Reproductive factors and the risk of incident dementia: A cohort study of UK Biobank participants

Abstract

Background Women’s reproductive factors have been associated with the risk of dementia; however, these findings remain uncertain. This study aimed to examine the risk of incident all-cause dementia associated with reproductive factors in women and the number of children in both sexes and whether the associations vary by age, socioeconomic status (SES), smoking status, and body mass index (BMI) in the UK Biobank. Methods and findings A total of 273,240 women and 228,957 men without prevalent dementia from the UK Biobank were included in the analyses. Cox proportional hazard regressions estimated hazard ratios (HRs) for reproductive factors with incident all-cause dementia. Multiple adjusted models included age at study entry, SES, ethnicity, smoking status, systolic blood pressure, BMI, history of diabetes mellitus, total cholesterol, antihypertensive drugs, and lipid-lowering drugs. Over a median of 11.8 years follow-up, 1,866 dementia cases were recorded in women and 2,202 in men. Multiple adjusted HRs ((95% confidence intervals (CIs)), p-value) for dementia were 1.20 (1.08, 1.34) (p = 0.016) for menarche <12 years and 1.19 (1.07, 1.34) (p = 0.024) for menarche >14 years compared to 13 years; 0.85 (0.74, 0.98) (p = 0.026) for ever been pregnant; 1.43 (1.26, 1.62) (p < 0.001) for age at first live birth <21 compared to 25 to 26 years; 0.82 (0.71, 0.94) (p = 0.006) for each abortion; 1.32 (1.15, 1.51) (p = 0.008) for natural menopause at <47 compared to 50 years; 1.12 (1.01, 1.25) (p = 0.039) for hysterectomy; 2.35 (1.06, 5.23) (p = 0.037) for hysterectomy with previous oophorectomy; and 0.80 (0.72, 0.88) (p < 0.001) for oral contraceptive pills use. The U-shaped associations between the number of children and the risk of dementia were similar for both sexes: Compared with those with 2 children, for those without children, the multiple adjusted HR ((95% CIs), p-value) was 1.18 (1.04, 1.33) (p = 0.027) for women and 1.10 (0.98, 1.23) (p = 0.164) for men, and the women-to-men ratio of HRs was 1.09 (0.92, 1.28) (p = 0.403); for those with 4 or more children, the HR was 1.14 (0.98, 1.33) (p = 0.132) for women and 1.26 (1.10, 1.45) (p = 0.003) for men, and the women-to-men ratio of HRs was 0.93 (0.76, 1.14) (p = 0.530). There was evidence that hysterectomy (HR, 1.31 (1.09, 1.59), p = 0.013) and oophorectomy (HR, 1.39 (1.08, 1.78), p = 0.002) were associated with a higher risk of dementia among women of relatively lower SES only. Limitations of the study include potential residual confounding and self-reported measures of reproductive factors, as well as the limited representativeness of the UK Biobank population. Conclusions In this study, we observed that some reproductive events related to shorter cumulative endogenous estrogen exposure in women were associated with higher dementia risk, and there was a similar association between the number of children and dementia risk between women and men.

Female-specific factors are associated with cognition in the UK Biobank cohort

“…However, the definition of surgical menopause varied across studies, rendering firm conclusions difficult. In general, our findings for reproductive years align with another study using data from UK Biobank, showing that a shorter reproductive span, younger age at menopause and a history of hysterectomy were associated with greater risk for all-cause dementia 52 . Similarly, a shorter reproductive span with early age at natural or surgical menopause has also been linked to a higher risk of incident cardiovascular disease 53 .…”

“…The positive effects of parity on visual memory and simple processing speed corroborate previous results 19,20 . While a number of studies suggest a non-linear effect of number of childbirths on cognition 5,21 and all-cause dementia 52 , other studies did not replicate these associations 19 . Further studies are needed to confirm if any positive effect of parity on late-life cognition may be less pronounced in single-and grand-parous individuals.…”

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

“…This aligns with previous studies showing beneficial effects of a longer reproductive span on a number of brain health markers (Georgakis et al, 2016;Schelbaum et al, 2021;Subramaniapillai et al, 2022;Zeydan et al, 2019) and dementia risk (Gong et al, 2022). In line with previous studies (Day et al, 2015(Day et al, , 2017Zhao et al, 2021) we found an association between polygenic and phenotypic variance in reproductive span, but we found no associations between PGS and the brain measures, nor did PGS alter the interactions when included as a covariate.…”

“…Studies indicate that 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 lasting effects on brain structure and body composition even after menopause. For example, a longer reproductive span has 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 (AD) (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 the understanding of how the genetics underlying reproductive span relate to body composition and brain structure is limited (Roa-Díaz et al, 2021).…”

Race, class, caste, disability, sterilisation and hysterectomy

“…The discourse of state costs and economic benefits in describing the value of hysterectomy has not considered long-term patient well-being or individual needs and interests (Fisher 1986). Nonetheless, a growing body of evidence suggests that there are important risk factors for diseases of ageing such as dementia and stroke, which are elevated by premenopausal hysterectomy (even with ovarian conservation) and which both increase aged-care costs to the state and are an important question for older patient well-being (Gong et al 2022;Shuster et al 2010;Bove et al 2014). Gynaecological surgeons practising premenopausal hysterectomy between 1870 and 2000 could not have been expected to take account of such long-term side effects which were only known to medical research from the early 2000s.…”