Estrogens are pivotal regulators of brain function throughout the lifespan, exerting profound effects from early embryonic development to aging. Extensive experimental evidence underscores the multifaceted protective roles of estrogens on neurons and neurotransmitter systems, particularly in the context of Alzheimer's disease (AD) pathogenesis. Studies have consistently revealed a greater risk of AD development in women compared to men, with postmenopausal women exhibiting heightened susceptibility. This connection between sex factors and long-term estrogen deprivation highlights the significance of estrogen signaling in AD progression. Estrogen's influence extends to key processes implicated in AD, including amyloid precursor protein (APP) processing and neuronal health maintenance mediated by brain-derived neurotrophic factor (BDNF). Reduced BDNF expression, often observed in AD, underscores estrogen's role in preserving neuronal integrity. Notably, hormone replacement therapy (HRT) has emerged as a sex-specific and time-dependent strategy for primary cardiovascular disease (CVD) prevention, offering an excellent risk profile against aging-related disorders like AD. Evidence suggests that HRT may mitigate AD onset and progression in postmenopausal women, further emphasizing the importance of estrogen signaling in AD pathophysiology. This review comprehensively examines the physiological and pathological changes associated with estrogen in AD, elucidating the therapeutic potential of estrogen-based interventions such as HRT. By synthesizing current knowledge, it aims to provide insights into the intricate interplay between estrogen signaling and AD pathogenesis, thereby informing future research directions and therapeutic strategies for this debilitating neurodegenerative disorder.

Premature ovarian insufficiency (POI) refers to loss of ovarian activity before the age 40 years. POI has significant detrimental effects on health (infertility, cardiovascular diseases, type 2 diabetes, reduced bone density, dementia), well-being and longevity. This summary is a practical toolkit for health-care professionals (HCPs) looking after women with POI.

A workgroup comprising specialists in gynaecology, reproductive medicine, endocrinology, genetics and family medicine reviewed relevant guidelines and literature on POI to establish recom-mendations for the diagnosis and management of POI in Singapore.

A summary to assist HCPs manage POI was produced, outlining: (1) the aetiology and conse-quences of POI; (2) making the diagnosis; (3) hormone therapy (HT) prescribing options including for those with additional medical conditions; (4) counselling women with POI about HT; and (5) long-term management of POI.

Timely diagnosis and management of POI is vital to prevent long-term adverse consequences, except infertility. HT is the mainstay of treatment and there are no alternatives as effective. Contraindications are very few; estrogen-sensitive cancer is the main contraindication, and caution in prescribing may be needed with established coexisting cardiovascular disease. Estrogen dosage is higher than when treating normal menopause, and as a result, the patient might require more progestogen for endometrial protection. Minimising cardiovascular risk factors by following a healthy lifestyle is important. POI is a significant public health issue and it is imperative that women have affordable access to appropriate HT. Large-scale research on POI in Asian women is needed.

Accumulating evidence suggests that the effects of menopausal hormone therapy (MHT) on risk of Alzheimer disease (AD) and all-cause dementia are influenced by timing of initiation relative to age, time-since-menopause, and the type of formulation. Randomized clinical trials (RCTs) of MHT conducted in postmenopausal women ages 65 and older indicated an increased risk of dementia. While RCTs conducted in midlife are lacking, observational research has provided evidence for associations between midlife estrogen-only therapy (ET) use and a reduced risk of AD and dementia, whereas estrogen-progestogen therapy (EPT) was associated with more variable outcomes. However, existing studies are heterogenous, and conventional endpoints might not adequately assess MHT's potential for AD prevention. Herein, several approaches are being discussed, and the case is being made for utilizing AD biomarkers for assessment of early, AD-specific outcomes in relation to MHT use. From a clinical standpoint, findings that MHT may lower dementia risk warrant consideration as existing therapies like acetylcholinesterase inhibitors and memantine lack preventative efficacy, and vaccines for primary or secondary prevention are not yet available. MHT-associated risks, including breast cancer, stroke and venous thromboembolism, are generally considered rare (<10 events/10 000 women). Overall, the literature supports renewed research interest in evaluating MHT as a female-specific, time-sensitive approach for AD risk reduction, which is key to applying cumulated data in clinical decision making concerning AD prevention.

Menopausal hormone therapy (MHT), along with the apolipoprotein E (APOE) ε4 allele, has been suggested as a possible risk factor for Alzheimer's disease (AD). However, the relationship between MHT and cerebrospinal fluid (CSF) biomarkers is unknown: we investigated this association, and whether APOE ε4 carrier status moderates it.

In an observational study of 136 cognitively unimpaired female participants (Mage = 66.0; standard deviation = 6.3), we examined whether MHT use alone or in interaction with APOE ε4 carrier status was associated with CSF levels of phosphorylated tau (p-tau), amyloid beta (Aβ)40, Aβ42, p-tau/Aβ42, and Aβ42/40 ratios.

Significant interactions were found between APOE ε4 and MHT use for CSF biomarkers. APOE ε4 carriers who were MHT users showed worse levels of CSF p-tau/Aβ42 and Aβ42/40 ratios than all other users and non-users.

The presence of both APOE ε4 and MHT may be associated with elevated amyloid deposition and AD pathology in this sample of participants who demonstrated high familial AD risk.

Significant interactions were found between apolipoprotein E (APOE) ε4 and menopausal hormone therapy (MHT) use for cerebrospinal fluid (CSF) phosphorylated tau (p-tau)/amyloid beta (Aβ)42 and Aβ42/40 ratios. APOE ε4 carriers who were MHT users showed worse levels of CSF biomarkers than non-users and non-carriers, both users and non-users. Younger age at MHT initiation was associated with worse levels of the p-tau/Aβ42 and Aβ42/40 ratios in carriers only. The presence of both APOE ε4 carriage and MHT use may be associated with elevated amyloid deposition and AD pathology. Further studies with larger sample sizes are necessary to confirm the differences observed in the current study.

Chinese women experience higher dementia rates than men, yet sex-specific risk factors are understudied. We examined how menopause age affects cognitive function and decline in aging Chinese women.

