8], this paper provides an updated evaluation of the association between consumption of phytoestrogen compounds (found in soy) and risk for cognitive decline and/or dementia. In particular, recent work in our lab (also reviewed here) found that consumption of tofu (unfermented soy) in later life was associated with a 20% increased risk for incident dementia. It is plausible that the age

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effects of tofu on cognition could be concomitant with thyroid status. There is currently very limited research in this domain however this review provides a discussion of preliminary evidence of this link, as well as existing literature on other possible mediators.

Searches in PubMed and Scopus databases were conducted to identify relevant studies published after December 2013 (since our previous review included studies before this time). Searched keyword terms were „phytoestrogen‟ (OR „soy‟ OR „isoflavone‟ OR „genistein‟) and „cognition‟ (OR „cognitive function„ OR „memory‟ OR „dementia‟). A further search that also included the keyword „thyroid‟ was carried out with no date limits for publication. However no relevant results were found. Included studies were also selected on the following eligibility criteria: (1) observational study or randomised controlled trial (RCT) carried out in humans; (2) study participants were older or middle-aged adults (not young adults or children); (3) investigated soy products contained isoflavones; (4) the study outcome was related to cognition or dementia. Results of the literature search are outlined in Figure 1.

1.1 Dietary phytoestrogens and biological actions

The soybean is a legume native to East Asia and thus prevalent in East Asian diet [9]. Due to its high protein content, soy is also often used as a meat substitute in vegetarian cuisine. Soy-based products include, but are not limited to, oil, dairy alternatives (e.g. milk, butter, cheese), flour, sauce, miso (soybean paste), tofu (non-fermented soy) and tempe (fermented soy).

Phytoestrogen compounds are bioactive plant chemicals found in soy. These compounds have a structural similarity to 17β-estradiol and thus phytoestrogens have the ability to mediate estrogenic responses via interaction with estrogen receptors (ER). When circulating estrogen levels in the body are high (e.g. during the ovulatory menstrual cycle phase in pre-menopausal women), phytoestrogens can act as ER antagonists by competing with activity of natural estrogens. On the other hand, when circulating estrogen is low (e.g. in men or post-menopausal women), phytoestrogens can operate as ER agonists [9]. Phytoestrogens have a preference for ER-β receptor, but are only weakly estrogenic and have a much lower potency than natural estrogens [10]

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Phytoestrogens can be divided by chemical structure into sub-classes of isoflavones, lignans, coumestans & stilbens. Of these, isoflavones are the most similar in structure to estradiol and thus are the most bioactive and estrogenic phytochemical. Soy-based foods contribute the largest source of isoflavones in the diet [11]. Isoflavones can exist as one of two chemical forms, namely biologically inactive glucosides or bioactive aglycones. In foods, isoflavones primarily exist as glucosides that are converted to aglycones by bacterial microflora in the intestine. These aglycones may then be absorbed by the intestine or be further converted into metabolites. Isoflavone metabolites may have an increased or decreased physiological effect in comparison to their precursors [12].

Estrogenic effects of soy can be attributed to the aglycones genistein, diadzein and glycitein, although levels of these molecules vary considerably across soy food products. Genistein is the most potent isoflavone, whereas daidzein and glycitein have an affinity to ER that is approximately 100-500 times lower than genistein [9]. Diadzein is metabolised to equol, which is highly estrogenic and much more potent than its precursor. Variability in bacterial microflora associated with production of equol, can also influence metabolism, bioavailablity and functional activity of isoflavones [13][14]. However, there are individual (genetic) and cross-cultural differences in the ability to produce equol in the intestines [15]. Glycitein can only be obtained through dietary consumption of soy [16] and has weaker estrogenic activity in comparison to other soy isoflavones [17].

Phytoestrogen consumption has been shown to impact a number of physiological pathways associated with menopausal symptoms, osteoporosis, cancer, as well as cardiovascular, immune, metabolic and thyroid diseases [18][19]. In the context of cognitive function, pharmacodynamics of phytoestrogens are relevant considering localisation of ER‟s throughout the brain, including the hippocampus [20][21] and prefrontal cortex [22], which are important for learning, memory and higher-order cognition. These brain areas are also vulnerable to age-related decline [23].

2. SUMMARY OF STUDIES

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Data from both observational studies (Table 1) and RCTs (Table 2) are in humans are largely inconsistent, with approximately 50% showing positive effects of isoflavones on cognition and the other half resulting in null or negative findings [8].

