Reaping the hormonal rewards: investigating the role of sex hormones and cognitive performance in healthy older adults

doi:10.21203/rs.3.rs-3210292/v1

Background

Sex differences in cognitive performance have been extensively documented in scientific research, and these disparities continue to be observed in later stages of life. Gaining a comprehensive understanding of the underlying factors contributing to cognition in general and sex differences in specific is imperative to promote healthy cognitive ageing. Among these factors, sex hormones, specifically oestrogen and testosterone, have been implicated in cognitive performance variations. Nevertheless, there is a relative scarcity of studies investigating the relationship between sex hormones and cognitive performance in older adults. Hence, the current study aimed to investigate sex differences in cognitive performance and elucidate the association between sex hormones and these performance discrepancies.

Methods

Using confirmatory factor analysis in a sample of 121 older adults (aged ≥ 80 years), cognitive performance measures were divided into two cognitive components: executive functioning and memory. Subsequently, two mediation analyses were conducted. The first analysis aimed to determine the direct effects of sex and sex hormones (oestrogen and testosterone) on executive functioning and memory. The second analysis incorporated an oestrogen-by-sex interaction further to investigate the effects of oestrogen on cognitive performance.

Results

The results revealed that females outperformed males in executive functioning and memory, while oestrogen directly impacted performance. Furthermore, oestrogen exhibited a stronger association with executive functioning in females than in males. These findings indicate the possibility that early life or lifelong brain shaping influenced by sex hormones leads to the existence and persistence of sex differences in cognitive performance, with oestrogen playing a significant role in developing and maintaining female cognitive performance.

Conclusion

Overall, these findings have implications for basic research and clinical and cognitive ageing research development to promote cognitive health. Understanding the differences in cognitive abilities and the influence of sex-specific hormones between males and females can inform the research design and interventions to support healthy cognitive ageing.

Cognition

older adults

executive function

hormones

memory

oestrogen

sex differences

sex dimorphism

testosterone

Sex differences in cognitive performance are established throughout childhood, adolescents, and adulthood. Although older adults have a decline in cognition, it has been seen that sex differences remain. Many things may influence cognitive performance, including sex-specific hormones like oestrogen and testosterone. However, it remains unclear whether these hormones continue to affect aspects of cognition in older adults. Our study aimed to assess the sex differences in cognitive performance (executive functions and memory) and whether sex hormones play a role in these differences.

We analysed the executive function and memory performance of 121 older adults over 80 years old (56 males, 65 females). We also collected saliva samples of oestrogen and testosterone.

Our results found that females perform better in executive function and memory-based tasks. In females, it was also seen that oestrogen was important for the differences in executive function performance.

Overall, it could be determined that in adults over the age of 80, there are differences in executive functions and memory, with females outperforming the males. Also, oestrogen is important for the differences in executive functioning, even though the oestrogen level is not different between sexes at this age. This could mean that females with lifelong exposure to oestrogen may benefit from this even at older ages.

In the present study, we employed unique structural equation models to identify and distinguish two distinct cognitive domains: executive function and memory. Our initial findings revealed sex differences in both cognitive domains, with females outperforming males in both areas.
Despite the absence of a significant difference in oestrogen levels between sexes, our analysis revealed that oestrogen was a predictive factor for executive function performance.
An oestrogen-by-sex interaction was observed, suggesting oestrogen affects executive functions solely in females.
These findings indicate the possibility that early life or lifelong brain shaping influenced by sex hormones leads to the existence and persistence of sex differences in cognitive performance.