Data were from 7419 postmenopausal women 45-101 years of age at baseline in the China Health and Retirement Longitudinal Study (CHARLS; 2011-2018). Menopause age was categorized using clinical cutoffs (<40, 40-44, 45-49, 50-55, >55 years). Cognitive function was assessed with neuropsychological tests up to four times over 7 years, and associations were analyzed using multivariable-adjusted linear mixed-effects regression.

Compared to menopause at 50-55 years (3661/7419; 49.3%), premature (<40; 235/7419; 3.2%), early (40-44; 623/7419; 8.4%), and late menopause (>55; 366/7419; 4.9%) were associated with lower baseline cognitive scores. Although the rate of cognitive decline did not differ significantly across menopause age groups, late menopause showed a trend toward faster decline.

Cognitive health interventions should consider extreme menopausal age as a risk factor.

Extreme menopausal ages-premature (<40), early (40-44), and late (>55)-are linked to lower baseline cognition versus menopause ages 50-55, persisting over 7 years. Cognitive disadvantage for late menopause (>55) versus 50-55 tends to increase over time. Health interventions should consider extreme menopause ages in women's cognitive health.

We examined how symptoms across the mood spectrum relate to Alzheimer's disease (AD) biomarkers in older women at high risk for AD. Participants included 25 women aged 65+ with mild cognitive deficits and elevated AD genetic risk. The Profile of Mood States Questionnaire measured mood symptoms and a total mood disturbance (TMD) score. Tau burden in the meta-temporal region of interest was measured using MK-6240 Tau positron emission tomography (PET) imaging. A subset (n = 12) also had p-Tau181, and Aß40/42 levels measured in plasma. Higher TMD scores related to higher tau PET standardized uptake value ratio (SUVR). Greater negative mood symptoms correlated with higher tau PET SUVR, while greater vigor correlated with lower SUVR. Similar results were seen with plasma p-Tau181 levels, but not with Aβ40/42 levels. In conclusion, positive and negative mood symptoms related to tau pathology in older women at high risk for AD, highlighting a role of mental well-being in AD risk.

Age at menarche (AAM) is a sign of puberty of females. It is a heritable trait associated with various adult diseases. However, the genetic mechanism that determines AAM and links it to disease risk is poorly understood. Aiming to uncover the genetic basis for AAM, we conducted a joint association study in up to 438,089 women from 3 genome-wide association studies of European and East Asian ancestries. A series of bioinformatical analyses and causal inference were then followed to explore in-depth annotations at the associated loci and infer the causal relationship between AAM and other complex traits/diseases. This largest meta-analysis identified a total of 21 novel AAM associated loci at the genome wide significance level (P < 5.0  × 10-8), 4 of which were European ancestry-specific loci. Functional annotations prioritized 33 candidate genes at newly identified loci. Significant genetic correlations were observed between AAM and 67 complex traits. Further causal inference demonstrated the effects of AAM on 13 traits, including forced vital capacity (FVC), high blood pressure, age at first live birth, etc, indicating that earlier AAM causes lower FVC, worse lung function, hypertension and earlier age at first (last) live birth. Enrichment analysis identified 5 enriched tissues, including the hypothalamus middle, hypothalamo hypophyseal system, neurosecretory systems, hypothalamus and retina. Our findings may provide useful insights that elucidate the mechanisms determining AAM and the genetic interplay between AAM and some traits of women.

Commentary on: Nerattini M, Jett S, Andy C, et al Systematic review and meta-analysis of the effects of menopause hormone therapy on risk of Alzheimer's disease and dementia. Front Aging Neurosci. 2023;15:1260427. Series Editor: Dr Teck Khong, DTB Associate Editor, Clinical Pharmacology, St George's,University of London, UK.

An earlier age of menopause (AOM) is hypothesized to increase vulnerability to the neuropathological processes of dementia which begin in midlife.

We tested this hypothesis in a sample of 10,832 women from the Swedish Twin Registry, stratified by menopause etiology. Survival models showed that a U-shaped association was present for women whose menopause occurred spontaneously. Sensitivity analyses conducted in hormone naïve, APOE ε4+ and AOM restricted subsamples showed largely analogous patterns of results.

Supporting conclusions from basic research, our results suggest that estrogens (proxied here by AOM) interact with several biological pathways mediating dementia disease processes. In line with trends in hormone research across the past century, our findings challenge the oversimplified 'more-is-better' perspective on hormone exposure. Specifically, the non-linear association we observed between AOM and dementia risk points to the involvement of distinct and interacting biological mechanisms beyond just estrogen levels.

Alzheimer's disease and other dementia have a higher incidence among women and that risk factors specific to the female sex could be involved. Few studies looked into female reproductive factors and their association with dementia in low-and middle-income countries.

We analyzed the baseline data from the Brazilian Longitudinal Study of Aging (ELSI-Brazil) and included data from 2594 women aged 60 years and older. We used an algorithm approach to determine dementia status and performed logistic regressions using as predictors the self-reported total length of the reproductive period, total parity and use of hormonal replacement therapy. We also analyzed the effects of hormonal replacement therapy use for different age groups and the effects of number of living children.

Reproductive period length, hormonal replacement therapy use and parity as a continuous measure were not significantly associated with dementia status. When compared with 0 births, the group with 5-8 had more dementia while the other groups displayed no differences. For the number of living children, but a higher occurrence of dementia was found among women with more children.

We did not find any association between continuous parity, reproductive period length or hormonal replacement therapy use and dementia. Social factors of motherhood appear to play an important role, and group specific effects of parity and hormonal replacement therapy require further study.

It is not clear whether the association between younger age at menopause and increased risk of dementia is modified by type of menopause. We examined the association of age at menopause or hysterectomy with dementia risk in three groups of women: those with natural menopause, premenopausal bilateral oophorectomy (surgical menopause) or premenopausal hysterectomy (without bilateral oophorectomy).

Individual-level data from 233 802 women in five prospective cohort studies (from four countries) were harmonized and pooled. Cox proportional hazards models were used to assess the associations of age at natural menopause, surgical menopause or premenopausal hysterectomy, with age at dementia, death (where available) or end of follow-up, whichever came first.

