Reproductive factors and their association with physical and comprehensive frailty in middle-aged and older women: a large-scale population-based study.

STUDY QUESTION: Are women's reproductive factors associated with physical frailty and comprehensive frailty in middle-age and later life? SUMMARY ANSWER: Early menarche at <13 years, age at menopause <45 years, surgical menopause, experiencing miscarriage and a shorter reproductive period of <35 years were associated with increased odds of frailty, while having two or three children was related to decreased likelihood of frailty. WHAT IS KNOWN ALREADY: Evidence has shown that women are frailer than men in all age groups and across different populations, although women have longer lifespans. Female-specific reproductive factors may be related to risk of frailty in women. STUDY DESIGN SIZE DURATION: A population-based cross-sectional study involved 189 898 women from the UK Biobank. PARTICIPANTS/MATERIALS SETTING METHODS: Frailty phenotype and frailty index were used to assess physical frailty and comprehensive frailty (assessed using 38 health indicators for physical and mental wellbeing), respectively. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% CI between reproductive factors and likelihood of physical frailty and comprehensive frailty. Restricted cubic spline models were used to test the non-linear associations between them. In addition, we examined the combined effect of categorized age at menopause and menopause hormone therapy (MHT) on frailty. MAIN RESULTS AND THE ROLE OF CHANCE: There was a J-shape relationship between age at menarche, reproductive period, and frailty; age at menarche <13 years and >16 years, and reproductive period <35 years or >40 years were all associated with increased odds of frailty. There was a negative linear relationship between menopausal age (either natural or surgical) and odds of frailty. Surgical menopause was associated with 30% higher odds of physical frailty (1.34, 1.27-1.43) and 30% higher odds of comprehensive frailty (1.30, 1.25-1.35). Having two or three children was linked to the lowest likelihood of physical frailty (0.48, 0.38-0.59) and comprehensive frailty (0.72, 0.64-0.81). Experiencing a miscarriage increased the odds of frailty. MHT use was linked to increased odds of physical frailty in women with normal age at natural menopause (after 45 years), while no elevated likelihood was observed in women with early natural menopause taking MHT. LIMITATIONS REASONS FOR CAUTION: The reproductive factors were self-reported and the data might be subject to recall bias. We lacked information on the types and initiation time of MHT, could not identify infertile women who later became pregnant, and the number of infertile women may be underestimated. Individuals participating in the UK Biobank are not representative of the general UK population, limiting the generalization of our findings. WIDER IMPLICATION OF THE FINDINGS: The reproductive factors experienced by women throughout their life course can potentially predict frailty in middle and old age. Identifying these reproductive factors as potential predictors of frailty can inform healthcare providers and policymakers about the importance of considering a woman's reproductive history when assessing their risk for frailty. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the National Key Research and Development Program of China (2022YFC2703800), National Natural Science Foundation of China (82273702), Science Fund Program for Excellent Young Scholars of Shandong Province (Overseas) (2022HWYQ-030), Taishan Scholars Project Special Fund (No. tsqnz20221103), and the Qilu Young Scholar (Tier-1) Program (202099000066). All authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

The relationship between male and female endogenous reproductive hormones levels and subjective cognitive decline score: A cross-sectional analysis of the Pingyin cohort study.

OBJECTIVE: Reproductive hormones might impact disease course in cognitive decline. We examined the association between male and female endogenous reproductive hormones and subjective cognitive decline (SCD) score. DESIGN, PATIENTS AND MEASUREMENTS: A cross-sectional study design was used with baseline data from the Pingyin cohort study, involving 1943 participants aged 45-70 years. Oestrogen (E2), testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) were measured in females and E2 and testosterone were measured in males. We categorised hormones into three levels of low, intermediate and high level. The 9-item subjective cognitive decline questionnaire (SCD-Q9) scores were collected to assess the symptoms of SCD. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence interval (CI) between categorised hormone levels and SCD status. Multivariable linear regression models were also used. RESULTS: Overall, 1943 participants were involved and 1285 (66.1%) were female. The mean age at baseline was 59.1 (standard deviation 7.1) years. Women with high testosterone levels had a higher probability of having SCD compared with those with low testosterone levels (OR 1.43, 95% CI 1.01-2.05). Men with a high level of testosterone (0.59, 0.35-0.98) and high testosterone/E2 ratio (0.55, 0.33-0.90) were related to decreased chances of having SCD. Each one-unit increase of testosterone was linked to reduced SCD score in males [(ß: -.029, 95% CI (-0.052, -0.007)]. CONCLUSION: There was sex-specific relationship between hormone levels and SCD abnormal. Those with higher testosterone levels in females may increase likelihood of experiencing SCD. Males with higher testosterone levels and higher testosterone/E2 ratio may be associated with reduced likelihood of SCD. The roles of endogenous reproductive hormone levels and their dynamic changes in cognitive function need further investigation.

