Associations Between Age at Menopause, Vascular Risk, and 3-Year Cognitive Change in the Canadian Longitudinal Study on Aging.

BACKGROUND AND OBJECTIVES: Mounting evidence supports sex differences in Alzheimer disease (AD) risk. Vascular and hormonal factors may together contribute to AD risk in female adults. We investigated whether age at menopause, vascular risk, and history of hormone therapy (HT) containing estrogens together influence cognition over a 3-year follow-up period. We hypothesized that earlier menopause and elevated vascular risk would have a synergistic association with lower cognitive scores at follow-up and that HT containing estrogens would attenuate this synergistic association to preserve cognition. METHODS: We used data from postmenopausal female participants and age-matched male participants in the Canadian Longitudinal Study on Aging. Vascular risk was calculated using a summary score of elevated blood pressure, antihypertensive medications, elevated low-density lipoprotein cholesterol, diabetes, smoking, and obesity. Cognition was measured with a global cognitive composite at baseline and 3-year follow-up. Linear models tested independent and interactive associations of age at menopause, vascular risk, and HT history with cognition at 3-year follow-up, adjusting for baseline cognition, baseline age, years of education, and test language (English/French). RESULTS: We included 8,360 postmenopausal female participants (mean age at baseline = 65.0 ± 8.53 years, mean age at menopause = 50.1 ± 4.62 years) and 8,360 age-matched male participants for comparison. There was an interaction between age at menopause and vascular risk, such that earlier menopause and higher vascular risk were synergistically associated with lower cognitive scores at follow-up (ß = 0.013, 95% CI 0.001-0.025, p = 0.03). In stratified analyses, vascular risk was associated with lower cognitive scores in female participants with earlier menopause (menopausal ages 35-48 years; ß = -0.044, 95% CI -0.066 to -0.022, p < 0.001), but not average (ages 49-52 years; ß = -0.007, 95% CI -0.027 to 0.012, p = 0.46) or later menopause (ages 53-65 years; ß = 0.003, 95% CI -0.020 to 0.025, p = 0.82). The negative association of vascular risk with cognition in female participants with earlier menopause was stronger than the equivalent association in age-matched male participants. HT history did not further modify the synergistic association of age at menopause and vascular risk with follow-up cognition (ß = -0.005, 95% CI -0.032 to 0.021, p = 0.69). DISCUSSION: Endocrine and vascular processes may synergistically contribute to increased risk of cognitive decline in female adults. These findings have implications for the development of sex-specific dementia prevention strategies.

The double-edged sword of PCOS and gender: exploring gender-diverse experiences of polycystic ovary syndrome.

Background: Past research on polycystic ovary syndrome (PCOS), a chronic endocrine condition, has focused on the experiences of cisgender women. Aims: The purpose of the present study was to address the knowledge gap about gender-diverse individuals by exploring their lived experiences with PCOS and to better understand if and how their gender identity affected their experience of PCOS. Methods: To explore this, we recruited nine non-binary people and one transgender man with a PCOS diagnosis for qualitative interviews. Results: Three overarching themes emerged: PCOS as a burden, PCOS as an occasion, and PCOS as a benefit. While some aspects of PCOS created an additional burden for our participants, other symptoms such as excess body and facial hair could be empowering and affirming, revealing a positive aspect of this chronic condition. Conclusion: This study is the first to describe the lived experiences of gender-diverse individuals with PCOS, uncovering burdens as well as some benefits. Future research in this population may reveal not only the particulars of what PCOS is like for them but also more generalizable insights into the highly gendered perception and treatment of PCOS.

Gray matter volume in women with the BRCA mutation with and without ovarian removal: evidence for increased risk of late-life Alzheimer's disease or dementia.