Males and females have often demonstrated notable differences in cognitive abilities [1]. Typically, men perform better than women on spatial tasks involving mental manipulation and visualisation of three-dimensional objects, such as mental rotation and matching [1–7]. On the other hand, women tend to outperform men on tests assessing verbal fluency and synonym generation [1–3, 5–7], which require quick retrieval and accurate production of words based on phonetic and semantic recognition. Moreover, the female advantage in verbal processing also relates to various memory-based tasks, where females have greater recall and faster response time [8]. The magnitude of these differences ranges according to cognitive task, with the most notable difference observed in mental rotation-based tasks and long-term memory [9]. Certain fundamental cognitive processes, such as attentional control, cognitive inhibition, and cognitive flexibility, fall under the umbrella of executive functions (EF) and have shown sex-specific traits. For instance, Sjoberg and Cole [10] found that females outperformed males in the Go/No Go task, indicating that females may possess greater inhibitory abilities. Similarly, Gatgiulo and colleagues [11] demonstrated that females exhibit higher cognitive flexibility using an operant strategy shifting paradigm. When considering the collective evidence, including studies by Wierenga et al. [12] and Grimmson and Reyes [13], there appears to be a consistent tendency towards a sex difference in EF. These findings suggest that males and females may differ in their cognitive strengths within these domains.

Sex differences in cognitive performance persist across the lifespan, including in older adulthood. Munro et al. [14] conducted a study involving 957 participants aged 67–88 years (480 females and 477 males), identifying that older women displayed superior performance compared to men on tests assessing psychomotor speed, verbal learning, and memory. Conversely, men outperformed women on tasks involving visual construction and perception. These findings are consistent across the literature, which indicates that sex differences observed early in life continue to manifest in older adulthood, highlighting the enduring nature of these cognitive disparities [15–18]. However, it is not explicitly understood in older adults if sex determines greater EF.

Several potential mechanistic explanations exist for the differences in cognitive performance between the sexes. These sex differences have been purportedly attributed to various biological factors, such as neuronal lateralisation [19, 20], region-specific brain dimorphisms [20–22], and circulating sex hormone levels [23–27]. Differences in hormone levels are thought to originate from hormonal exposure of the foetal brain, which has been suggested to have direct effects on the development of the brain and specific neural pathways [20, 28, 29]. Collectively, this hormone exposure has been suggested in the psychoendocrine theory to determine the basis for differential action and cognition performance in males and females [30]. Whilst literature has demonstrated that hormonal exposure across the lifespan and the brain’s sensitivity to sex hormones may affect brain development, neuroprotection, and cognition [26, 31, 32]., the effects of sex hormones on cognition seem to become evident when high circulating sex hormone levels are present. For example, studies have demonstrated that higher testosterone levels are associated with better performance in visuospatial tasks [27, 33]. Interestingly, females also demonstrate improved performance in visual and spatial tasks (in which men typically excel) during the early follicular phase of the menstrual cycle, when sex hormones are at the lowest concentration, suggesting an inverse relationship between oestrogen and visual and spatial tasks [34], albeit these differences were found to be relatively small and not to the same magnitude to the relationship between testosterone and these performance tasks [33]. Additionally, oestrogen has been found to be associated with greater verbal and nonverbal memory [35]. For example, Pauls et al. (2013) identified that females performed greatest in memory tasks during adolescence (aged 16–24 years), followed by young adults (aged 25–44 years) and finally older adults (45–69 years). These age periods reflect time epochs relating to the greatest to lowest oestrogen concentrations, which could be hypothesised that oestrogen is an important factor for cognitive performance.

Cognitive performance decline is a well-documented phenomenon that occurs during the ageing process, with a notable decrease typically observed from the mid-'50s onward [36, 37]. This decline primarily affects fluid mental abilities, including memory, EF, processing speed, and reasoning [36]. While these changes are a natural aspect of ageing, there is considerable variation among older adults in terms of cognitive performance and the rate of its decline. Several factors, besides age, such as education level, physical activity and other lifestyle factors, have been associated with this heterogeneity [38]. However, the impact of sex and hormonal factors on cognitive ageing and its implications for promoting healthy cognitive ageing has often been overlooked, despite their potential significance.

