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

Abstract

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.

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

“…Multiple mechanisms (such as menopause, reproductive duration) might underly the relationship between endogenous estrogen exposure and frailty. Postmenopausal estrogen decline contributes to increased bone loss ( Khosla and Pacifici, 2021 ), muscle weakness (known as sarcopenia) ( Messier et al , 2011 ; Buckinx and Aubertin-Leheudre, 2022 ), a higher risk of CVD ( Zhu et al , 2019 ), metabolic dysregulation ( Mauvais-Jarvis et al , 2013 ; Jeong and Park, 2022 ), heightened inflammation ( Abildgaard et al , 2020 ; Khalafi et al , 2021 ), and cognitive functions ( Hao et al , 2023 ), all of which contribute to frailty.…”

“…Hysterectomy was defined as removal of the uterus before natural menopause without bilateral oophorectomy, and age of hysterectomy was categorized as ≤40, 41–45, 46–50, 51–55, and >55 years. Age at natural menopause was categorized as pre-menopause, perimenopause, ≤40 (premature), 41–45 (early), 46–50, 51–55, and >55 years (late menopause) ( Hao et al , 2023 ). Perimenopausal women were defined as those who were experiencing irregular menstrual cycles (<14 days or >90 days), or those who had not menstruated in the past 3 months but had menstruated within the last 12 months.…”

Brain volumetric changes in menopausal women and its association with cognitive function: a structured review

“…Nevertheless, women could have premature or early menopause if their FMP occurs before 40 and 45 years of age, respectively, due to various causes, including surgical and non-surgical ( Shuster et al, 2010 ). Early menopause is associated with shorter lifetime exposure to endogenous sex hormones, which negatively impacts neurological health ( Matyi et al, 2019 ; Hao et al, 2023 ) and the cardiovascular system ( Zhu et al, 2019 ). In contrast, prolonged exposure to endogenous hormones exerts neuroprotective effects, as evidenced by a larger GM volume of the superior parietal lobule and left precuneus ( Schelbaum et al, 2021 ).…”

Association of infertility and recurrent pregnancy loss with the risk of dementia

“…A growing number of studies suggest female reproductive histories, such as later age at menarche, nulliparity, premature and early menopause (Supplementary Table 1), as the risk factors of dementia [5][6][7][8][9][10][11][12][13]. These studies suggest shorter cumulative exposure to oestrogen as a key underlying mechanism.…”