OBJECTIVE: Ovarian removal prior to spontaneous/natural menopause (SM) is associated with increased risk of late life dementias including Alzheimer's disease. This increased risk may be related to the sudden and early loss of endogenous estradiol. Women with breast cancer gene mutations (BRCAm) are counseled to undergo oophorectomy prior to SM to significantly reduce their risk of developing breast, ovarian, and cervical cancers. There is limited evidence of the neurological effects of ovarian removal prior to the age of SM showing women without the BRCAm had cortical thinning in medial temporal lobe structures. A second study in women with BRCAm and bilateral salpingo-oophorectomy (BSO) noted changes in cognition. METHODS: The present, cross-sectional study examined whole-brain differences in gray matter (GM) volume using high-resolution, quantitative magnetic resonance imaging in women with BRCAm and intact ovaries (BRCA-preBSO [study cohort with BRCA mutation prior to oophorectomy]; n = 9) and after surgery with (BSO + estradiol-based therapy [ERT]; n = 10) and without (BSO; n = 10) postsurgical estradiol hormone therapy compared with age-matched women (age-matched controls; n = 10) with their ovaries. RESULTS: The BRCA-preBSO and BSO groups showed significantly lower GM volume in the left medial temporal and frontal lobe structures. BSO + ERT exhibited few areas of lower GM volume compared with age-matched controls. Novel to this study, we also observed that all three BRCAm groups exhibited significantly higher GM volume compared with age-matched controls, suggesting continued plasticity. CONCLUSIONS: The present study provides evidence, through lower GM volume, to support both the possibility that the BRCAm, alone, and early life BSO may play a role in increasing the risk for late-life dementia. At least for BRCAm with BSO, postsurgical ERT seems to ameliorate GM losses.

Learning exceptions to category rules varies across the menstrual cycle.

Ways in which ovarian hormones affect cognition have been long overlooked despite strong evidence of their effects on the brain. To address this gap, we study performance on a rule-plus-exception category learning task, a complex task that requires careful coordination of core cognitive mechanisms, across the menstrual cycle (N = 171). Results show that the menstrual cycle distinctly affects exception learning in a manner that parallels the typical rise and fall of estradiol across the cycle. Participants in their high estradiol phase outperform participants in their low estradiol phase and demonstrate more rapid learning of exceptions than a male comparison group. A likely mechanism underlying this effect is estradiol's impact on pattern separation and completion pathways in the hippocampus. These results provide novel evidence for the effects of the menstrual cycle on category learning, and underscore the importance of considering female sex-related variables in cognitive neuroscience research.

Menopause Status and Within-Group Differences in Chronological Age Affect the Functional Neural Correlates of Spatial Context Memory in Middle-Aged Females.

Reductions in the ability to encode and retrieve past experiences in rich spatial contextual detail (episodic memory) are apparent by midlife-a time when most females experience spontaneous menopause. Yet, little is known about how menopause status affects episodic memory-related brain activity at encoding and retrieval in middle-aged premenopausal and postmenopausal females, and whether any observed group differences in brain activity and memory performance correlate with chronological age within group. We conducted an event-related task fMRI study of episodic memory for spatial context to address this knowledge gap. Multivariate behavioral partial least squares was used to investigate how chronological age and retrieval accuracy correlated with brain activity in 31 premenopausal females (age range, 39.55-53.30 years; mean age, 44.28 years; SD age, 3.12 years) and 41 postmenopausal females (age range, 46.70-65.14 years; mean age, 57.56 years; SD age, 3.93 years). We found that postmenopausal status, and advanced age within postmenopause, was associated with lower spatial context memory. The fMRI analysis showed that only in postmenopausal females, advanced age was correlated with decreased activity in occipitotemporal, parahippocampal, and inferior parietal cortices during encoding and retrieval, and poorer spatial context memory performance. In contrast, only premenopausal females exhibited an overlap in encoding and retrieval activity in angular gyrus, midline cortical regions, and prefrontal cortex, which correlated with better spatial context retrieval accuracy. These results highlight how menopause status and chronological age, nested within menopause group, affect episodic memory and its neural correlates at midlife.SIGNIFICANCE STATEMENT This is the first fMRI study to examine how premenopause and postmenopause status affect the neural correlates of episodic memory encoding and retrieval, and how chronological age contributes to any observed group similarities and differences. We found that both menopause status (endocrine age) and chronological age affect spatial context memory and its neural correlates. Menopause status directly affected the direction of age-related and performance-related correlations with brain activity in inferior parietal, parahippocampal, and occipitotemporal cortices across encoding and retrieval. Moreover, we found that only premenopausal females exhibited cortical reinstatement of encoding-related activity in midline cortical, prefrontal, and angular gyrus, at retrieval. This suggests that spatial context memory abilities may rely on distinct brain systems at premenopause compared with postmenopause.

Disturbed sleep is associated with reduced verbal episodic memory and entorhinal cortex volume in younger middle-aged women with risk-reducing early ovarian removal.