Life course weight transitions from birth to childhood to midlife and risk of cardiovascular diseases and its subtypes.

BACKGROUND AND AIMS: Evidence on weight transitions across life stages and cardiovascular diseases (CVDs) is limited. We aimed to explore weight transition patterns from birth to childhood to midlife and risk of incident CVDs. METHODS: A total of 193,905 participants from the UK Biobank were included. Weight at birth, childhood, and midlife were collected at baseline (2006-2010). CVD outcomes were collected at year 2022. We constructed 27 transition patterns from birth to age 10 years to midlife. Cox proportional hazard models yielded hazard ratios (HRs) and 95% confidence intervals (CI) between weight transition patterns and CVDs. Mediation analyses were performed. Rate advancement periods (RAP) were also calculated. RESULTS: Several weight transition patterns were clearly linked to risk of CVDs, including "Low birth weight → high weight at age 10 years → obesity at midlife" (HR 2.64, 95% CI 2.24-3.11), "Low birth weight → low weight at age 10 years → obesity at midlife" (2.27, 1.93-2.66), "High birth weight → low weight at age 10 years → obesity at midlife" (2.29, 1.96-2.67), and "High birth weight → high weight at age 10 years → obesity at midlife" (2.14, 1.89-2.42), which showed even stronger association with HF. RAPs of these patterns were 8.3-10.6 years for CVD and 10.0-13.1 for HF. 50% of the association between birth weight and CVDs was mediated by weight at midlife. CONCLUSIONS: Our findings highlight the importance of weight management throughout the life course in reducing the risk of CVDs, especially maintaining a heathy weight at midlife.

Association and prediction of Life's Essential 8 score, genetic susceptibility with MCI, dementia, and MRI indices: A prospective cohort study.

BACKGROUND: To examine the associations of Life's Essential 8 (LE8) and its predictive performance with mild cognitive impairment (MCI), dementia and brain MRI indices. METHODS: We used cohort data from UK Biobank. LE8 was categorized into low (<50 score), moderate (50-79 score), and high (≥80 score) levels. Cox regression models considering death as a competing risk were used to estimate the hazard ratios (HRs) and 95%CI on the association between LE8 and MCI and dementia. Multivariable linear regression models were used to analyze LE8 every 10-score increase and brain MRI indices. Area under the curve (AUC) was used to measure the predictive performances of LE8. RESULTS: We included 126,785 participants with a mean (SD) age of 56.0 (8.0) years and 53.5 % were female. The median follow-up was 13.0 years. Compared to individuals with a low LE8 score, those with a high LE8 score were associated with decreased risk of MCI (0.49, 95%CI: 0.40-0.62), all-cause dementia (0.60, 0.44-0.80), vascular dementia (VD, 0.44, 0.21-0.94), and non-Alzheimer non-vascular dementia (NAVD, 0.55, 0.35-0.84). High LE8 score was associated with increased total brain volume, hippocampus volume, grey matter volume, and grey matter in hippocampus volume (p all ≤0.001). LE8 combined age and sex had good performance for predicting all-cause dementia (AUC: 84.1 %), AD (85.4 %), VD (87.6 %), NAVD (81.4 %), and MCI (75.3 %). LIMITATIONS: Our findings only reflect the characteristics of UKB participants. CONCLUSIONS: High LE8 score was associated with reduced risk of MCI and dementia. It was also linked to brain MRI indices. LE8 score had good predicting performance for future risk of MCI and dementia.