2.1 Observational studies

A recent cross sectional study of Chinese elderly (n = 517, age = 50-95 years) showed that higher weekly intake of tofu was associated with worse verbal memory performance after controlling for age, gender, education and other dietary factors [24]. In those older than 68 years of age, higher tofu intake was found to be a significant risk factor for dementia. The negative effect of tofu was also demonstrated in Japanese-Americans (n = 3232 men, 502 women; age = 71-93 years) residing in the USA (Honolulu Aging Asia Study; HAAS), where higher consumption was associated with poorer overall cognitive test performance, enlargement of brain ventricles and lower brain weight [25]. In line with findings in China, further analysis of the HAAS cohort showed that the negative effects of soy were greatest in those older than 68 years of age [26]. Findings in an Indonesian sample (n = 791, age = 52-98 years) demonstrated negative effects of tofu on verbal memory [27], although tempe consumption was associated with better memory in the elderly [27][28]. Benefits of tempe are also supported in animal models. For instance, a recent study using a rat model of AD found that consumption of isoflavones found in tempe, was more effective than those found in unfermented soybean, in reversing memory

impairment,

improving

brain

cholinergic

activities

and

reducing

neuroinflammation [29]. Similarly, ovariectomised rats fed with tempe had better shortterm performance on a labyrinth task (faster maze completion and longer distance covered in first 5 minutes), compared to other groups fed tofu, a soybean curd product, or estradiol [30]. Health benefits of tempe may be due to the high levels of genistein and daidzein in tempe compared to that found in the soybean [29], which is the basis of tofu. This suggests a possible dose-dependent relationship, where cognitive effects may depend on quantity of bioactive agylcones. Alternatively, potential negative effects of phytoestrogens may be counteracted by the folate and cobalamin present in tempe due to fermentation [27].

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A longitudinal study of Asian and non-Asian women living in the USA and undergoing menopause transition (n = 1616, age range = 42-52 years at entry), reported that high isoflavone intake was associated with lower verbal memory scores [31]. Although in late perimenopause and postmenopause, Asian women with high isoflavone intake did better on a test of processing speed. Here, type of test and ethnicity were both shown to mediate the association between cognition and phytoestrogens. The capacity to convert isoflavones to their bioactive metabolites (e.g. equol and p-ethyl-phenol) has also been shown to vary cross-culturally [15][31] and may be responsible for differences in findings between ethnic groups. On the other hand, group differences may reflect dissimilarities in soy products consumed. For instance, soybeans, tofu and soy milk were the leading sources of isoflavones in Asians, whereas soymilk, tofu and meat substitutes were highest ranking in non-Asians. It is possible that soy products may differ in terms of potency and resulting biological (cognitive) effects.

Two cross-sectional studies measuring soy intake in the same Dutch sample of postmenopausal women, both reported no effect of isoflavones on cognitive function [32][33]. However, in the first of these studies [32] mean isoflavone intake was substantially lower than that observed in the Asian population samples. In the second study, authors reported that their null findings may have been because processing speed and executive function was assessed, rather than memory. Typically estrogen supplementation has been associated with effects on verbal or visual memory domains [33]. 2.2 Randomised controlled trials (RCTs) In the longest reported RCT carried out in the US (Women‟s Isoflavone Soy Health; WISH trial), healthy postmenopausal women (n = 350, mean age = 61 years) were randomly assigned to receive soy protein supplementation or a milk protein placebo for 30 months [34]. The quantity soy supplementation reflected the upper range of soy consumed in traditional Asian diets [35]. Overall, there were no significant between-group differences in global cognition from baseline. Sub-group analysis demonstrated that women 5-10 years postmenopause and those under 60 years of age were most likely to show cognitive benefits from supplementation. This supports the critical window of opportunity hypothesis, where estrogenic compounds may be most beneficial in midlife

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but not necessarily in the older elderly [36]. Additionally in WISH, consistent equol producers

demonstrated

a

trend

towards

improved

cognition

when

taking

supplementation, although a small sample size may have limited the ability to detect significant here. More recent analyses within the WISH cohort [37], found that change in urinary excretion or plasma levels of individual and total isoflavones were not associated with changes in global cognition or measures of episodic memory (verbal and visual), across the duration of the trial. However, changes in detected isoflavone levels were negatively associated with general intelligence in older postmenopausal women. Overall these findings suggest that cognitive domain and age since menopause could be identified as possible mediating factors. Several other RCT‟s have also failed to show effects of isoflavone supplementation on cognition [38][39][40][41][42][43]. These studies ranged from 12 weeks to 12 months and examined a variety of cognitive domains. There are a number of possible explanations for observed null findings, including type of cognitive test (not having a measure of verbal or visuospatial function), type of isoflavone supplement used (low aglycone dose), ethnicity and age of women (>60 years of age). These factors are discussed in more detail in section 3 below.