The study followed women to the median age of 72 years (quartiles 67, 76 years). The median follow-up time was 13 years, with 3262 dementia cases during this period. Compared with women with menopause at 50-52 years, women with menopause <40 years had a higher risk of dementia (adjusted hazard ratio (aHR): 1.47, 95% confidence interval (CI): 1.39, 1.56). This level of risk was comparable to that of current smoking and stroke, which are well-established risk factors for dementia. Increased risk of dementia associated with surgical menopause or premenopausal hysterectomy (compared to natural menopause) was not apparent after adjustment for age at menopause (aHR 0.99, 95% CI: 0.93, 1.04 and aHR 0.97, 95% CI: 0.95, 1.00, respectively).

Women who experience menopause before the age of 40 years have a higher risk of dementia irrespective of type of menopause.

Evidence for the effect of early menopause on cognition among older women is not consistent and is scant among the Indian population.

We aimed to examine the effect of early menopause (≤45 years) on cognitive performance and brain morphology among older dementia-free females of the TLSA cohort using a multiple linear regression analysis.

In a sample of 528 women, 144 (27%) had early menopause. The linear regression analysis showed that women with early menopause performed poorly in cognition and had lesser total gray matter volume [β = -11973.94, p = 0.033], left middle frontal [β = -353.14, p = 0.033], and left superior frontal [β = -460.97, p < 0.026] volume.

Dementia-free women with early menopause had poorer cognition, lower total gray matter, and frontal lobe. More research is needed to explore the link between earlier menopause and cognitive decline and develop ways to address it.

Evidence on the effect of early menopause on brain morphology is inconsistent and scant in low and middle-income countries, such as India. In a cohort of dementia-free individuals in urban Bangalore, we observed that participants with early menopause had significantly lower cognitive performance and lower total gray matter and frontal lobe volume. We recommend increasing awareness of this fact among the medical community and the general public. There is an urgent need to explore the underlying biological mechanism and to discover effective interventions to mitigate the effect.

Emerging evidence has shown the association between female reproductive histories (e.g., menarche age, parity, premature and early menopause) and the risk of dementia. However, little attention has been given to infertility and pregnancy loss. To examine the associations of infertility, recurrent miscarriages, and stillbirth with the risk of dementia, this study used data from four cohorts in the International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events. Women with data on at least one of the reproductive exposures of interest, dementia, and all covariates were included. Histories of infertility, miscarriage, and stillbirth were self-reported. Dementia (including Alzheimer's disease) was identified through surveys, aged care, pharmaceutical, hospital, and death registry data. Cause-specific Cox regression models were used to estimate the hazard ratios of dementia, accounting for well-established risk factors of dementia, study variability, and within-study correlation. Overall, 291,055 women were included at a median (interquartile range) age of 55.0 (47.0-62.0) at baseline. During the median (interquartile range) follow-up period of 13.0 (12.0-14.0) years, 3334 (1.2%) women developed dementia. Compared to women without stillbirth, a history of recurrent stillbirths (≥ 2) was associated with 64% higher risk of dementia (adjusted hazard ratio = 1.64, 95% confidence interval: 1.46-1.85). Compared to women without miscarriage, women with recurrent miscarriages (≥ 3) were at 22% higher risk of dementia (adjusted hazard ratio = 1.22, 95% confidence interval: 1.19-1.25). These findings suggest that recurrent stillbirths is a risk factor for dementia and may need to be considered in risk assessment of dementia in women.

Dementia is associated with older adults; however, it can also affect younger individuals, known as young-onset dementia (YOD), when diagnosed before the age of 65 years. We aimed to conduct a retrospective cohort study involving middle-aged women to investigate the association between premorbid depression and YOD development.

We included 1.6 million women aged 40-60 years who underwent health checkups under the Korean National Health Insurance Service and investigated the association between depression and YOD.

Women with depression had a significantly higher risk of developing YOD than women without depression. Among premenopausal women, those with depression had a 2.67-fold increased risk, whereas postmenopausal women with depression had a 2.50-fold increased risk. Late age at menarche (> 16 years) and young age at menopause (< 40 years) was associated with an increased risk of YOD.

Depression in middle-aged women is a significant risk factor for the development of YOD. Understanding the role of reproductive factors can aid in the development of targeted therapeutic interventions to prevent or delay YOD.

Objective: The purpose of this integrative review is to assess the existing evidence regarding the effects of a person's lactation history on later-life development of Alzheimer's disease. Methods: The authors searched the electronic databases PubMed, Cumulative Index to Nursing and Allied Health Literature, Scopus, and Excerpta Medica dataBASE, and performed backward reference searches using search terms such as, "Alzheimer's disease, dementia," and "breastfeeding, lactation." Authors selected relevant records through the application of inclusion and exclusion criteria and reading the titles, abstracts, or records in full. Results: In total, 400 articles were identified, and 10 articles meeting inclusion criteria were analyzed. Authors extracted data following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and scored levels of evidence according to Melnyk and Fineout-Overholt. Data were organized according to themes of breastfeeding duration, ever having breastfed, and indirect effects of breastfeeding. Conclusions: Breastfeeding may have neuroprotective effects for the lactating person and reduce the risk of later-life development of Alzheimer's disease. However, future research is necessary to determine the generalizability of this association.

Women have an over 50% greater risk of dementia than men, which is a main topic of much research. This review aims to investigate the impact of a woman's reproductive history on dementia risk. The consequences of stillbirth are long-term health and psychosocial problems for women. Because of the awareness of an endangered pregnancy, many parents experience deep anxiety and stress in subsequent pregnancies. There are contradictory conclusions from research about abortion and the risk of dementia correlation. When it comes to the late age of first birth, which is said to be above 35 years old, it was observed that older mothers have a decreased risk of dementia compared to those who gave birth in their 20s; however, being a child of the older mother is connected with a higher risk of developing dementia. Using hormonal contraception can result in decreased risk of dementia as estrogen stimulates microglia-related Aβ removal and reduces tau hyperphosphorylation. The influence of postmenopausal hormonal therapy and the duration of the reproductive period on developing dementia remains unclear. Although female disorders like endometriosis and polycystic ovary syndrome are reported to increase the risk of dementia, the research on this topic is very limited, especially when it comes to endometriosis, and needs further investigation. Interestingly, there is no conclusion on whether hypertensive disorders of pregnancy increase the risk of dementia, but most articles seem to confirm this theory.

