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

Abstract

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.

Associations of Parity With Change in Global Cognition and Incident Cognitive Impairment in Older Women

“…In present-day affluent societies (high-income countries, e.g., Sweden), higher number of parity seems to be linked with higher income, status, labor force participation, and more resources, thereby playing a pivotal protective role in cognitive decline and dementia ( Andersson and Scott, 2007 ; Sobotka et al, 2011 ). In addition, increasing number of parity might be related to a later age of menopause and longer duration of reproductive span, all of which are associated with better cognitive performance and delayed cognitive decline ( Georgakis et al, 2016 ; Fu et al, 2021 ).…”

Associations between abdominal adipose tissue, reproductive span, and brain characteristics in post-menopausal women

“…In females, levels of oestrogen exposure pre-menopause may influence both brain health and body composition post-menopause, emphasising the complex interactions between neuroendocrine and metabolic processes across the female lifespan. For example, levels of cumulative oestrogen exposure, often assessed by reproductive span (age at menarche to age at menopause; ( Fu et al, 2022 , Gilsanz et al, 2019 , Jett et al, 2022 ), have been linked to larger GM volumes ( Schelbaum et al, 2021 ), lower WM brain age ( Subramaniapillai et al, 2022 ), and lower dementia risk in older-age samples ( Fox et al, 2013 , Gilsanz et al, 2019 , Gong et al, 2022 ), although contrasting results have linked a longer reproductive span to increased risk of Alzheimer’s disease ( Najar et al, 2020 , Geerlings et al, 2001 ). Age at menarche and menopause are also known to have genetic components ( Fernández-Rhodes et al, 2018 , Wang et al, 2019 , Ruth et al, 2021 ), but it is unclear how the genetics underlying reproductive span relate to body composition and brain structure ( Roa-Díaz et al, 2021 ).…”

Reproductive factors and cognitive impairment in natural menopausal women: A cross-sectional study

“…Taiwan Biobank data also indicated that late menarche was associated with poor cognitive function ( 16 ). A meta-analysis showed that older age at menopause and a longer reproductive period were associated with a lower risk of dementia ( 33 , 34 ).…”