Conversely, two UK studies in postmenopausal women (aged 50-66 years) found positive effects of isoflavone consumption on measures of memory and tests of frontal lobe function (e.g. flexibility and planning), after treatment durations of 6 weeks [44] and 12 weeks [45]. In a 6 month US study (Soy and Postmenopausal Health In Aging Study; SOPHIA), isoflavone treatment was also associated with some cognitive improvements. These improvements were observed for verbal fluency as well as a test of visuospatial tracking and attention (trail-making), but were significantly greater for the category fluency test, even after controlling for age and education. Furthermore, effects in the trail-making task were observed in the younger (50-59 years) but not older age group (60-74 years), when compared to placebo, supporting the theory that estrogenic compounds may be most beneficial in those under the age of 60. Another smaller, mixed-gender study of older adults (15 males and 15 females, aged 62-89 years), found that isoflavone supplementation was positively related to visuospatial memory, verbal fluency and speed dexterity [10]. Interestingly, assays revealed that plasma genistein and daidzein levels,

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but not equol, increased with isoflavone administration. These results support the finding that proportion of equol producers may decrease with age [46]. However, this is contradictory to evidence suggesting that effects of soy may be more potent in those who have an ability to produce equol [47]. Two cross-over RCT studies carried out in postmenopausal women [48] and healthy men [49] have also shown positive associations of isoflavones on cognitive function.

3. POSSIBLE MEDIATORS

Overall, there are mixed data from human studies regarding the cognitive effects of phytoestrogens. Possible reasons for these inconsistencies are discussed below including thyroid status, inter-individual variants that may affect isoflavone bioavailability (e.g. age, gender, ethnicity) and factors of the study design (e.g. type of soy product, isoflavone dosage, frequency of dietary intake, type of cognitive test used).

3.1 Thyroid status

Evidence for the link between soy consumption, thyroid function and cognition is two-fold. Firstly, soy consumption has been shown to exacerbate thyroid dysfunction in human studies of those with subclinical thyroid disorders [50][51][52]. As an indication of dysfunction, low levels of free thyroxine (FT4; produced by the thyroid gland) and high levels of thyroid stimulating hormone (TSH; produce by anterior pituitary gland) are associated with hypothyroidism, whereas the converse indicates hyperthyroidism. Thyroid dysfunction may be overt (clinically diagnosable) or sub-clinical (no direct clinical symptoms present but may be indicative of early stages of the disease). A 2006 review examined the relationship between soy phytoestrogens and thyroid function in 14 clinical trials [50]. In the healthy adults, data demonstrated no effect or only modest effects of soy on thyroid function. However, in those with subclinical hypothyroidism, soy consumption was shown to cause further depression of thyroid function. A later randomised, double blind, crossover study [51] investigated the effects of phytoestrogen consumption on 60 patients with subclinical hypothyroidism. Overall, high-dose (16mg/day vs. 2mg/day) consumption was associated with a 3 times higher risk of progressing to overt hypothyroidism.

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Secondly, there is evidence that both hypofunction of the thyroid, and also subclinical hyperthyroidism, may increase risk for cognitive decline and dementia in older adults [53][54][55][56][57][58]. Hypothyroidsm is related to low uptake of glucose, which prevents the brain from sustaining energy consuming processes involved in neurotransmission, memory and higher order brain functions [53]. This can be present before evidence of clinical symptoms of AD are present [59][60] and thus may contribute to cognitive decline. On the other hand, hyperthyroidism is linked to disruption of the cholinergic system [57][61][62][63] and systemic oxidative stress [57][64][65], which are both pathological markers of AD. Phytoestrogens have been shown to suppress thyroid function, by interacting with pathways involved in thyroid hormone synthesis, metabolism and hormone transport proteins [18][66]. Evidence for these goitrogenic properties of phytoestrogens have been found in experimental studies of rodents, although there is limited research into the effects of isoflavones in aged animals. Genistein and to a lesser extent daidzein, have been shown to inhibit activity of thyroid peroxidase, which is an enzyme involved in synthesis of thyroid hormones [67][68][69]. Additionally, genistein and daidzein have also been shown to disrupt the hypothalamic-pituitary axis in orchidechtomized middle-aged rats [70]. Nevertheless, it is possible that dietary soy consumption may only result in anti-thyroid effects in the presence of other goitrogenic factors, such as lowered iodine levels [71][72].

