Summary 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, I 2 =56.0%), AD (0.67, 0.44–0.99, I 2 =78.3%), VD (0.87, 0.80–0.94) and CI (0.82, 0.71–0.94, I 2 =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.

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.

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.

AimsTo 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 MethodsThis 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.ResultsUsing 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.ConclusionIn 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.

Background Diabetes and dementia share common lifestyle risk factors, while few studies have examined the effect of seven healthy lifestyle factors as recommended by the diabetes management guidelines on all-cause and cause-specific dementia in individuals with type 2 diabetes (T2DM). Also, the roles of diabetes duration and insulin therapy in their association remain unclear. Methods This study analyzed data of 459 840 participants from the UK Biobank. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the association of an overall healthy lifestyle score (derived from smoking, social connection, alcohol consumption, physical activity, sedentary, sleep duration and diet) with all-cause and cause-specific dementia of Alzheimer's disease (AD), Vascular dementia (VD) and Non-Alzheimer non-vascular dementia (NAVD), using people without T2DM as the reference group. We also analyzed the role of diabetes duration and insulin use on the association between lifestyle score and dementia. Results During a mean follow-up of 12.1 years, 5 268 incident dementia events were recorded. Using diabetes-free participants who had a lifestyle score of 5–7 as reference group, in diabetes-free participants, we observed a clear trend that higher healthy lifestyle score was related to lower risk of all-cause and cause-specific dementia. However, in people with T2DM, we did not observe such a trend with all-cause dementia. People with lifestyle score of 2–3, 4 and 5–7 all had around two-time risk of all-cause dementia (HR: 2.20–2.36), while those with a score of 0–1 had over three-time risk (HR: 3.14, 95% CI 2.34–4.21). After separating the analyses with dementia subtypes, a dose-response trend was only observed with VD (each two-point increase: 0.75, 0.61–0.93), and no significant association with AD (0.95, 0.77–1.16). The reduced risk of all-cause dementia, AD, VD, and NACD with higher lifestyle score was only observed in patients with diabetes duration less than 10 years, or in patients with no insulin use. Conclusions In people with T2DM, higher healthy lifestyle score was associated with lower risk of all-cause dementia, while the relationship with cause-specific dementia was inconsistent. A dose-response trend was only observed with VD, not with AD. The beneficial effect of healthy lifestyle was only observed in people with diabetes duration less than 10 years, or in those with no insulin use.

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.

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 &gt;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.

Introduction: Evidence on the association between age at menopause and risk of dementia has been inconsistent. Some studies observed that later menopause was related to lower risk of dementia, while others reported no association, or even came to the opposite. Estradiol plays an important role in a wide range of neurological functions in brain, so the reduction of endogenous estrogen at menopause may aggravate brain changes related to neurodegenerative diseases, and accelerate the progression of dementia. Hypothesis: Based on the neuroprotective effects of estrogen, we hypothesized that earlier menopause might be related to higher risk of and earlier onset of dementia, compared with menopause at normal age or later. Methods: We used cohort data from UK Biobank and a total of 153 291 postmenopausal women were included. Age at menopause was categorized as <40 (premature), 40-44 (early), 45-49, 50-51 (reference), 52-55, and >55 years. The main outcome was all-cause dementia, a comprehensive outcome including Alzheimer's disease (AD), vascular dementia (VD) and dementia classified elsewhere. We used Cox proportional hazards model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) on the association between menopausal age and all-cause dementia. We also stratified the age when dementia was diagnosed into ≤65 years and >65 years to explore the association between age at menopause and timing of experiencing dementia. All HRs were adjusted for age at last follow-up, race, education level, BMI, cigarette smoking, alcohol drinking, cardiovascular disease status, diabetes status, income, leisure activities and physical activities. We also used restricted cubic splines to analyze the dose-response relationship between menopausal age and dementia. Results: Among the 153 291 women, there were 1688 woman suffering from all-cause dementia. The average follow-up time was 11.7 years. Compared with menopausal age of 50-51 years, the HRs (95% CI) with dementia in women with menopausal age <40, 40-44, 45-49, 52-55 and >55 years were 1.53 (1.22-1.91), 1.07 (0.89-1.28), 1.08 (0.94-1.25), 0.81 (0.70-0.94), and 0.91 (0.78-1.06) respectively. Restricted cubic spline also showed an inverse dose-response relationship between them. In addition, compared to women with menopausal age of 50-51 years, women with early menopause (<45 years) had elevated risk of experiencing all-caused dementia before age 65 years (1.31, 1.07-1.72; P <0.001). Conclusions: Compared to women with menopausal age of 50-51 years, women with premature menopause (<40 years) had around 35% higher risk of having all-cause dementia, and women with early menopause (<45 years) were 1.3 times more likely to experience presenile dementia before age 65 years. Women with early menopause may need a close monitoring of their cognitive decline in clinical practice.