Of particular interest is the role of sex hormones, as cognitive decline and decreased performance often coincide with menopause in females (average age 51; [26]). Menopause is characterised by diminished ovarian response to pituitary gonadotropins and a significant reduction in overall oestrogen concentrations, particularly the predominant form of oestrogen, oestradiol. This decline in oestrogen levels has been linked to impairments in verbal memory, verbal fluency, and attention, as well as subjective memory complaints during menopause [26, 39]. Oestrogen's involvement in mitochondrial function may explain these associations, as decreasing oestrogen levels could lead to reduced glucose utilisation in the brain, ultimately affecting synaptic plasticity and cognitive function. Moreover, research suggests that oestrogen is involved in various signalling cascades. One such pathway involves upregulating the expression of tropomyosin receptor kinase A, which subsequently activates nerve growth factors, thereby eliciting neurotrophic effects that have been identified as crucial for maintaining cognitive function and providing neurocognitive protection [26]. A further example of oestrogen benefits on cognitive performance can be observed in research using hormonal replacement therapy. A recent meta-analysis from Zhou and colleagues [40] revealed that the hormone replacement therapy (oestrogen replacement) group exhibited significant improvements in Alzheimer Disease Assessment Scale-Cognitive subscale scores relative to those observed in the placebo group, demonstrating that cognitive performance can benefit from exogenous oestrogen replacement.

Furthermore, oestrogen has been suggested to possess neuroprotective properties, and a decrease in its concentration following menopause may contribute to the higher prevalence and greater severity of Alzheimer's disease in women compared to men [41, 42]. Animal studies have frequently demonstrated that reduced oestrogen levels in ovariectomized mammals enhanced neurodegenerative processes and increased brain damage [43].

In males, while there is no equivalent biological event to menopause, hypogonadism, which is characterised by the reduced functional activity of the gonads leading to decreased testosterone production, is prevalent in 5.1% among older adults aged 70–79 years, whilst research has also revealed that approximately 20% of males over the age of 60 have total testosterone levels below the normal range [44]. This percentage increases to 50% among those over 80 years old [44]. Although not as extensively studied as oestrogen, testosterone has also demonstrated certain neuroprotective properties. For instance, it has been observed to prevent dendritic atrophy in motoneurons following the induced death of neighbouring neurons [45].

Sex and sex hormones exert a significant influence on cognitive abilities and the potential regulation and decline of cognition with age. However, limited research has explored the intricate interplay between sex, sex hormones, and cognitive performance specifically in healthy older adults. Consequently, the object of the study is to investigate the associations between sex, hormonal differences, and cognitive performance within older adults of 80-plus years. By elucidating these intricate relationships, this study aims to provide valuable insights into the underlying mechanisms contributing to age-related cognitive decline in healthy older adults. Our primary hypothesis posits that sex will be the predominant predictor of cognitive performance differences, with females exhibiting superior performance in the cognitive tasks, such as EF and memory. Moreover, we hypothesise that oestrogen plays a mediating role in the observed sex-specific effects on cognitive abilities. This hypothesis stems from the notion of prolonged exposure to oestrogen throughout the lifespan and its involvement in brain development, neuroprotection, and regulatory functions of cognitive processes.

Subjects

A total of 244 participants, aged 79–93 years (M = 82.5, SD = 2.5) and born between 1926 and 1939, were recruited from the Sensor-based Systems for Early Detection of Dementia (SENDA) project [46]. Among them, 160 participants volunteered to provide saliva samples. However, 10 did not return their samples and for 29 participants data was missing for at least one of the variables included in the final model, resulting in a final sample of 121 older adults (56 males and 65 females, Table 1). Recruitment strategies and inclusion and exclusion criteria can be found in the published study protocol [46]. Additionally, participants were excluded from the current analysis if they used hormone replacement therapy medication. All participants can be classified as non-demented but may exhibit age-related or mild cognitive impairments. The Montreal Cognitive Assessment (MOCA, [47]) of participants ranged from 20 to 30 points. Participants provided written informed consent before participating in the study, which the Research Ethics Committee approved at the faculty of Behavioral and Social Sciences at Chemnitz University of Technology, Germany (V-232-17-KM-SENDA-07112017). The trial was retrospectively registered at German Clinical Trials Register (DRKS) with registration number DRKS00013167.