For much of human evolution, the average lifespan was <40 years, due in part to disease, infant mortality, predators, food insecurity, and, for females, complications of childbirth. Thus, for much of evolution, many females did not reach the age of menopause (45-50 years of age) and it is mainly in the past several hundred years that the lifespan has been extended to >75 years, primarily due to public health advances, medical interventions, antibiotics, and nutrition. Therefore, the underlying biological mechanisms responsible for disease risk following menopause must have evolved during the complex processes leading to Homo sapiens to serve functions in the pre-menopausal state. Furthermore, as a primary function for the survival of the species is effective reproduction, it is likely that most of the advantages of having such post-menopausal risks relate to reproduction and the ability to address environmental stresses. This opinion/perspective will be discussed in the context of how such post-menopausal risks could enhance reproduction, with improved survival of offspring, and perhaps why such risks are preserved. Not all post-menopausal females exhibit risk for this set of diseases, and those who do develop such diseases do not have all of the conditions. The diseases of the post-menopausal state do not operate as a unified complex, but as independent variables, with the potential for some overlap. The how and why there would be such heterogeneity if the risk factors serve essential functions during the reproductive years is also discussed and the concept of sets of reversible epigenetic changes associated with puberty, pregnancy, and lactation is offered to explain the observations regarding the distribution of post-menopausal conditions and their potential roles in reproduction. While the involvement of an epigenetic system with a dynamic "modification-demodification-remodification" paradigm contributing to disease risk is a hypothesis at this point, validation of it could lead to a better understanding of post-menopausal disease risk in the context of reproduction with commonalities may also lead to future improved interventions to control such risk after menopause.

Pubertal timing, including age at menarche (AAM), is a heritable trait linked to lifetime health outcomes. Here, we investigate genetic mechanisms underlying AAM by combining genome-wide association study (GWAS) data with investigations of two rare genetic conditions clinically associated with altered AAM: Williams syndrome (WS), a 7q11.23 hemideletion characterized by early puberty; and duplication of the same genes (7q11.23 Duplication syndrome [Dup7]) characterized by delayed puberty. First, we confirm that AAM-derived polygenic scores in typically developing children (TD) explain a modest amount of variance in AAM (R2 = 0.09; p = 0.04). Next, we demonstrate that 7q11.23 copy number impacts AAM (WS < TD < Dup7; p = 1.2x10-8, η2 = 0.45) and pituitary volume (WS < TD < Dup7; p = 3x10-5, ηp2 = 0.2) with greater effect sizes. Finally, we relate an AAM-GWAS signal in 7q11.23 to altered expression in postmortem brains of STAG3L2 (p = 1.7x10-17), a gene we also find differentially expressed with 7q11.23 copy number (p = 0.03). Collectively, these data explicate the role of 7q11.23 in pubertal onset, with STAG3L2 and pituitary development as potential mediators.

The typical age at menopause is 50-51 years in high-income countries. However, early menopause is common, with around 8% of women in high-income countries and 12% of women globally experiencing menopause between the ages of 40 years and 44 years. Menopause before age 40 years (premature ovarian insufficiency) affects an additional 2-4% of women. Both early menopause and premature ovarian insufficiency can herald an increased risk of chronic disease, including osteoporosis and cardiovascular disease. People who enter menopause at younger ages might also experience distress and feel less supported than those who reach menopause at the average age. Clinical practice guidelines are available for the diagnosis and management of premature ovarian insufficiency, but there is a gap in clinical guidance for early menopause. We argue that instead of distinct age thresholds being applied, early menopause should be seen on a spectrum between premature ovarian insufficiency and menopause at the average age. This Series paper presents evidence for the short-term and long-term consequences of early menopause. We offer a practical framework for clinicians to guide diagnosis and management of early menopause, which considers the nature and severity of symptoms, age and medical history, and the individual's wishes and priorities to optimise their quality of life and short-term and long-term health. We conclude with recommendations for future research to address key gaps in the current evidence.

Despite evidence from preclinical studies suggesting estrogen's neuroprotective effects, the use of menopausal hormone therapy (MHT) to support cognitive function remains controversial.

We used random-effect meta-analysis and multi-level meta-regression to derive pooled standardized mean difference (SMD) and 95% confidence intervals (C.I.) from 34 randomized controlled trials, including 14,914 treated and 12,679 placebo participants.

Associations between MHT and cognitive function in some domains and tests of interest varied by formulation and treatment timing. While MHT had no overall effects on cognitive domain scores, treatment for surgical menopause, mostly estrogen-only therapy, improved global cognition (SMD=1.575, 95% CI 0.228, 2.921; P=0.043) compared to placebo. When initiated specifically in midlife or close to menopause onset, estrogen therapy was associated with improved verbal memory (SMD=0.394, 95% CI 0.014, 0.774; P=0.046), while late-life initiation had no effects. Overall, estrogen-progestogen therapy for spontaneous menopause was associated with a decline in Mini Mental State Exam (MMSE) scores as compared to placebo, with most studies administering treatment in a late-life population (SMD=-1.853, 95% CI -2.974, -0.733; P = 0.030). In analysis of timing of initiation, estrogen-progestogen therapy had no significant effects in midlife but was associated with improved verbal memory in late-life (P = 0.049). Duration of treatment >1 year was associated with worsening in visual memory as compared to shorter duration. Analysis of individual cognitive tests yielded more variable results of positive and negative effects associated with MHT.

These findings suggest time-dependent effects of MHT on certain aspects of cognition, with variations based on formulation and timing of initiation, underscoring the need for further research with larger samples and more homogeneous study designs.

The risk for dementia is increased in postmenopausal women. The incidences of premature menopause and dementia have increased in patients with chronic kidney disease (CKD). The potential benefits of hormone replacement therapy (HRT) on cognitive function may be a more critical issue for patients with CKD.