Introduction: Women with early ovarian removal (<48 years) have an elevated risk for both late-life Alzheimer's disease (AD) and insomnia, a modifiable risk factor. In early midlife, they also show reduced verbal episodic memory and hippocampal volume. Whether these reductions correlate with a sleep phenotype consistent with insomnia risk remains unexplored. Methods: We recruited thirty-one younger middleaged women with risk-reducing early bilateral salpingo-oophorectomy (BSO), fifteen of whom were taking estradiol-based hormone replacement therapy (BSO+ERT) and sixteen who were not (BSO). Fourteen age-matched premenopausal (AMC) and seventeen spontaneously peri-postmenopausal (SM) women who were ~10y older and not taking ERT were also enrolled. Overnight polysomnography recordings were collected at participants' home across multiple nights (M=2.38 SEM=0.19), along with subjective sleep quality and hot flash ratings. In addition to group comparisons on sleep measures, associations with verbal episodic memory and medial temporal lobe volume were assessed. Results: Increased sleep latency and decreased sleep efficiency were observed on polysomnography recordings of those not taking ERT, consistent with insomnia symptoms. This phenotype was also observed in the older women in SM, implicating ovarian hormone loss. Further, sleep latency was associated with more forgetting on the paragraph recall task, previously shown to be altered in women with early BSO. Both increased sleep latency and reduced sleep efficiency were associated with smaller anterolateral entorhinal cortex volume. Discussion: Together, these findings confirm an association between ovarian hormone loss and insomnia symptoms, and importantly, identify an younger onset age in women with early ovarian removal, which may contribute to poorer cognitive and brain outcomes in these women.

Sex and menstrual cycle influence human spatial navigation strategies and performance.

Which facets of human spatial navigation do sex and menstrual cycle influence? To answer this question, a cross-sectional online study of reproductive age women and men was conducted in which participants were asked to demonstrate and self-report their spatial navigation skills and strategies. Participants self-reported their sex and current menstrual phase [early follicular (EF), late follicular/periovulatory (PO), and mid/late luteal (ML)], and completed a series of questionnaires and tasks measuring self-reported navigation strategy use, topographical memory, cognitive map formation, face recognition, and path integration. We found that sex influenced self-reported use of cognitive map- and scene-based strategies, face recognition, and path integration. Menstrual phase moderated the influence of sex: compared to men, women had better face recognition and worse path integration, but only during the PO phase; PO women were also better at path integration in the presence of a landmark compared to EF + ML women and men. These findings provide evidence that human spatial navigation varies with the menstrual cycle and suggest that sensitivity of the entorhinal cortex and longitudinal axis of the hippocampus to differential hormonal effects may account for this variation.

Steroid hormones: risk and resilience in women's Alzheimer disease.

More women have Alzheimer disease (AD) than men, but the reasons for this phenomenon are still unknown. Including women in clinical research and studying their biology is key to understand not just their increased risk but also their resilience against the disease. In this sense, women are more affected by AD than men, but their reserve or resilience mechanisms might delay symptom onset. The aim of this review was to explore what is known about mechanisms underlying women's risk and resilience in AD and identify emerging themes in this area that merit further research. We conducted a review of studies analyzing molecular mechanisms that may induce neuroplasticity in women, as well as cognitive and brain reserve. We also analyzed how the loss of steroid hormones in aging may be linked to AD. We included empirical studies with human and animal models, literature reviews as well as meta-analyses. Our search identified the importance of 17-b-estradiol (E2) as a mechanism driving cognitive and brain reserve in women. More broadly, our analysis revealed the following emerging perspectives: (1) the importance of steroid hormones and their effects on both neurons and glia for the study of risk and resilience in AD, (2) E2's crucial role in women's brain reserve, (3) women's verbal memory advantage as a cognitive reserve factor, and (4) E2's potential role in linguistic experiences such as multilingualism and hearing loss. Future directions for research include analyzing the reserve mechanisms of steroid hormones on neuronal and glial plasticity, as well as identifying the links between steroid hormone loss in aging and risk for AD.

Women's Brain Health: Midlife Ovarian Removal Affects Associative Memory.