Table 1

Sample characteristics. Data is provided as mean and (standard deviation).
	Whole sample (N = 121)	Male (n = 56)	Females (n = 65)
Age (years)	83.5 (2.5)	83.9 (2.5)	83.1 (2.4)
MoCA	25.8 (2.5)	25.5 (2.4)	26.1 (2.5)
Education (years)	14.0 (3.3)	15.5 (3.7)	12.8 (2.4)
Two-minute step test (#)	74.8 (21.0)	79.3 (17.4)	70.9 (23.1)
Oestrogen (pg/mL)	5.53 (3.08)	5.80 (3.45)	5.30 (2.73)
Testosterone (pg/mL)	51.51 (33.74)	64.16 (35.56)	40.61 (28.06)
Note. MoCA = Montreal Cognitive Assessment.

Measures

For a detailed description of all measures in the SENDA project, please refer to [46]. Cognitive assessments were performed at approximately eight-month intervals, with the number of assessments ranging from one to four depending on the enrolment date of each participant. The assessment closest to the date of saliva sample collection was chosen for each participant to represent their current cognitive status in relation to their hormone levels. The interval between cognitive testing and saliva sampling was between 22 and 93.6 weeks (M = 40.2, SD = 16.3).

Cognitive assessment

During two measurement days, each participant underwent a battery of established neuropsychological tests. These included the Digit Symbol Substitution Test [48], the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological test battery [49], the Serial Sevens Test [50], the Digit Span Forward Test [48] and the Flanker Test [51]. In the incongruent trials of the Flanker Test participants reacted as fast as possible via keypress to the colour of the centre target disk (green or red) while ignoring the opposite colour (red or green) of the surrounding flanker disks. From these tests 15 separate performance scores were obtained for each participant (Table 2).

PLEASE INSERT TABLE 2 HERE

Table 2 - Description of each cognitive performance score
Test	Score description	Cognitive function	Domain
Digit Symbol Substitution Test	Number of correctly filled out symbols in 90 seconds	Processing speed	EF
CERAD Neuropsycho-logical Test Battery	Number of correctly identified words in the Boston Naming Test (0-12)	Visual naming	-
CERAD Neuropsycho-logical Test Battery	Number for words recalled Trial 1 of the Word List Task (0-10)	Verbal memory	MEM
	Number for words recalled Trial 2 of the Word List Task (0-10)	Verbal memory	MEM
	Number for words recalled Trial 3 of the Word List Task (0-10)	Verbal memory	MEM
	Percent of correctly identified words in the Word List Recognition Task	Verbal memory	MEM
	Percent of correctly remembered words in the Word List Recall Task	Verbal memory	MEM
	Number of s-Words produced in one minute	Verbal fluency	EF
	Number of animals produced in one minute	Verbal fluency	EF
	Point score of the Figure Drawing Task (0-11)	Visuo-spatial ability	-
	Point score of the Figure Recall Task (0-11)	Visual Memory	MEM
	Trail Making Test A time	Processing speed	EF
	Trail Making Test B time	Task Switching	EF
Serial Sevens Test	Number of correct answers given in 15 seconds	Working memory	-
Digit Span Forward Test	Number of maximally remembered digits	Working memory	EF
Flanker Test	Average reaction time of incongruent trials	Inhibition	EF
	Accuracy of incongruent trials	Inhibition	EF
Note. MEM = memory, EF = executive function

Saliva hormone assessment

Saliva sample collection was conducted according to standardised guidelines. Participants were provided with saliva sample kits and instructions. On the day following receipt of the kits, participants were asked to provide unstimulated whole saliva samples upon awakening. To account for the pulsatile nature of hormone production and achieve a more precise concentration value, five saliva samples were provided over a period of one and a half hours, with approximately 20 minutes between each sample. Participants were instructed to refrain from consuming excessive amounts of dairy products, alcohol, and chocolate the evening prior to sample collection. On the day of sample collection, participants were asked to abstain from food and drink (except water), smoking, using toothpaste, and (when possible) medication intake until the sample had been collected. Any medication taken before or during the measurement time was documented and controlled to ensure no influence on hormone concentrations. Unstimulated whole saliva samples (~ 3 mL) were collected into sterile 5 mL plastic containers and sent to the research team within 48 hours of collection. The samples were immediately placed in a -20°C freezer until assayed to maintain sample integrity.