Women aged >40 years with or without HRT were identified using the 2009 National Health Screening Questionnaire. Women who were newly diagnosed with CKD between 2009 and 2013 were enrolled. HRT was used as an exposure variable, and participants were followed from the day CKD was diagnosed to December 2019. The hazard ratio (HR) for dementia was evaluated using Cox proportional hazards regression analysis.

We included 755 426 postmenopausal women with CKD. The median follow-up period was 7.3 (IQR, 5.8-8.7) years. All-cause dementia, Alzheimer's disease, and vascular dementia occurred in 107 848 (14.3%), 87 833 (11.6%), and 10 245 (1.4%) women, respectively. HRT was significantly associated with a lower risk for dementia in the adjusted Cox regression model (all-cause dementia: HR 0.80; 95% confidence interval [CI] 0.78-0.82; p < 0.001; Alzheimer's disease: HR 0.80; 95% CI 0.77-0.82; p < 0.001; vascular dementia: HR 0.80; 95% CI 0.74-0.87; p < 0.001).

HRT was significantly associated with a lower risk for CKD-related cognitive dysfunction in postmenopausal women. Prospective studies are needed to determine whether HRT lowers the risk for dementia in menopausal women with CKD.

Reproductive health history may contribute to cognitive aging and risk for Alzheimer's disease, but this is understudied among Hispanic/Latina women.

Participants included 2126 Hispanic/Latina postmenopausal women (44 to 75 years) from the Study of Latinos-Investigation of Neurocognitive Aging. Survey linear regressions separately modeled the associations between reproductive health measures (age at menarche, history of oral contraceptive use, number of pregnancies, number of live births, age at menopause, female hormone use at Visit 1, and reproductive span) with cognitive outcomes at Visit 2 (performance, 7-year change, and mild cognitive impairment [MCI] prevalence).

Younger age at menarche, oral contraceptive use, lower pregnancies, lower live births, and older age at menopause were associated with better cognitive performance. Older age at menarche was protective against cognitive change. Hormone use was linked to lower MCI prevalence.

Several aspects of reproductive health appear to impact cognitive aging among Hispanic/Latina women.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder responsible for over half of dementia cases, with two-thirds being women. Growing evidence from preclinical and clinical studies underscores the significance of sex-specific biological mechanisms in shaping AD risk. While older age is the greatest risk factor for AD, other distinct biological mechanisms increase the risk and progression of AD in women including sex hormones, brain structural differences, genetic background, immunomodulation and vascular disorders. Research indicates a correlation between declining estrogen levels during menopause and an increased risk of developing AD, highlighting a possible link with AD pathogenesis. The neuroprotective effects of estrogen vary with the age of treatment initiation, menopause stage, and type. This review assesses clinical and observational studies conducted in women, examining the influence of estrogen on cognitive function or addressing the ongoing question regarding the potential use of hormone replacement therapy (HRT) as a preventive or therapeutic option for AD. This review covers recent literature and discusses the working hypothesis, current use, controversies and challenges regarding HRT in preventing and treating age-related cognitive decline and AD. The available evidence indicates that estrogen plays a significant role in influencing dementia risk, with studies demonstrating both beneficial and detrimental effects of HRT. Recommendations regarding HRT usage should carefully consider the age when the hormonal supplementation is initiated, baseline characteristics such as genotype and cardiovascular health, and treatment duration until this approach can be more thoroughly investigated or progress in the development of alternative treatments can be made.

Sex difference exists in the prevalence of dementia and cognitive decline. The impacts of sex-specific reproductive risk factors across the lifespan on the risk of dementia or cognitive decline are still unclear. Herein, we conducted this systemic review and meta-analysis to finely depict the longitudinal associations between sex-specific reproductive factors and dementia or cognitive decline.

PubMed, EMBASE, and Cochrane Library were searched up to January 2023. Studies focused on the associations of female- and male-specific reproductive factors with dementia or cognitive decline were included. Multivariable-adjusted effects were pooled via the random effect models. Evidence credibility was scored by the GRADE system. The study protocol was pre-registered in PROSPERO and the registration number is CRD42021278732.

A total of 94 studies were identified for evidence synthesis, comprising 9,839,964 females and 3,436,520 males. Among the identified studies, 63 of them were included in the meta-analysis. According to the results, seven female-specific reproductive factors including late menarche (risk increase by 15%), nulliparous (11%), grand parity (32%), bilateral oophorectomy (8%), short reproductive period (14%), early menopause (22%), increased estradiol level (46%), and two male-specific reproductive factors, androgen deprivation therapy (18%), and serum sex hormone-binding globulin (22%) were associated with an elevated risk of dementia or cognitive decline.

These findings potentially reflect sex hormone-driven discrepancy in the occurrence of dementia and could help build sex-based precise strategies for preventing dementia.

Women are significantly more likely to develop Alzheimer's disease and related dementias (ADRD) than men. Suggestions to explain the sex differences in dementia incidence have included the influence of sex hormones with little attention paid to date as to the effect of hormonal contraception on brain health. The aim of this scoping review is to evaluate the current evidence base for associations between hormonal contraceptive use by women and non-binary people in early adulthood and brain health outcomes.

A literature search was conducted using EMBASE, Medline and Google Scholar, using the keywords "hormonal contraception" OR "contraception" OR "contraceptive" AND "Alzheimer*" OR "Brain Health" OR "Dementia".

Eleven papers were identified for inclusion in the narrative synthesis. Studies recruited participants from the UK, USA, China, South Korea and Indonesia. Studies included data from women who were post-menopausal with retrospective data collection, with only one study contemporaneously collecting data from participants during the period of hormonal contraceptive use. Studies reported associations between hormonal contraceptive use and a lower risk of ADRD, particularly Alzheimer's disease (AD), better cognition and larger grey matter volume. Some studies reported stronger associations with longer duration of hormonal contraceptive use, however, results were inconsistent. Four studies reported no significant associations between hormonal contraceptive use and measures of brain health, including brain age on MRI scans and risk of AD diagnosis.

Further research is needed on young adults taking hormonal contraceptives, on different types of hormonal contraceptives (other than oral) and to explore intersections between sex, gender, race and ethnicity.

https://doi.org/10.17605/OSF.IO/MVX63, identifier: OSF.io: 10.17605/OSF.IO/MVX63.