Association between ABO genotypes and risk of dementia and neuroimaging markers: roles of sex and APOE status.

Background: Whether the relationships between ABO blood genotypes (AA, AO, BB, BO, AB, and OO) and dementia are modified by gender and APOE status has been unclear. Methods: We used data from the UK Biobank, a population-based cohort study of 487,425 individuals. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) between ABO genotypes and risk of dementia. Multivariable linear regression models were used to estimate the relationship between ABO genotypes and MRI-based brain indices. Results: Overall, 487,425 participants were included at baseline. After 34 million person-years follow up, 7,548 patients developed all-cause dementia. Before stratifying by sex and APOE status, compared to OO genotype, BB genotype was associated with increased risk of all-cause dementia (1.36, 1.03-1.80) and other types dementia (1.65, 1.20-2.28). After stratifying by sex, only in males, BB genotype was associated with higher risk of all-cause dementia (1.44, 1.02-2.09) and other types of dementia (1.95, 1.30-2.93). AB genotype in males was also associated with increased AD (1.34, 1.04-1.72). After further stratifying by APOE e4 status, BB genotype with two APOE e4 alleles showed even stronger association with all-cause dementia 4.29 (1.57, 11.72) and other types dementia (5.49, 1.70-17.69) in males. Also in males, AA genotype with one APOE e4 was associated with increased risks of all-cause dementia (1.27, 1.04-1.55), AD (1.45, 1.09-1.94) and other types dementia (1.40, 1.08-1.81). Linear regression models showed that in both sexes with APOE e4, AA genotype was associated with reduced total grey matter volume. Conclusion: Sex and APOE e4 carrier status modified the association between ABO genotypes and risk of dementia. In males, BB genotype was consistently associated with increased risk of dementia, especially in those with two APOE e4 alleles. Also, in males with one APOE e4, AA genotype might be linked to higher risk of dementia.

Extension of interval between adjacent pulse delivery cycles to deal with myocardial ischemia by intravascular lithotripsy: case report.

BACKGROUND: Intravascular lithotripsy (IVL) represents a novel approach in the management of coronary calcification. This technique employs acoustic pressure waves, generated by a shockwave balloon, to effectively fracture both superficial and deep calcification in situ. The efficacy and safety of IVL have been convincingly demonstrated through the Disrupt CAD I-IV studies. While IVL is associated with the occurrence of atrial and ventricular arrhythmias, there is no evidence to indicate it causes myocardial ischemia. CASE DESCRIPTION: A 71-year-old man was admitted presenting with chest pain. His previous coronary angiography revealed stenosis and calcification in the left anterior descending branch. An attempt to predilate the lesion using two Lacrosse non-slip element balloons was unsuccessful. Ventricular premature beats and transient ST-segment depression were captured during the utilization of IVL. The operator gradually extended the pulse emission interval across two consecutive cycles to mitigate myocardial ischemia. Notably, when the interval reached 30s, the patient had no chest pain or ST-segment changes. Subsequent images of intravascular ultrasound confirmed calcification ruptures. Therapeutic intervention included the placement of a stent and the application of a drug-coated balloon in the left anterior descending branch. A telephonic follow-up six months later indicated the patient had no discomfort. CONCLUSIONS: This case underscores the effectiveness of gradually extending the pulse emission interval as a strategic complement to the clinical application of IVL. In certain clinical scenarios, it may become imperative to suspend the pulse delivery to improve myocardial blood supply.

Healthy lifestyle and all-cause and cause-specific dementia in individuals with type 2 diabetes and the roles of diabetes duration and insulin use in UK Biobank cohort.