In a 2008 review of thyroid function and cognition in older adults [53], thyroid dysfunction was linked to impairments in memory, visuosptial organisation, attention and reaction time. In more recent studies, both clinical hypothyroidism and subclinical hyperthyroidism have been associated with cognitive decline and risk for dementia [73][74][75][76][77][78]. However, findings for cognitive effects of subclinical thyroid disorder have not been consistently replicated [79][80][81]. Interestingly, more subtle variations of thyroid hormones within a euthyroid reference range have also been associated with cognitive function. For instance, high-normal levels of FT4 have been associated with lower cognitive performance, as well as increased risk for dementia and AD pathology [54][55][82][83].

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The above evidence provides a plausible link between soy consumption, thyroid status and cognition or dementia risk. This is also relevant given that incidence of both dementia and thyroid disease is more common with aged population and females in particular [6][84]. However, further research is needed to investigate this association.

3.2 Inter-individual variability

Isoflavone metabolism has been shown to vary between rodents and humans, making it difficult to translate preliminary findings in animals to human interventions. For instance in a recent study [85], biologically active forms of isoflavone concentrations were determined in rodents and healthy adults fed soy-based diets or pure isoflavone supplements. Regardless of type of isoflavone consumed, circulating concentrations of genistein in mice were 58-150 times higher than that found in the human samples. In comparison to rodents, humans have a much greater ability to breakdown isoflavones from glucosides to aglycones, which are more biologically active [86]. The comparatively low oral bioavailability of soy isoflavones in humans [87] may also explain inter-individual variations in the associated cognitive effects. This has prompted development of engineered soy products, which may be more effective as therapeutic agents. For example increasing aglycone content [88] and isoflavone particle size [89] has been shown to increase biological effects of soy.

It is possible that the effects of isoflavones on various endogenous systems are mediated by an equol-producing phenotype. Equol‟s binding ability is of similar strength to genistein, and it has been found to be three times as estrogenic as its parent daidzein [90]. It is estimated that approximately 25-30% of Caucasian adults have the ability to breakdown diadzein into its bioactive metabolite equol, whereas in populations where soy is more regularly consumed (such as Asian or vegetarian diets) frequency of equol producers is 50-60% [86]. The proportion of equol producers has also been found to decrease with age [15]. A study investigating urinary excretion of equol reported higher equol production in postmenopausal women, compared to premenopausal women and men [91]. This suggests that menopausal status and gender may also affect isoflavone metabolism, however findings for age and gender differences in equol production have not been consistently replicated [92][93]. In a recent study, plasma isoflavone

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concentrations (daidzein, equol, genistein and glycitein) in postmenopausal women were evaluated after exposure to isoflavone supplements or soy foods [94]. Here, median total isoflavone concentrations were higher for equol producers, regardless of type of soy product consumed. However the authors reported significant inter-individual variations in plasma concentrations, which were not explained by adjustment for background dietary assessments.

Generally RCTs reporting a negative or null effects of isoflavone treatment on cognitive function have included participants older than 60 years of age [15][34][35][40][41][42]. A number of observational studies also demonstrate negative associations in those over 68 years of age only [24][26][27]. One possibility is that isoflavone metabolism and absorption is largely dependent on gastrointestinal function, which may be comprised in older adults [10]. Some studies comparing urinary excretion of isoflavones after consumption of different soy-based foods have reported no effect of age (pre- versus post- menopausal women) on urinary genistein & daidzein [91][95]. However, in one of these studies [95] participants were not above the age of 60. In the other study [91], the age range of post-menopausal women was between 48 and 69 years, however due to the small sample size (N=20), there may not have been enough older adults (>60 years of age) to detect an effect. Another “age-dependent” hypothesis suggests that cells undergoing pathological changes (likely to be more prevalent in the older brain) respond negatively to estrogenic compounds, whereas the reverse is the case for healthy neurons [96].