Despite a large preclinical literature demonstrating neuroprotective effects of estrogen, use of menopausal hormone therapy (HT) for Alzheimer's disease (AD) risk reduction has been controversial. Herein, we conducted a systematic review and meta-analysis of HT effects on AD and dementia risk.

Our systematic search yielded 6 RCT reports (21,065 treated and 20,997 placebo participants) and 45 observational reports (768,866 patient cases and 5.5 million controls). We used fixed and random effect meta-analysis to derive pooled relative risk (RR) and 95% confidence intervals (C.I.) from these studies.

Randomized controlled trials conducted in postmenopausal women ages 65 and older show an increased risk of dementia with HT use compared with placebo [RR = 1.38, 95% C.I. 1.16-1.64, p < 0.001], driven by estrogen-plus-progestogen therapy (EPT) [RR = 1.64, 95% C.I. 1.20-2.25, p = 0.002] and no significant effects of estrogen-only therapy (ET) [RR = 1.19, 95% C.I. 0.92-1.54, p = 0.18]. Conversely, observational studies indicate a reduced risk of AD [RR = 0.78, 95% C.I. 0.64-0.95, p = 0.013] and all-cause dementia [RR = .81, 95% C.I. 0.70-0.94, p = 0.007] with HT use, with protective effects noted with ET [RR = 0.86, 95% C.I. 0.77-0.95, p = 0.002] but not with EPT [RR = 0.910, 95% C.I. 0.775-1.069, p = 0.251]. Stratified analysis of pooled estimates indicates a 32% reduced risk of dementia with midlife ET [RR = 0.685, 95% C.I. 0.513-0.915, p = 0.010] and non-significant reductions with midlife EPT [RR = 0.775, 95% C.I. 0.474-1.266, p = 0.309]. Late-life HT use was associated with increased risk, albeit not significant [EPT: RR = 1.323, 95% C.I. 0.979-1.789, p = 0.069; ET: RR = 1.066, 95% C.I. 0.996-1.140, p = 0.066].

These findings support renewed research interest in evaluating midlife estrogen therapy for AD risk reduction.

Studies have shown a relationship between oestrogen and Alzheimer's disease. However, there is neither clear nor strong evidence on the use of oestrogen-only therapy in reducing the risk of Alzheimer's disease.

To assess the effects of oestrogen-only therapy on reducing the risk of Alzheimer's disease.

Inclusion criteria was determined with the PICO framework. Outcome was cognitive function measured by neuropsychological tests and strict protocols. Exclusion criteria included non-Alzheimer's dementia, progesterone-only therapy and pre-menopausal women. Searches were conducted in nine electronic healthcare databases, last searched in July 2022. Quality assessments conducted on randomised controlled trials (RCTs) were performed with the GRADE assessment, and cohort studies and case-control studies were assessed with the Newcastle-Ottawa Scale. Extracted data were used to analyse participants, interventions and outcomes.

Twenty-four studies satisfied the search criteria (four RCTs, nine cohort studies, 11 case-control studies). Fifteen studies showed positive associations for oestrogen-only therapy reducing the risk of Alzheimer's disease, and the remaining nine found no evidence of association.

Fifteen studies showed that oestrogen-only therapy effectively reduced the risk of Alzheimer's disease, whereas nine showed no correlation. Studies also investigated oestrogen-related variables such as length of oestrogen exposure, being an apolipoprotein E ε4 carrier and concomitant use of non-steroidal anti-inflammatory drugs, and their role in neuroprotection. This review was limited by the limited ranges of duration of oestrogen treatment and type of oestrogen-only therapy used. In conclusion, oestrogen-only therapy has potential for use in preventing Alzheimer's disease, although current evidence is inconclusive and requires further study.

Objective: Reproductive factors, including parity, may contribute to dementia risk, due to hormonal, physiological, social, and demographic factors. We hypothesized that higher parity would be associated with increased dementia risk. Materials and Methods: We utilized data from the Atherosclerosis Risk in Communities (ARIC) community-based cohort study. Participants were recruited in 1987-1989 and followed through 2017. Participants, all born between 1921 and 1945, were from four U.S. communities in Forsyth County, NC; Jackson, MS; Minneapolis, MN; and Washington County, MD. We included all female participants seen at ARIC visit three or five for whom parity and dementia outcomes were available (N = 7,921). The primary exposure was self-reported number of live births. Our primary outcome was dementia, diagnosed via neurocognitive assessments, informant interviews, and expert adjudication. We created Cox proportional hazards models to evaluate the association between parity and incident dementia, adjusting for demographic factors, education level, apolipoprotein E allele status, and vascular risk factors. We tested for interactions by race and birth cohort. Results: The adjusted hazard ratio was 0.82 (95% confidence intervals [CI] 0.69-0.99) for dementia in women with 0-1 births and 0.85 (95% CI 0.72-0.99) for women with 5+ births, compared to women with 2 births (reference group). This association was present in women born from 1924 to 1934, but not in women born in 1935 or later (p-interaction <0.001). Conclusion: We found an inverted U-shaped association of parity with dementia risk. This effect was modified by birth cohort, suggesting that the association may depend on demographic and sociocultural factors.

Among other risk factors, the decline in estrogen concentrations during menopause may compromise cognitive function. Whether early menopause (EM) is associated with an increased risk of dementia remains unclear. The purpose of this study was to systematically review and meta-analyze current evidence regarding the association between EM or premature ovarian insufficiency (POI) and the risk of dementia of any type.

A comprehensive literature search was conducted through the PubMed, Scopus and CENTRAL databases up to August 2022. Study quality was assessed using the Newcastle-Ottawa scale. Associations were calculated as odds ratio (OR) with 95 % confidence interval (CI). The I2 index was employed for heterogeneity.