The concentrations of oestradiol and testosterone in saliva were determined using commercially available enzyme-linked immunosorbent assays (ELISAs) (DRG Instruments GmbH, Marburg, Germany). The assays were performed in singlet in accordance with the manufacturer's instructions using the BioTek ELISA Miroplatten-Wascher ELX-50 and BioTek ELISA Mikrotiterplatten-Reader EL-800 (BioTek, Vermont, USA). The intra-assay coefficients of variation for salivary oestradiol and testosterone for the collected samples were 4.6% and 7.5%, respectively.

Control Variables

Education was recorded as the number of years spent in school and higher education according to CERAD-NP recommendations [49]. Cardiovascular fitness was measured with the two-minute step test as the number of completed lifts of the right knee in two minutes [52]. The target height was marked for each person individually as the height of the halfway point between the midpoint of the person's patella and the top of their iliac crest (cf. Table 1 for sample characteristics).

Statistical Analyses

Statistical analyses were performed using lavaan package in R [53]. All structural equation models were estimated using the ‘MLR’ estimator to control for non-normality of the data. First, confirmatory factor analysis was performed to combine the cognitive test scores into the two aggregated cognitive factors, EF and memory, following the results from [54]. Next, the effect of sex directly and mediated via hormones oestrogen and testosterone on EF and memory were estimated while controlling for education and cardiovascular fitness. In the final model an additional interaction term (oestrogen by sex) was included to better understand the effect of oestrogen on EF and memory. Standardized coefficients (direct paths: β, indirect effects: ab), model fits and R² were reported for each model. Results were considered significant at alpha = .05.

After checking the data distribution of all cognitive scores for normality, the Boston Naming Test and the Figure Drawing Test were not included into the factor analysis because of strong ceiling effects. In addition, the Serial Sevens Test did not load significantly on the EF factor and was removed to obtain good model fit (χ2(75) = 101.8, p = .021; AIC = 9597.62; robust CFI = 0.91; robust RMSEA = .057, p (RMSEA ≤ .05) = .309, SRMR = .079). The two factors EF and memory of the factor model (Fig. 1) were used as dependent variable in the next analysis steps.

PLEASE INSERT FIGURE 1 HERE

In the mediation model (χ2(136) = 210.334, p < .001; AIC = 11376.356; robust CFI = 0.82; robust RMSEA = .070, p (RMSEA ≤ .05) = .029, SRMR = .086) a direct effect of sex on EF (β = .42, p = .001) and memory (β = .45, p < .001) was revealed after controlling for education and cardiovascular fitness (Fig. 2A). No significant indirect effect of sex mediated through hormones on EF (oestrogen: ab = − .025, p = .294, testosterone: ab = .062, p = .142) or memory (oestrogen: ab = − .013, p = .472, testosterone: ab = .044, p = .176) was presented. Looking at the partial paths in the model revealed that males had significantly higher testosterone levels (β = − .305, p = .002) while there was no difference in oestrogen levels (β = − .091, p = .270) between males and females. Oestrogen was a significant predictor of EF (β = .276, p = .003) but not of memory (β = .139, p = .235). The included predictors explained 32% of the variance of the EF factor and 23% of the memory factor.