3.3 Factors of the study design

Compositional differences between distinct types of soy isoflavones may affect their bioavailability and metabolism in the human body [97][98]. This is especially a problem as the intervention studies to date have used different sources and types of soy isoflavones. Some studies used isolated isoflavones, while others used intact soy protein. For instance, a study carried out by Cassidy and colleagues [92] highlighted factors that may affect pharmacodynamics of soy isoflavones ingested from different types of soy foods. Here, healthy adults (premenopausal women, n = 21; postmenopausal women, n=17; men, n = 21) were recruited in a crossover-design to examine the effect of age and

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gender on the bioavailability of isoflavones present in 3 types of soy foods (soy milk, textured vegetable protein and tempe). Results demonstrated gender differences in peak concentration of daidzein, with higher levels obtained in women. Compared to textured vegetable protein, consumption of tempe resulted in higher serum peak levels of isoflavones; although soy milk was absorbed faster and peak levels were attained earlier than with other soy products. These findings suggest that gender and type of soy product can influence isoflavone bioavailability and pharmacokinetics. However, isoflavone bioavailablity has not always been shown to vary across food sources [99].

RCTs to date have all tended to use large quantities of daily-administered isoflavones, which far exceed the levels consumed in a typical Asian diet. This has implications for efficacy and safety of soy supplements. It is not yet established whether a linear relationship exists between isoflavone dose and bioavailability [95][100][101]. Indeed, two studies [95][102] have reported a positive non-linear relationship between isoflavone intake and peak concentrations of daidzein and genistein. Therefore greater isoflavone consumption may not result in higher quantities being metabolised, suggesting a possible saturation effect. Furthermore, different aglycones may have individual dose-repose curves. For example, van der Velpen and colleages [94] found that over a range of isoflavone intakes (from 0 to 100 mg/day), doubling of the dose (per kilogram of body weight) increased plasma concentrations from 55 to 62% for daidzein, genistein and equol (only in producers), although the effect was much smaller for glycitein. Also, saturation from multiple daily dosing of soy foods or supplements, appear to be more apparent for genistein than daidzein at the higher dose level [103]. Further evidence is needed to determine optimal isoflavone dose for cognitive function and it is likely that this will differ depending on type of aglycone.

It is unclear whether habitual intake and regularity of isoflavone consumption may also affect bioavailability. Significant effects (whether these are protective or detrimental) have been found in Asian populations who regularly consume large amounts of isoflavones. On the other hand null results have been reported in Caucasian populations treated with phytoestrogen supplements and/or those who consumed very low and infrequent quantities of isoflavones through their diets. It is postulated that habitual diet may alter bacterial profile in the intestine, which may in turn affect isoflavone metabolism and equol

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production [104]. However, in both Caucasian and Japanese populations, short-term consumption of prebiotic supplements (which influence intestinal bacteria) do not appear to affect production of equol or bioavailability of soy isoflavones [104][121]. Additionally, Wiseman and colleagues [106] found no significant effects of habitual intake on isoflavone concentrations (in plasma, urine and faeces). However, the length of these studies may be too short to appropriately assess “habitual” intake effects.

Variations in the cognitive effects of phytoestrogens observed across studies may also be due to task-specific effects of isoflavones. These effects are likely to be related to regional expression of ERα and ERβ. For instance, the hippocampus and prefrontal cortex contain a high density of estrogen receptors [107][108]. However, ratio of ERα: ERβ is more equal in the hippocampus, in comparison to the prefrontal cortex where density of ERα is much lower than ERβ [109][110]. Soy isoflavones have a higher affinity for ERβ than ERα, therefore importance of measuring effects of isoflavones on tasks that engage the prefrontal cortex has been highlighted [110]. Prefrontal tasks include verbal learning, verbal fluency, visuospatial tasks and some tests of executive function, which have all been shown to be particularly sensitive to phytoestrogens across a number of observational studies and RCT‟s [15][27][28][31][33][34][43][45][48][96]. There is also evidence that aging is associated with greater decreases in ERβ- compared to ERαmRNA expression [111]. Thus, prefrontal brain areas that have a larger density of ERβ over ERα may be less responsive to estrogenic substances in older age [110].