AIMS: To examine the effect of a healthy lifestyle score derived from seven lifestyle factors recommended by the diabetes management guidelines on all-cause and cause-specific dementia in individuals with type 2 diabetes mellitus (T2DM), and how diabetes duration and insulin use status modify their association. MATERIALS AND METHODS: This study analysed data of 459 840 participants from the UK Biobank. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals for the association of an overall healthy lifestyle score with all-cause and cause-specific dementia of Alzheimer's disease, vascular dementia and non-Alzheimer non-vascular dementia. RESULTS: Using diabetes-free participants who scored 5-7 as the reference group, in diabetes-free participants, we observed higher healthy lifestyle score was related to lower risk of all-cause and cause-specific dementia. However, in people with T2DM, those scored 2-3, 4 and 5-7 all had around the two-time risk of all-cause dementia (HR: 2.20-2.36), while those scored 0-1 had over a three-time risk (HR: 3.14, 95% confidence interval 2.34-4.21). A dose-response trend was observed with vascular dementia (each 2-point increase: 0.75, 0.61-0.93) and no significant association with Alzheimer's disease (0.95, 0.77-1.16). The reduced risk of all-cause and cause-specific dementia with higher lifestyle score was observed in patients with a diabetes duration less than 10 years, or in patients with no insulin use. CONCLUSION: In people with T2DM, higher healthy lifestyle score was associated with lower risk of all-cause dementia. Diabetes duration and insulin use moderated the association between healthy lifestyle score and risk of dementia.

Age at menopause and all-cause and cause-specific dementia: a prospective analysis of the UK Biobank cohort.

STUDY QUESTION: Are there associations between natural or surgical menopause and incident dementia by age at menopause? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN, SIZE, DURATION: A population-based cohort study involving 160 080 women who participated in the UK Biobank study. PARTICIPANTS/MATERIALS, SETTING, METHODS: 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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. LIMITATIONS, REASONS FOR CAUTION: Menopausal age was based on women's self-report, which might cause recall bias. WIDER IMPLICATION OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTERESTS: 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. TRIAL REGISTRATION NUMBER: N/A.

Midlife Life's Simple 7, Psychosocial Health, and Physical Frailty, Hospital Frailty, and Comprehensive Frailty 10 Years Later.

This study aims to examine the associations between midlife Life's Simple 7 (LS7) status, psychosocial health (social isolation and loneliness), and late-life multidimensional frailty indicators, and to investigate their synergistic effect on frailty. We used cohort data from the UK Biobank. Frailty was assessed using physical frailty phenotype, hospital frailty risk score, and frailty index. Cox proportional-hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) on the association between the LS7 score, psychosocial health, and frailty. For the association of LS7 with physical and comprehensive frailty, 39,047 individuals were included. After a median follow-up of 9.0 years, 1329 (3.4%) people were identified with physical frailty, and 5699 (14.6%) with comprehensive frailty. For the association of LS7 with hospital frailty, 366,570 people were included. After a median follow-up of 12.0 years, 18,737 (5.1%) people were identified with hospital frailty. Compared to people with a poor LS7 score, those with an intermediate (physical frailty: 0.64, 0.54-0.77; hospital frailty: 0.60, 0.58-0.62; and comprehensive frailty: 0.77, 0.69-0.86) and optimal LS7 score (physical frailty: 0.31, 0.25-0.39; hospital frailty: 0.39, 0.37-0.41; and comprehensive frailty: 0.62, 0.55-0.69) were associated with a lower risk of frailty. Poor psychosocial health was associated with an increased risk of frailty. People who had a poor psychosocial status and poor LS7 score had the highest risk of frailty. A better LS7 score in midlife was associated with a reduced risk of physical, hospital, and comprehensive frailty. There was a synergistic effect of psychosocial status and LS7 on frailty.

Number of Live Births, Age at the Time of Having a Child, Span of Births and Risk of Dementia: A Population-Based Cohort Study of 253,611 U.K. Women.