To further elucidate the relationship between oestrogen and cognition, the final model also included an oestrogen by sex interaction term (Fig. 2B). In this model (χ2(150) = 285.900, p < .001; AIC = 11374.467; robust CFI = 0.730; robust RMSEA = .088, p (RMSEA ≤ .05) < .001, SRMR = .091) the interaction term was significantly related to EF (β = .42, p = .035) and the effects of sex (β = .10, p = .635) and oestrogen (β = .11, p = .211) were reduced. This can be interpreted as a stronger relationship between oestrogen and EF in females compared to males (Fig. 3). From the variance of the EF factor 32% and of the memory factor 25% could be explained using the included predictors.

PLEASE INSERT FIGURE 2 HERE

PLEASE INSERT FIGURE 3 HERE

Building upon this initial exploration, the study’s primary objective was to investigate sex differences in cognitive performance and explore the potential association between current levels of sex-specific hormones (oestrogen and testosterone) and these cognitive outcomes. Therefore, we utilised a factor analysis to identify cognitive domains based on the applied cognitive battery developed within the SENDA project [46]. The analysis yielded two distinct domains, namely EF and memory. Consistent with prior research, we found notable sex differences in the identified cognitive domains. Specifically, females exhibited superior performance in EF and memory compared to males. Despite these sex differences, no mediating effects of hormones on cognitive domains were observed, although it is worth noting that oestrogen alone emerged as a significant predictor of EF performance. Additionally, an investigation of the interaction between oestrogen and sex was conducted, considering the direct effects of both variables. The analysis demonstrated a significant relationship between the oestrogen-by-sex interaction and EF, suggesting a stronger association between oestrogen and EF in females than males. Interestingly, as a result of this interaction, the direct effects of sex and oestrogen were attenuated. These findings suggest that oestrogen, which plays a crucial role in shaping and developing the female brain, continues to exert a significant impact on cognitive performance even in older age.

Our study yielded significant findings regarding the impact of sex on the two cognitive domains, namely EF and memory. Consistent with existing literature spanning various age groups, our results indicated that females tend to outperform males in both domains. Sex differences in cognitive performance are generally characterised by small effect sizes [9]. However, it is worth noting that tasks related to visual short-term memory and memory tend to exhibit larger effect sizes [9] For instance, we utilised the Digit Span test, a widely used measure of working memory [48], and the Wordlist Learning test, which evaluates long-term memory [49]. The observed sex differences in cognitive performance may be further amplified due to larger effects and given the critical role of memory in both domains (EF and memory), its impact is likely to contribute to the pronounced disparities between males and females. Moreover, our findings align with recent research conducted by Jockwitz et al. [18], who reported that older females (aged 55 to 87 years) displayed superior performance in verbal fluency, verbal episodic memory, processing speed, and interference tasks. Many of these tasks can be categorised as EFs. Consequently, our study reinforces the notion that healthy older female adults tend to exhibit enhanced performance in tasks that require higher-level of EF or memory capabilities.

It has been well established that during the ageing process, cognition generally declines [36, 37]. However, our study contributes to the existing literature by suggesting that the relative differences between sexes remain consistent as individuals age. Notably, previous research by de Frias et al. [2] examined cognitive performance in a sample ranging from 35 to 80 years old at baseline. Their findings revealed enduring sex differences over a ten-year follow-up period, with women exhibiting superior performance in tasks assessing verbal episodic memory and verbal fluency, while men outperformed women in tasks involving visuospatial functions. Moreover, studies conducted by Maitland et al. [4], Pauls et al. [55], and Jockwitz et al. [18] have further supported the stability of sex differences, particularly in the verbal versus spatial domains, amongst older individuals. While the visuospatial domains were not directly assessed in this study, the derivation of the EF domain through factor analysis, incorporating processing speed, inhibition, attentional control, and working memory, provides a different outlook on cognitive performance that has yet been conducted in previous research. The current findings confirm that collectively differences in cognitive abilities persist even during the later decades of life.