Eleven studies (nine assessed as of good and two as of fair quality) were included in the meta-analysis (n = 4,716,862). Women with EM demonstrated a greater risk of dementia of any type than women of normal age at menopause (OR 1.37, 95 % CI 1.22-1.54; I2 93%). However, after excluding a large retrospective cohort study, the results were altered (OR 1.07, 95 % CI 0.78-1.48; I2 94%). Increased risk of dementia was also found in women with POI (OR 1.18, 95 % CI 1.15-1.21; I2 0%). Subgroup analysis showed that this risk was mostly evident in cohort studies, and those which included women with natural menopause.

Women with EM or POI may be at increased risk of dementia compared with women of normal age at menopause, but further research investigating that hypothesis is warranted.

Menopause marks the end of the reproductive phase of life. Based on epidemiological studies, abnormal age at natural menopause (ANM) is thought to contribute to a number of adverse outcomes, such as osteoporosis, cardiovascular disease, and cancer. However, the causality of these associations remains unclear. A powerful epidemiological method known as Mendelian randomization (MR) can be used to clarify the causality between ANM and other diseases or traits. The present review describes MR studies that included ANM as an exposure, outcome and mediator. The findings of MR analyses on ANM have revealed that higher body mass index, poor educational level, early age at menarche, early age at first live birth, early age at first sexual intercourse, and autoimmune thyroid disease appear to be involved in early ANM etiology. The etiology of late ANM appears to be influenced by higher free thyroxine 4 and methylene tetrahydrofolate reductase gene mutations. Furthermore, early ANM has been found to be causally associated with an increased risk of osteoporosis, fracture, type 2 diabetes mellitus, glycosylated hemoglobin, and the homeostasis model of insulin resistance level. In addition, late ANM has been found to be causally associated with an increased systolic blood pressure, higher risk of breast cancer, endometrial cancer, endometrioid ovarian carcinoma, lung cancer, longevity, airflow obstruction, and lower risk of Parkinson's disease. ANM is also a mediator for breast cancer caused by birth weight and childhood body size. However, due to the different instrumental variables used, some results of studies are inconsistent. Future studies with more valid genetic variants are needed for traits with discrepancies between MRs or between MR and other types of epidemiological studies.

Are there associations between natural or surgical menopause and incident dementia by age at menopause?

Compared to age at menopause of 46-50 years, earlier natural menopause (≤40 and 41-45 years) was related to higher risk of all-cause dementia, while a U-shape relationship was observed between age at surgical menopause and risk of dementia.

Menopause marks the end of female reproductive period. Age at menopause reflects the length of exposure to endogenous estrogen. Evidence on the association between age at natural, surgical menopause, and risk of dementia has been inconsistent.

A population-based cohort study involving 160 080 women who participated in the UK Biobank study.

Women with no dementia at baseline, and had no missing data on key exposure variables and covariates were included. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs on the association of categorical menopause age with incident all-cause dementia, Alzheimer's disease (AD) and vascular dementia (VD). Restricted cubic splines were used to model the non-linear relationship between continuous age at natural, surgical menopause, and risk of dementia. In addition, we analyzed the interaction effect of ever-used menopausal hormone therapy (MHT) at baseline, income level, leisure activities, and age at menopause on risk of dementia.

Compared to women with age at menopause of 46-50 years, women with earlier natural menopause younger than 40 years (1.36, 1.01-1.83) and 41-45 years (1.19, 1.03-1.39) had a higher risk of all-cause dementia, while late natural menopause >55 years was linked to lower risk of dementia (0.83, 0.71-0.98). Compared to natural menopause, surgical menopause was associated with 10% higher risk of dementia (1.10, 0.98-1.24). A U-shape relationship was observed between surgical menopause and risk of dementia. Women with surgical menopause before age 40 years (1.94, 1.38-2.73) and after age 55 years (1.65, 1.21-2.24) were both linked to increased risk of all-cause dementia. Women with early natural menopause without ever taking MHT at baseline had an increased risk of AD. Also, in each categorized age at the menopause level, higher income level or higher number of leisure activities was linked to a lowers risk of dementia.

Menopausal age was based on women's self-report, which might cause recall bias.

Women who experienced natural menopause or had surgical menopause at an earlier age need close monitoring and engagement for preventive health measures to delay the development of dementia.

This work was supported by the Start-up Foundation for Scientific Research in Shandong University (202099000066), Science Fund Program for Excellent Young Scholars of Shandong Provence (Overseas) (2022HWYQ-030), and the National Natural Science Foundation of China (82273702). There are no competing interests.

N/A.

To date, there is no homogeneous evidence of whether earlier age at menopause is associated with incident dementia. In addition, the underlying mechanism and driven mediators are largely unknown. We aimed to fill these knowledge gaps.

This community-based cohort study included 154,549 postmenopausal women without dementia at enrolment (between 2006 and 2010) from the UK Biobank who were followed up until June 2021. We followed up until June 2021. Age at menopause was entered as a categorical variable (<40, 40-49, and ≥50 years) with ≥50 years taken as a reference. The primary outcome was all-cause dementia in a time-to-event analysis and the secondary outcomes included Alzheimer's disease, vascular dementia, and other types of dementia. In addition, we investigated the association between magnetic resonance (MR) brain structure indices with earlier menopause, and explored the potential underlying driven mediators on the relationship between earlier menopause and dementia.

2266 (1.47%) dementia cases were observed over a median follow-up period of 12.3 years. After adjusting for confounders, women with earlier menopause showed a higher risk of all-cause dementia compared with those ≥50 years (adjusted-HRs [95% CIs]: 1.21 [1.09-1.34] and 1.71 [1.38-2.11] in the 40-49 years and <40 years groups, respectively; P for trend <0.001). No significant interactions between earlier menopause and polygenic risk score, cardiometabolic factors, type of menopause, or hormone-replacement therapy strata were found. Earlier menopause was negatively associated with brain MR global and regional grey matter indices, and positively associated with white matter hyperintensity. The relationship between earlier menopause and dementia was partially mediated by menopause-related comorbidities including sleep disturbance, mental health disorder, frailty, chronic pain, and metabolic syndrome, with the proportion (95% CI) of mediation effect being 3.35% (2.18-5.40), 1.38% (1.05-3.20), 5.23% (3.12-7.83), 3.64% (2.88-5.62) and 3.01% (2.29-4.40), respectively. Multiple mediator analysis showed a combined effect being 13.21% (11.11-18.20).