Objectives: The association between birth-related factors and dementia is unclear. We aimed to investigate their association and subsequent risk of dementia in a large-scale follow-up prospective study. Materials and Methods: This population-based cohort study used data from U.K. Biobank (2006-2010), and the median follow-up was 12.0 years. Multivariable-adjusted Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) between number of children, age of first live birth, age of last live birth, span of births, and dementia. Restricted cubic spline models were used to quantify dose-response relationships. Results: A total of 253,611 women with mean age (standard deviation) of 56.3 (8.0) years were included. Compared with women with no child, women who had three or more children and first birth at age before 25 years, had elevated risk of all-cause dementia (HR: 1.30, 95% CI: 1.10-1.54), Alzheimer's disease (AD; 1.21, 1.00-1.46), and vascular dementia (VD; 1.59, 1.19-2.13). Also, women with three or more children and the last birth at age before 30 years, had increased risk of all-cause dementia (1.33, 1.11-1.59), AD (1.27, 1.03-1.57), and VD (1.55, 1.12-2.13). Moreover, women who had three or more children in <7 years, had an increased risk of all-cause dementia (1.25, 1.04-1.49). Dose-response relationship showed a lowest risk of dementia at having two children, and having three or more children in 7-9 years. Conclusions: Number of children, age of births, and span of births were all related to risk of dementia. These findings may help developing fertility policies or dementia prevention programs.

Sex-specific associations between diabetes and dementia: the role of age at onset of disease, insulin use and complications.

BACKGROUND: Whether the association of type 2 diabetes (T2DM) with dementia was differed by sex remains unclear, and the roles of age at onset of disease, insulin use and diabetes' complications in their association are unknown. METHODS: This study analyzed data of 447 931 participants from the UK Biobank. We used Cox proportional hazards models to estimate sex-specific hazard ratios (HRs) and 95% confidence intervals (CI), and women-to-men ratio of HRs (RHR) for the association between T2DM and incident dementia [all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD)]. The roles of age at onset of disease, insulin use and diabetes' complications in their association were also analyzed. RESULTS: Compared to people with no diabetes at all, people with T2DM had increased risk of all-cause dementia (HR 2.85, 95% CI 2.56-3.17). The HRs between T2DM and AD were higher in women than men, with an RHR (95%CI) of 1.56 (1.20, 2.02). There was a trend that people who experienced T2DM before age 55 had higher risk of VD than those who had T2DM after age 55. In addition, there was a trend that T2DM had higher effect on VD that occurred before age 75 years than events that occurred after age 75. Patients with T2DM using insulin had higher risk of all-cause dementia than those without insulin, with an RHR (95%CI) of 1.54 (1.00-2.37). People with complications had doubled risk of all-cause dementia, AD and VD. CONCLUSIONS: Adopting a sex-sensitive strategy to address the risk of dementia in patients with T2DM is instrumental for a precision medicine approach. Meanwhile, it is warranted to consider patients' age at onset of T2DM, insulin use status and complications conditions.

Sex Differences in Memory: Do Female Reproductive Factors Explain the Differences?

Background: The sex differences in memory impairment were inconclusive, and the effect of female reproductive factors (age at menarche, age at menopause, and reproductive period) on the differences was not clear. We aimed to examine the sex differences in objective and subjective memory impairment in postmenopausal women and age- and education-matched men and explore whether the differences were differed by female reproductive factors. Methods: Data were obtained from the China Health and Retirement Longitudinal Study. Using the case-control matching method, 3,218 paired postmenopausal women and men matched for age and education were selected. Memory was assessed using the three-word recall task and a self-rated question. Poisson regression models with a robust error variance were used. Results: The relative risk was 1.22 (95% confidence interval 1.08-1.38) for objective memory impairment in women compared with men (23.87% vs. 27.36%), and 1.51 (1.36-1.67) for subjective memory impairment (39.34% vs. 28.25%) after adjusting the confounders. The higher risk of objective memory impairment in women was different among groups of age at menarche in a linear pattern, with younger age at menarche associated with higher risks of objective memory impairment (p < 0.001 for trend). It was also different among groups of menopausal age and reproductive period in an approximate U-shaped pattern, with a similar risk of objective memory with men in women menopause at 52-53 years and having a reproductive period of 31-33 years and higher risks in women with earlier or later menopause (RRs raging form 1.17 to1.41) and a shorter or longer period of reproduction (RR, 1.23-1.29). The higher risks of subjective memory impairment in women were not different among different groups of reproductive factors. Conclusions: Postmenopausal women were at an increased risk of objective and subjective memory impairment than men. The higher risks in objective memory, but not subjective memory, were varied by age at menarche, age at menopause, and reproductive periods, which may help understand the underlying mechanisms of sex differences in cognitive ageing and guide precise intervention to preventing dementia among older women and men.