5. CONCLUSION

Given the prevalence of cognitive decline and dementia in the aging population, understanding modifiable lifestyle factors that could prevent or delay onset is imperative. Dietary consumption of some soy products in older age has been shown to increase risk for cognitive decline and dementia in older adults. Phytoestrogen compounds in soy have the potential to influence cognition via their interaction with estrogen receptors. However, data from observational studies and RCT‟s in humans are largely inconsistent, with approximately 50% showing positive effects of isoflavones on cognition and the other half resulting in null/negative findings. A number of possible mediators are emerging from the current literature, which may explain these inconsistencies and inform further research in

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this domain. In general, phytoestrogen consumption appears to be associated with the best cognitive outcomes in individuals who have a healthy thyroid status and are aged below 60-68 years of age. Ability to produce equol may increase biological effects of soy whether this is negative or positive. In terms of the phytoestrogen source, tempe (fermented soy) has been shown to be neuroprotective, whereas tofu (non-fermented soy) consumption may be detrimental in older adults. Cognitive tests that may be most sensitive to phytoestrogens include tasks that involve recruitment of the prefrontal cortex, such as verbal learning, verbal fluency, visuospatial tasks and some tests of executive function. Optimal isoflavone dosage, frequency of intake and possible interactions between these two factors is yet to be determined.

ACKNOWLEDGEMENTS We would like to acknowledge the Alzheimer‟s Research Trust, which funded the Aging in Indonesia study (ART/PPG2006A/2). We would like to thank all the participants and staff in Indonesia who were involved in this project as well as Human Sciences Staff and all participants involved in the study to date. We would also like to thank Loughborough University, who funded the PhD studentship that made it possible to write this review.

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[107] M. González, A. Cabrera-Socorro, C.G. Pérez-Garcia, J.D. Fraser, F.J. López, R. Alonzo, G. Meyer, Distribution patterns of estrogen receptor alpha and beta in the human cortex and hippocampus during development and adulthood, J. Comp. Neurol. 503 (2007) 790-802. [108] D. Montague, C.S. Weickert, E. Tomaskovik-Crook, Oestrogen Receptor α Localisation in the Prefrontal Cortex of Three Mammalian Species, J. Neuroendocrinol. 20 (2008) 893-903. [109] P.J. Shughrue, M.V. Lane, I Merchenthaler, Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system, J. Comp. Neurol. 388 (1997) 507-525. [110] S.L. Neese, V.C. Wang, D.R. Doerge, K.A. Woodling, J.E. Andrade, W.G. Helferich, D.L. Korol, S.L. Schantz. Impact of dietary genistein and aging on executive function in rats, Neurotoxicol. Teratol. 32 (2010) 200-211. [111] M.E. Wilson, K.L. Rosewell, M.L. Kashon, P.J. Shughrue, I. Merchenthaler, P.M. Wise, Age differentially influences estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) gene expression in specific regions of the rat brain, Mech. Ageing Dev. 123 (2002) 593-601. [128] M.M. Rice, A.B. Graves, S.M. McCurry, L. Gibbons, J. Bowen, W. McCormick, Third international symposium on he role of soy in preventing chronic disease, Washington, DC, Oct 41-Nov 3 (1999) vol 130 p6765. [129] D. Kritz-Silverstein, D. Von Mühlen, E. Barrett-Connor, M.A. Bressel, Isoflavones and cognitive function in older women: the Soy and Postmenopausal Health in Aging (SOPHIA) Study, Menopause 10 (2003) 196-202. [130] H. Wang, P.A. Murphy, Isoflavone content in commercial soybean foods, J. Agric. Food Chem. 42 (1994) 1666-1673.

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Figure Captions Figure 1. Flow diagram of database search and results.

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Tables Table 1. Human observational studies of soy isoflavones and cognitive function Study author and year

Design

Duration

Participants

Soy intake measures

Results

(A) Studies investigating tofu (aglycone composition = approx. 146mg daidzein, 162mg genistein, 29mg glycitein [130]) White et al. 2000 (Honolulu Ageing Asia Study) [25]

Longitudinal

Baseline in 1965-1967 and followups in 19711974. Cognitive assessment in 19911993

Asian sample (3734 men, 502 women/spouses, age 71-93 yrs)

Tofu consumption from FFQ and interviews (husband's answers used as proxy for wife's consumption)

Higher midlife tofu consumption associated with lower CASI scores in men and their spouses.

Rice et al. 2000 (Kame Project conference abstract) [128]

Longitudinal

2 year follow-up of cognition

Asian sample (767 women, 634 men, aged >65 yrs)

Tofu consumption was categorized as low (<1/wk), moderate (1– 2/wk), and high (3+/wk)

High tofu consumers had significantly lower CASI scores than low or moderate consumers across both genders.