Women with early bilateral salpingo-oophorectomy (BSO; removal of ovaries and fallopian tubes) have greater Alzheimer's disease (AD) risk than women in spontaneous/natural menopause (SM), but early biomarkers of this risk are not well-characterized. Considering associative memory deficits may presage preclinical AD, we wondered if one of the earliest changes might be in associative memory and whether younger women with BSO had changes similar to those observed in SM. Women with BSO (with and without 17ß-estradiol replacement therapy (ERT)), their age-matched premenopausal controls (AMC), and older women in SM completed a functional magnetic resonance imaging face-name associative memory task shown to predict early AD. Brain activation during encoding was compared between groups: AMC (n=25), BSO no ERT (BSO; n=15), BSO+ERT (n=16), and SM without hormone therapy (n=16). Region-of-interest analyses revealed AMC did not contribute to functional group differences. BSO+ERT had higher hippocampal activation than BSO and SM. This hippocampal activation correlated positively with urinary metabolite levels of 17ß-estradiol. Multivariate partial least squares analyses showed BSO+ERT had a different network-level activation pattern than BSO and SM. Thus, despite being approximately 10 years younger, women with BSO without ERT had similar brain function to those with SM, suggesting early 17ß-estradiol loss may lead to an altered functional brain phenotype which could influence late-life AD risk, making face-name encoding a potential biomarker for midlife women with increased AD risk. Despite similarities in activation, BSO and SM groups showed opposite within-hippocampus connectivity, suggesting menopause type is an important consideration when assessing brain function.

Hormonal contraception and cognition: Considering the influence of endogenous ovarian hormones and genes for clinical translation.

Despite the well-known influence of ovarian hormones on the brain and widespread use of hormonal contraception (HC) since the 1960s, our knowledge of HC's cognitive effects remains limited. To date, the cognitive findings have been inconsistent. In order to establish what might make HC studies more consistent, we surveyed the literature on HCs and cognition to determine whether studies considered HC formulation, phase, pharmacokinetics, duration, and gene interactions, and assessed whether oversight of these factors might contribute to variable findings. We found that synthetic HC hormones exert dose-dependent effects, the day of oral contraceptive (Pill) ingestion is critical for understanding cognitive changes, and gene-cognition relationships differ in women taking the Pill likely due to suppressed endogenous hormones. When these factors were overlooked, results were not consistent. We close with recommendations for research more likely to yield consistent findings and be therefore, translatable.

Reproductive health care appointments: How the institutional organization of obstetric/gynecological work shapes the experiences of women with female genital cutting in Toronto, Canada.

We investigated the social relations shaping the reproductive health care experiences of women with female genital cutting (FGC) in Toronto, Canada. Using Institutional Ethnography, we interviewed eight women with FGC and seven obstetrician/gynecologists (OB/GYN). We found a disjuncture between women's needs during appointments that extended beyond the reproductive body and range of care that doctors were able to provide. Women engaged in emotional healthwork during appointments by explaining FGC to doctors, reading doctors' body language, and getting through vulvar/vaginal examinations. Women reported that if they had emotional reactions during appointments, they were often referred to a mental health specialist, a referral on which they did not act. OB/GYNs described their specialty as "surgical"-training centered around treating reproductive abnormalities and not mental health issues. Therefore, the disjuncture between women's needs and OB/GYNs' institutional training highlights the difficulties inherent when bodies of "difference" encounter the reproductive health care system.

Sex and Gender Science: The World Writes on the Body.

Sex and Gender Science seeks to better acknowledge that the body cannot be removed from the world it inhabits. We believe that to best answer any neuroscience question, the biological and the social need to be addressed through both objective means to learn, "how it is like" and subjective means to learn, "what it is like." We call bringing the biological and social together, "Situated Neuroscience" and the mixing of approaches to do so, Very Mixed Methods. Taken together, they constitute an approach to Sex and Gender Science. In this chapter, we describe neural phenomena for which considering sex and gender together produces a fuller knowledge base: sleep, pain, memory, and concussion. For these brain phenomena examples, studying only quantitative measures does not reveal the full impact of these lived experiences on the brain but studying only the qualitative would not reveal how the brain responds. We discuss how Sex and Gender Science allows us to begin to bring together biology and its social context and acknowledge where context can contribute to resolving ignorance to offer more expansive, complementary, and interrelating pictures of an intricate neuro-landscape.

How Canadian Law Shapes the Health Care Experiences of Women with Female Genital Mutilation/Cutting/Circumcision and Their Providers: A Disjuncture Between Expectation and Actuality.