While numerous studies have identified sex differences in cognitive performance among older adults, only a limited number have explored potential biological determinants for these disparities. Oestrogen has emerged as a prominent candidate influencing cognitive performance, supported by various studies [3, 11, 25, 29, 31, 35]. Existing literature has demonstrated an association between a longer reproductive window (reflecting increased exposure to oestrogen) and better cognitive health in later life [56, 57]. In cellular and animal models, oestrogen has exhibited neuroprotective properties, promoting brain-derived neurotrophic factor and enhancing synaptic spine density in the hippocampus [58]. These findings suggest that oestrogen exposure may contribute to the preservation of neural health in late life, which may suggest as to why oestrogen was found to predict EF in older adults.

The lack of an indirect effect of sex through hormones in our study may be attributed to the age of the participants. The current cohort consisted of individuals aged 80 and above, all females were menopausal and not undergoing hormonal replacement therapy. Consequently, the concentration levels of oestrogen did not differ significantly between males and females (albeit being significantly different to younger females [59]). Nonetheless, collectively these findings suggest that the effects of oestrogen on cognitive performance persist throughout the lifespan, and the previous exposure to higher levels of oestrogen concentration may play a more substantial role in explaining the observed sex differences in performance [56, 57].

Previous research has indicated that cognitive differences between the sexes may be influenced by prenatal and neonatal organisational effects of the brain [1, 29, 30, 35]. Sex hormones are known to have organisational effects on the structure and function of specific brain areas during foetal development [60, 61]. Subsequently, during post-pubertal stages, sex hormone levels further enhance the prenatally established neural “hard-wiring” through an activation effect [30]. According to the psychoendocrine theory, substantial quantities of a sex hormone during prenatal life organize neural substrates for specific behaviours or functions. These effects become increasingly evident after puberty when high levels of the same hormone circulate in the body. Consequently, this suggests that oestrogen may continue to benefit cognition due to the retained capacity resulting from its previous ergogenic effects on cognitive function.

To further support this concept, an additional model was conducted, incorporating an oestrogen-by-sex interaction. The results of this analysis demonstrated a significant association with EF, while simultaneously diminishing the individual effects of sex and oestrogen (Fig. 3). These findings suggest a stronger relationship between oestrogen and EF in females compared to males. Therefore, the aforementioned mechanisms throughout the lifespan may account for the enduring sex differences observed in males versus females. Additionally, despite the decline in absolute oestrogen concentrations during ageing, the female brain has a greater number of oestrogen receptors. It could be speculated that due to the affinity with the receptors this may provide the neuroprotective effects mentioned previously alongside the retained cognitive benefits associated with oestrogen. However, it is important to note that these assertions are speculative and should be subject to further investigation in future research. In contrast to the findings for EF, memory displayed sex differences but was not related to oestrogen or testosterone. This might indicate that other biological, but also social or environmental factors and their interactions might partially cause the observed differences between males and females in memory and EF [31].

In the present study, we did not find any cognitive performance measures that showed a significant advantage for males over females. Furthermore, we did not observe any associations between testosterone levels and cognitive performance across various cognitive domains. One plausible explanation for these findings is the well-documented male advantage in tasks involving mental rotation and visual spatial abilities, which has been consistently demonstrated in previous research. However, it is important to note that our study did not include specific tests assessing visual spatial functioning within the cognitive testing battery and across the cognitive domains. As a result, our ability to detect male superiority in cognitive tasks was limited. We did find a significant difference in testosterone levels between males and females, as illustrated in Fig. 2A, which has been suggested to potentially influence performance on visual spatial tasks based on existing literature [27]. Therefore, it would be valuable to explore the relationship between these tasks and testosterone in future research studies employing a similar design.

The current study demonstrated both strengths and limitations. Notably, the study employed confirmatory factor analysis to develop comprehensive variables that capture a holistic perspective of cognition, reflecting real-life cognitive processes instead of focusing on isolated aspects.

Across research the age range of participants often varies widely, leading to substantial variations in cognitive and hormonal states within the population [14, 18]. By exclusively including older adults aged ≥ 80 years, the current study achieved a more homogeneous sample in terms of cognitive and hormonal characteristics compared to other studies. When investigating sex differences, it is crucial to consider the various factors that might contribute to their development.