Hogervorst et al. 2008 [27]

Crosssectional

-

Asian sample (791 men and women, aged 52-98 yrs)

Tofu consumption (intake per wk) derived from validated FFQ

High tofu consumption associated with worse immediate recall memory on HVLT, particularly in those >68yrs.

Hogervorst et al. 2011 [28]

Crosssectional

-

Asian sample (142 men and women, aged 59-97 yrs)

Tofu consumption (intake per wk) derived from validated FFQ

1. Positive linear association of tofu consumption with immediate recall (HVLT) in those with average age of 67 yrs. 2. There was a trend for a negative association between tofu consumption and recall in those with average age of 80yrs, although this did not reach significance (contrary to the earlier findings from Hogervorst et al. 2008).

Xu et al. 2015 [24]

Crosssectional

-

Asian sample (517 men and women, aged 50-95 yrs)

Tofu consumption (intake per wk) derived from validated FFQ

1. Tofu intake negatively associated with immediate recall memory on HVLT. 2. In those over the age of 68 yrs, increased tofu consumption was associated with increased risk for dementia and MCI.

Soni et al. (unpublished) [26]

Longitudinal

Baseline in 1965-1967 and followups in 19711974. Cognitive assessment in 19911993

Asian sample (2752 men, mean age = 56 yrs in 19651974.

Tofu consumption (intake per wk) derived from FFQ

Higher consumption of tofu in later life (>68 yrs) but not midlife (<68 yrs) was associated with lower CASI scores.

(B) Studies investigating tempe (aglycone composition = approx. 273mg daidzein, 320mg genistein, 32mg glycitein [130])

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Hogervorst et al. 2008 [27]

Crosssectional

-

Asian sample (791 men and women, aged 52-98 yrs)

Tempe consumption (intake per wk) derived from validated FFQ

High tempe consumption associated with better immediate recall memory on HVLT, particularly in those >68yrs.

Hogervorst et al. 2011 [28]

Crosssectional

-

Asian sample (142 men and women, aged 59-97 yrs)

Tofu consumption (intake per wk) derived from validated FFQ

1. Positive linear association of tempe consumption and immediate recall (HVLT) in those with average age of 67 yrs. 2. No association between tempe and recall in those with average age of 80 yrs.

(C) Studies investigating general isoflavone intake (across multiple dietary sources – not limited to phytoestrogens from soy based products) Franco et al. 2005 [32]

Crosssectional

-

Western sample (394 PMW, mean age = 66 yrs)

Validated FFQ – computed daily intakes of phytoestrogens including daidzein and genistein

Isoflavone intake not related to MMSE score, regardless of time since menopause onset.

KreijkampKaspers et al. 2007 [33]

Crosssectional

Estimated diet over past year

Western sample (301 PMW, aged 60-75 yrs)

Validated FFQ and structured interview with trained dietician– computed daily intakes of phytoestrogens including daidzein and genistein

Isoflavone intake not related to cognitive function across a number of domains.

Greendale et al. 2012 [31]

Longitudinal

Food consumption in past year preceding interview

Asian and nonAsian sample (1616 women)

FFQ and interview. Computed daily intakes of phytoestrogens including daidzein, genistein and glycetin

1. Asian women with high isoflavone intakes did better on processing speed. 2. In early perimenopause high isoflavone Asian and nonAsian consumers performed worse on verbal memory.

Legend to table 1: CASI = Cognitive Abilities Screening Instrument; MMSE = Mini-mental State Examination; HVLT = Hopkins Verbal Learning Test; FFQ = Food Frequency Questionnaire; MCI = Mild Cognitive Impairment; PMW = post-menopausal women; wk = week; yrs = years.

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Table 2. Human intervention studies of soy isoflavones and cognitive function Study

Design

Duration

Participants

Intervention

Outcomes

Duffy et al. 2003 [45]

RDBP, P

12 weeks

Western sample (33 PMW, aged 5065 yrs)

1. Soy supplementation (30 mg/ 2 times daily)

Isoflavone group showed improvements in picture recall, sustained attention, learning rule reversals and planning.greater

2. Placebo

KritzSilverstein et al. 2003 [129]

RDBP,P

6 months

Western sample (56 PMW, aged 5574 yrs)

1. Soy supplementation (110 mg/day) 2. Placebo

KreijkampKaspers et al. 2004 [33]

RDBP, P

12 months

Western sample (175 women, aged 60-65 yrs)

1. Isoflavone supplementation (99m/day; 52mg genistein, 41mg daizein, 6mg glycitein)

Isoflavone treatment group showed greater improvements in category fluency, verbal fluency and taskswitching compared to the placebo group. However, only differences in category fluency were statistically significant.