This study explored how the reproductive health care experiences of women with female genital mutilation/cutting/circumcision (FGC) were shaped. We used Institutional Ethnography, a sociological approach which allows for the study of social relations and the coordination of health care. From qualitatively interviewing eight women with FGC, we learned that they felt excluded within the Canadian health care system because they were unable to access reconstructive surgery, which was not covered by Ontario's universal health coverage (Ontario Health Insurance Plan). We then talked with seven obstetricians/gynecologists (OB/GYNs) and learned that while it was legal to perform certain genital (e.g., female genital cosmetic surgery) and reproductive (e.g., elective caesarean section) surgeries commonly requested by Western-born women, it was not legal for them to perform other genital surgeries often requested by immigrant populations (e.g., reinfibulation), nor were these covered by OHIP (e.g., clitoral reconstructive surgery). From participants' comparison of clitoral reconstructive surgery and reinfibulation to female genital cosmetic and gender confirming surgeries, it became clear that the law and policies within the health care system favored surgeries elected by Western adults over those wished for by women with FGC. We found that the law had an impact on the choices that OB/GYNs and the women they treated could make, shaping their respective experiences. This created ethical dilemmas for OB/GYNs and a sense of exclusion from the health care system for women with FGC.

Review of the effects of polycystic ovary syndrome on Cognition: Looking beyond the androgen hypothesis.

Polycystic-ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age, and many features associated with PCOS - such as elevated androgens, insulin resistance and inflammation - are known to affect cognition. However, effects of PCOS on cognition are not well-understood. Here we review the current literature on PCOS and cognition, note the extent of PCOS symptomatology studied in relation to cognitive outcomes, and identify key research gaps and common methodological concerns. Findings indicate a pattern of worse performance across cognitive domains and brain measures in women with PCOS relative to non-PCOS controls, as well as a lack of evidence for the common assumption that women with PCOS will have higher performance on tasks with a demonstrated male-advantage due to high testosterone levels. We suggest strategies for moving beyond the focus on elevated androgens, in favor of research practices that account for the nuances and heterogeneity of PCOS symptoms.

Scene memory and hippocampal volume in middle-aged women with early hormone loss.

The present study explored whether early midlife bilateral salpingo-oophorectomy (BSO), a female-specific risk factor for dementia, is associated with reduced medial temporal lobe structure and function. Younger middle-aged women with the BRCA1/2 mutation and a BSO prior to spontaneous menopause (SM) were recruited. We determined the performance of women with BSO not taking estradiol-based hormone therapy (n = 18) on a task measuring object and scene recognition and quantified medial temporal lobe subregion volumes using manually segmented high-resolution T2-weighted MRI scans. Comparisons were made to those with BSO taking estradiol-based hormone therapy (n = 20), age-matched premenopausal controls (n = 28), and older women in SM not taking hormone therapy matched for duration of hormone deprivation (n = 17). Reduced hippocampal integrity specific to the BSO group not taking hormone therapy was observed, reflected by significantly smaller dentate gyrus/CA2/CA3 volumes and lower scene recognition memory performance. These findings show that hippocampal subfield volume may be useful for identifying early midlife changes in women at elevated risk for dementia.

Explicit and Implicit Gender-Related Stereotyping in Transgender, Gender Expansive, and Cisgender Adults.

Little is known about gender-related stereotyping among transgender and gender expansive adults. Using the Ambivalent Sexism Inventory (AIS; Glick & Fiske, 1996), we examined explicit gender attitudes in 3298 cisgender, transgender, and gender expansive respondents designated female at birth (FAB; n = 1976 cisgender, n = 108 transgender, n = 188 gender expansive) and male at birth (MAB; n = 922 cisgender, n = 52 transgender, n = 52 gender expansive). In order to learn more about implicit gender-related stereotyping, a subset of 822 participants (FAB; n = 445 cisgender, n = 32 transgender, n = 51 gender expansive. MAB; n = 254 cisgender, n = 21 transgender, n = 19 gender expansive) completed the gender-leadership Implicit Association Test (IAT; Dasgupta & Asgari, 2004). Cisgender men scored significantly higher than all other groups on hostile sexism, but patterns of endorsement for benevolent sexism and implicit attitudes were more nuanced, with cisgender women and gender expansive FAB often scoring significantly below other groups. We observed that transgender men and transgender women, along with cisgender men and gender expansive MAB, moderately endorsed essentialist views regarding differences between men and women (i.e., complementary gender differentiation). These data reveal novel patterns of gender-related stereotyping, with some corresponding to sex designated at birth and others corresponding to current gender identification. Together, these findings suggest that one's experienced gender, designated sex at birth, and the intersection between them may relate to gender stereotyping, underscoring the importance of including transgender and gender expansive individuals in this research.

A new angle on mental rotation ability in transgender men: Modulation by ovarian milieu.