Sex differences in the association between cardiovascular diseases and dementia subtypes: a prospective analysis of 464,616 UK Biobank participants.

BACKGROUND: Whether the association of cardiovascular diseases (CVDs) with dementia differs by sex remains unclear, and the role of socioeconomic, lifestyle, genetic, and medical factors in their association is unknown. METHODS: We used data from the UK Biobank, a population-based cohort study of 502,649 individuals. We used Cox proportional hazards models to estimate sex-specific hazard ratios (HRs) and 95% confidence intervals (CI), and women-to-men ratio of HRs (RHR) for the association between CVD (coronary heart diseases (CHD), stroke, and heart failure) and incident dementia (all-cause dementia, Alzheimer's Disease (AD), and vascular dementia (VD)). The moderator roles of socioeconomic (education, income), lifestyle (smoking, BMI, leisure activities, and physical activity), genetic factors (APOE allele status), and medical history were also analyzed. RESULTS: Compared to people who did not experience a CVD event, the HRs (95%CI) between CVD and all-cause dementia were higher in women compared to men, with an RHR (Female/Male) of 1.20 (1.13, 1.28). Specifically, the HRs for AD were higher in women with CHD and heart failure compared to men, with an RHR (95%CI) of 1.63 (1.39, 1.91) and 1.32 (1.07, 1.62) respectively. The HRs for VD were higher in men with heart failure than women, with RHR (95%CI) of 0.73 (0.57, 0.93). An interaction effect was observed between socioeconomic, lifestyle, genetic factors, and medical history in the sex-specific association between CVD and dementia. CONCLUSION: Women with CVD were 1.5 times more likely to experience AD than men, while had 15% lower risk of having VD than men.

Association of reproductive factors with dementia: A systematic review and dose-response meta-analyses of observational studies.

BACKGROUND: Associations between endogenous estrogen exposure indicators and risk of subtypes of dementia have been unclear. METHODS: Databases (PubMed, EMBASE and Web of Science) were searched electronically on 1st July and updated regularly until 12nd November 2021. Observational studies of English language were selected if reported an effect estimate [e.g., odds ratio (OR), rate ratio (RR) or hazard ratio (HR)] and 95% CI for the association between any exposure (age of menarche, age at menopause, reproductive period, estradiol level) and any endpoint variable [all-cause dementia, Alzheimer's disease (AD), vascular dementia (VD), cognitive impairment (CI)]. Random-effects models and dose-response meta-analyses were used to calculate estimates and to show the linear/nonlinear relationship. PROSPERO CRD42021274827. FINDINGS: We included 22 studies (475 9764 women) in this analysis. We found no clear relationship between late menarche (≥14 vs <14 years) and dementia, CI in categorical meta-analysis compared to a J-shape relationship in dose-response meta-analyses. Later menopause (≥45 vs <45 years) was consistently associated with a lower risk of all-cause dementia (pooled RR: 0.87, 95%CI: 0.78-0.97, I2=56.0%), AD (0.67, 0.44-0.99, I2=78.3%), VD (0.87, 0.80-0.94) and CI (0.82, 0.71-0.94, I2=19.3%) in categorical meta-analysis, showing similar results in dose-response meta-analyses. An inverse relationship between longer reproductive duration (≥35 vs <35 years) and dementia was observed in dose-response meta-analysis. In addition, estradiol levels after menopause were inversely correlated with the risk of AD and CI. INTERPRETATION: In this study, later menopause and longer reproductive period were associated with a lower risk of dementia, while the relationship for menarchal age was J-shaped. There was an inverse relationship between higher postmenopausal estrogen levels and risk of AD and CI. Longitudinal study are needed to further explore the association between life-time estrogen exposure and risk of subtypes of dementia. FUNDING: Start-up Foundation for Scientific Research in Shandong University.