No association between isoflavone intake and cognitive function across a number of domains.

2. Placebo

File et al. 2005 [44]

RDBP, P

6 weeks

Western sample (50 PMW, aged 5166 yrs)

1. Soy supplementation (60mg/ day) 2. Placebo

1. Isoflavone group showed improvements in nonverbal shortterm memory, tests of frontal lobe function, mental flexibility (rule reversal) and planning ability. 2. No significant improvement in long-term memory, category generation or sustained attention.

Casini et al. 2006 [48]

RDBP, CO

6 months

Western sample (78 PMW, mean age = 49.5 yrs)

1. Isoflavone supplementation (60mg/day; 40-45% genistein, 40-45% daidzein, 10-20% glycitein)

Isoflavone group showed better incidental learning on Digit Symbol Test and an improvement in mental flexibility and attention on the Digit Span Test.

2. Placebo tablet

Fournier et al. 2007 [43]

RDBP, P

16 weeks

Western sample (79 PMW, aged 4865 yrs)

1. Cow's milk and placebo supplement 2. Soy milk (72mg/day) and placebo supplement

1. Soy isoflavones supplement not related to improvement across a number of cognitive domains. 2. Soy milk group showed a decline in verbal working memory.

3. Isoflavone supplement (70mg/day; 30mg dadizein, 33mg genistein, 7mg glycitein) and cow‟s milk

Ho et al. 2007 [42]

RDBP, P

6 months

Asian sample (191 PMW, aged 56-76 yrs)

1. Isoflavone supplementation (80mg/day)

No association between isoflavone intake and cognitive function across a number of domains.

2. Placebo

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Basaria et al. 2009 [38]

RDBP

12 weeks

Western sample (93 PMW, mean age = 56 yrs)

1. Soy supplementation (160mg/day; 64mg genistein, 63mg dadizein, 34mg glycitein)

No association between isoflavone intake and cognitive function across a number of domains.

2. Placebo

Gleason et al. 2009 [15]

RDBP, P

6 months

Western sample (15 men, 15 women, aged 6289 yrs)

1. Soy supplementation (100mg/day; 85% dadzein and genistein)

Isoflavone subjects improved on tests of visuospatial memory and construction, verbal fluency and speeded dexterity.

2. Placebo

Maki et al. 2009 [39]

RDBP

12 months

Western sample (66 PMW, mean age = 53 yrs)

1. Phytoestrogen – red clover (120mg/day) 2. Botanical treatment – black cohosh (128mg/day)

No effects of red clover (phytoestrogen) supplement or black cahosh on cognitive functions across a number of cognitive domains.

3. Hormone therapy – CEE/MPA (0.625mg conjugated equine estrogens plus 2.5mg medroxyprogesterone acetate) 4. Placebo

Thorp et al. 2009 [49]

RDBP, CO

6 weeks

Western sample (34 men, aged 3080 yrs)

1. Isoflavone supplementation (500mg/4 times daily; 68mg daidzein, 12mg, genistein, 36mg glycitin)

Isoflavone supplementation improved spatial working memory

2. Placebo

Henderson et al. 2012 [34]

RDBP, P

30 months

Western sample (350 PMW, aged 45-92 yrs)

1. Soy supplementation (91mg/day; 52mg genistein, 36mg daidzein, 3mg glycitein) 2. Placebo

St John et al. 2014 [37]

RDBP, P

30 months

Western sample (350 PMW, aged 45-92 yrs)

1. Soy supplementation (91mg/day; 52mg genistein, 36mg daidzein, 3mg glycitein) 2. Placebo

1. No group differences in global cognition from baseline. 2. Greater improvement on a visual memory factor in isoflavone group, but no group differences in other 3 cognitive factors or individual test scores.

1. Mean change from baseline in urine excretion of isoflavones was not associated with global cognition score. 2. Urinary isoflavone excretion inversely associated with general intelligence, but not verbal or visual episodic memory.

Legend to table 2: RDBP = Randomised Double Blind Placebo Controlled Trial; P = Parallel Design; CO = Crossover Design.

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