Organizational/activational theory posits that transgender individuals should perform in the direction of their gender, not their sex, on cognitive tasks that show sex differences-the largest of which are observed on visuospatial tasks. Yet, tests of this hypothesis have been mixed for transgender men (TM). One possible reason is that performance shifts associated with the hormonal milieu at testing have not been fully considered in TM. Although "activating" influences, like gender-affirming hormone therapy (GAHT), are well-characterized in this population, endogenous ones, like ovarian cycling, have gone unaddressed. To provide a more complete picture of hormonal activation, we explored an influence of ovarian milieu on visuospatial performance of TM, and its potential contributions toward effects of sex and GAHT. We administered two male-favoring mental rotation tests (MRTs), and a sex-neutral control task to 22 TM naïve to GAHT (TM-), 29 TM receiving GAHT (TM+), and cisgender men (CM; n = 24) and women (CW; n = 43), testing cycling men (TM-) and women (CW) in either early follicular phase (Follicular) or midluteal phase (Luteal). On MRTs, performance of TM- varied across the menstrual cycle, and matched that of menstrual phase-matched CW. Additionally, cycling individuals in Follicular performed as strongly as TM+ and CM, all of whom performed above individuals in Luteal. Effects did not extend to a verbal control task, on which TM+ performed below others. Rather than conforming to static categories that suggest sex- or gender-typical organization of cognitive circuits, our findings support dynamic shifts in visuospatial ability of TM, and illustrate the need to consider activating effects of hormones beyond GAHT.

A portrait of obstructive sleep apnea risk factors in 27,210 middle-aged and older adults in the Canadian Longitudinal Study on Aging.

Determining the prevalence and characteristics of individuals susceptible to present with obstructive sleep apnea (OSA) is essential for developing targeted and efficient prevention and screening strategies. We included 27,210 participants aged ≥45 years old (50.3% women) from the Canadian Longitudinal Study on Aging. Using the STOP questionnaire combined to the percentage of body fat (%BF), we estimated the prevalence of individuals at high-risk for OSA in a sex and age-specific manner, and tested the relation with comorbidities, menopause and systemic inflammation. The prevalence was 17.5%, and was lower in women (13.1%) than in men (21.9%). A high level of high-sensitivity C-reactive protein was the strongest factor associated with OSA risk and this association was 1.3-2.3 times higher in women than in men. OSA risk increased with age, cardiovascular diseases, diabetes mellitus, anxio-depressive symptoms, asthma and arthritis. In women, post-menopausal status was associated with a high OSA risk. Nearly 1 adult out of 5 older than 45 is at risk for OSA in Canada. Comorbidities, menopause and systemic inflammation, more than age, explain increased OSA prevalence. Considering this high prevalence and associations with medical and mental comorbidities, health care practitioners should incorporate systematic OSA screening in their clinical procedures.

Association between risk of obstructive sleep apnea, inflammation and cognition after 45 years old in the Canadian Longitudinal Study on Aging.

BACKGROUND: The association between obstructive sleep apnea and cognitive functioning is not yet fully understood and could be influenced by factors such as sex, age and systemic inflammation. We determined the sex- and age-specific association between obstructive sleep apnea risk and cognitive performance, and the influence of systemic inflammation on this association. METHODS: We included 25,899 participants from the Canadian Longitudinal Study of Aging comprehensive cohort, aged 45-85 years (51% women). We conducted sex- and age-specific (45-59; 60-69; ≥70) general linear models between obstructive sleep apnea risk and cognitive scores, and tested the moderating and mediating effects of high-sensitivity C-reactive protein levels. Obstructive sleep apnea risk was estimated by combining the STOP and whole-body fat percentage. Cognitive tests assessed episodic verbal memory, executive functions and psychomotor speed. Levels of high-sensitivity C-reactive protein were obtained through blood samples. RESULTS: Higher obstructive sleep apnea risk was associated with poorer episodic memory in women aged 45-59 years, and poorer executive function (p < 0.05 on multiple tests) in women aged 45-59 and 60-69 years. No such association was found in men. High-sensitivity C-reactive protein levels mediated some associations between obstructive sleep apnea risk and executive function in women and men aged <70 years. CONCLUSIONS: Being at high-risk for obstructive sleep apnea is associated with poorer cognition in women aged <70 years. These associations were partly mediated by systemic inflammation. These results underscore the importance of obstructive sleep apnea diagnosis, treatment and appropriate follow-up, particularly in middle-aged women who might already show signs of early cognitive impairments.