Earlier age at menopause was associated with risk of incident dementia and deteriorating brain health. Further studies are warranted to clarify the underlying mechanisms by which earlier age at menopause is linked to an increased risk of dementia, and to determine public health strategies to attenuate this association.

National Natural Science Foundation of China, the Science and Technology Program of Guangzhou, the Key Area Research and Development Program of Guangdong Province, the China Postdoctoral Science Foundation, and the Guangdong Basic and Applied Basic Research Foundation.

Early and premature menopause, or premature ovarian insufficiency (POI), affects 1% of women under the age of 40 years. This paper reviews the main aspects of early and premature menopause and their impact on cognitive decline. Based on the literature, cognitive complaints are more common near menopause: a phase marked by a decrease in hormone levels, especially estrogen. A premature reduction in estrogen puts women at a higher risk for cardiovascular disease, parkinsonism, depression, osteoporosis, hypertension, weight gain, midlife diabetes, as well as cognitive disorders and dementia, such as Alzheimer's disease (AD). Experimental and epidemiological studies suggest that female sex hormones have long-lasting neuroprotective and anti-aging properties. Estrogens seem to prevent cognitive disorders arising from a cholinergic deficit in women and female animals in middle age premature menopause that affects the central nervous system (CNS) directly and indirectly, both transiently and in the long term, leads to cognitive impairment or even dementia, mainly due to the decrease in estrogen levels and comorbidity with cardiovascular risk factors, autoimmune diseases, and aging. Menopausal hormone therapy from menopause to the age of 60 years may provide a "window of opportunity" to reduce the risk of mild cognitive impairment (MCI) and AD in later life. Women with earlier menopause should be taken care of by various specialists such as gynecologists, endocrinologists, neurologists, and psychiatrists in order to maintain their mental health at the highest possible level.

Older females show greater cognitive gains from physical activity (PA) than males, which may be related to long-term consequences of female-specific reproductive events (eg, pregnancy) on cognitive health.

To determine whether previous parity could moderate the relationship between PA and cognitive decline in older women, we conducted secondary analyses of data from the Health, Aging, and Body Composition Study. We tested whether the association between average PA over 10 years and cognition (Modified Mini-Mental State Examination [3MS]) and executive functioning (digit symbol substitution test [DSST]) over 10 years varied by previous parity (nulliparity, low parity, medium parity, and grand multiparity). An analysis of covariance was performed with cognition (average and change over 10 years) as the dependent variables, parity as a categorical predictor, average PA as a continuous predictor, and a set of relevant covariates.

Significant interactions were found between PA and parity group for all 4 comparisons: average 3MS (p = .014), average DSST (p = .032), change in 3MS (p = .016), and change in DSST (p = .017). Simple slope analyses indicated the positive relationship between PA and average 3MS and DSST was only significant in the nulliparity and grand multiparity groups, and the positive relationship between PA and change in 3MS and DSST was only significant in the grand multiparity group.

The findings suggest the relationship between self-reported walking and cognitive performance was strongest in the groups at risk for cognitive decline and dementia, the nulliparous and grand multiparous groups.

To assess the association between the reproductive factors of age at menarche, age at menopause, and reproductive span and the incidence of myocardial infarction (MI) and ischemic stroke (IS).

We used a population-based retrospective cohort study from the National Health Insurance Service database of Korea including a total of 1,224,547 postmenopausal women. Associations between age at menarche (≤ 12, 13-14 [reference], 15, 16, and ≥ 17 years), age at menopause (< 40, 40-45, 46-50, 51-54 [reference], and ≥ 55 years), and reproductive span (< 30, 30-33, 34-36, 37-40 [reference], and ≥ 41 years) and the incidence of MI and IS were assessed by Cox proportional hazard models with adjustment for traditional cardiovascular risk factors and various reproductive factors.

During a median follow-up of 8.4 years, 25,181 MI and 38,996 IS cases were identified. Late menarche (≥ 16 years), early menopause (≤ 50 years), and short reproductive span (≤ 36 years) were linearly associated with a 6%, 12-40%, and 12-32% higher risk of MI, respectively. Meanwhile, a U-shaped association between age at menarche and risk of IS was found, with a 16% higher risk in early menarche (≤ 12 years) and a 7-9% higher risk in late menarche (≥ 16 years). Short reproductive span was linearly associated with an increased risk of MI, whereas both shorter and longer reproductive spans were associated with an increased risk of IS.

This study demonstrated different patterns of association between age at menarche and incidence of MI and IS: a linear association for MI versus a U-shaped association for IS. Female reproductive factors in addition to traditional cardiovascular risk factors should be considered when assessing overall cardiovascular risk in postmenopausal women.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for more than half of all dementia cases in the elderly. Interestingly, the clinical manifestations of AD disproportionately affect women, comprising two thirds of all AD cases. Although the underlying mechanisms for these sex differences are not fully elucidated, evidence suggests a link between menopause and a higher risk of developing AD, highlighting the critical role of decreased estrogen levels in AD pathogenesis. The focus of this review is to evaluate clinical and observational studies in women, which have investigated the impact of estrogens on cognition or attempted to answer the prevailing question regarding the use of hormone replacement therapy (HRT) as a preventive or therapeutic option for AD. The articles were retrieved through a systematic review of the databases: OVID, SCOPUS, and PubMed (keywords "memory", "dementia," "cognition," "Alzheimer's disease", "estrogen", "estradiol", "hormone therapy" and "hormone replacement therapy" and by searching reference sections from identified studies and review articles). This review presents the relevant literature available on the topic and discusses the mechanisms, effects, and hypotheses that contribute to the conflicting findings of HRT in the prevention and treatment of age-related cognitive deficits and AD. The literature suggests that estrogens have a clear role in modulating dementia risk, with reliable evidence showing that HRT can have both a beneficial and a deleterious effect. Importantly, recommendation for the use of HRT should consider the age of initiation and baseline characteristics, such as genotype and cardiovascular health, as well as the dosage, formulation, and duration of treatment until the risk factors that modulate the effects of HRT can be more thoroughly investigated or progress in the development of alternative treatments can be made.