It is well-established that males and females exhibit differences in brain structure and function, which can impact cognitive processing strategies [20, 60]. In addition, genetic and social factors play a role. The current study extended its investigation to explore the potential hormonal effects on cognitive performance while controlling for other known sex-specific factors such as education level and physical fitness. While the study observed significant differences in cognitive performance favouring females, a limitation arises from the absence of specific cognitive tests tailored specifically for males. Consequently, the cognitive profiles of both sexes may not have been fully represented in the study.

Finally, hormonal concentrations were collected at the same time point for all participants, although there might have been discrepancies between the time elapsed since their last cognitive measures and their hormonal assessments. However, this potential limitation was minimized by the study's recruitment strategy, which targeted a significant age group where hormone fluctuations are not expected to be substantial within the observed timeframes.

PERSPECTIVES AND SIGNIFICANCE

The present study provides further evidence for sex differences in cognitive performance that persist even into late life. Importantly, the study emphasises the potential significance of oestrogen in influencing cognitive abilities, even in post-reproductive life phases. The results demonstrate a direct association between oestrogen and EF, highlighting the crucial role of oestrogen in accounting for the observed sex differences. Particularly noteworthy is the more pronounced oestrogenic effect observed in females (interaction effect), despite the absence of a significant difference in the absolute concentration of oestrogen between males and females. This observation indicates the possibility of either early life or lifelong brain shaping influenced by sex hormones. These findings support the notion that oestrogen may have substantial effects on cognitive development, performance, neuroprotection, and the maintenance of cognitive abilities in females across the lifespan. Therefore, it is essential to incorporate sex hormones, including oestrogen, in research on sex differences, irrespective of age and similar hormone concentration levels. Future investigations should focus on examining the effects of hormones in male-specific cognitive domains (such as mental rotation), as this would provide a more comprehensive understanding of impact on cognitive performance in older adults. Additionally, extending the current findings to pathological conditions such as Alzheimer's disease would be valuable in elucidating the potential role of oestrogen in cognitive impairment.

Taken collectively, the current research demonstrates that oestrogen is an important sex hormone which has implications for cognitive performance for females, even into later life. As such, the findings emphasise the importance of not only taking sex differences into account but to consider the concentration and life-long exposure of oestrogen. Considering the differences in cognitive performance and the influence of sex-specific hormones between males and females this holds implications not only for basic research but also for advancing clinical and cognitive aging investigations and designing interventions focused on enhancing cognitive health and aging.

Ethics approval and consent to participate

The local research ethics committee approved at the faculty of Behavioral and Social Sciences at Chemnitz University of Technology, approved the study protocols that were performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients involved in the study.

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by the European Social Fund for Germany and the Sächsische Aufbaubank-Förderbank (SAB) of the Free State of Saxony (Grant No. 100310502). This funding source had no role in the study design, in the collection, analysis, and interpretation of data, or in the writing of the report.

Authors' contributions

CVR developed the global research design of the SENDA project and provided overall project administration, funding acquisition, resources, and supervision. RJ, CVR, and KM contributed to the specific study design of the current research question. CVR RJ, SF and KM curated data. SF performed statistical analyses. RJ and SF drafted the manuscript. CVR, KM and MD critically revised the manuscript. All authors read and approved the final manuscript.

Acknowledgements

The authors would like to thank all the participants for their contribution. A special thank you is also extended to all members of the SENDA team from the Chemnitz University of Technology for their support in subject recruitment, attainment, and data collection.

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Reaping the hormonal rewards: investigating the role of sex hormones and cognitive performance in healthy older adults

Status:

Version 1

Abstract

Figures

PLAIN ENGLISH SUMMARY

HIGHLIGHTS

BACKGROUND

METHODS

Subjects

Measures

Cognitive assessment

Saliva hormone assessment

Control Variables

Statistical Analyses

RESULTS

DISCUSSION

PERSPECTIVES AND SIGNIFICANCE

CONCLUSION

Declarations

References

Status:

Version 1