Reproductive Factors and Risk of Dementia in Natural Postmenopausal Women: a Cross-sectional Study

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This study aims to evaluate the association or interaction between reproductive factors and the risk of dementia in Chinese women with natural menopause. Methods: The cross-sectional study was conducted in 112 community primary health care centers in rural northern China between April 2019 and January 2020. A total of 4,275 women aged ≥ 65 years who had natural menopause were included. Reproductive factors were recorded by self-report. Reproductive period was calculated as age at menopause minus age at menarche. Results: Compared to those without dementia, women with dementia were significantly older at menarche and younger at menopause; had significantly shorter duration of reproductive period; and had more pregnancies and parities. There were 0.757, 0.698, and 0.708 times to get dementia for women who experienced reproductive periods with 31-33 years, 34-36 years, and ≥ 37 years, respectively, as compared with ≤ 30 years. Reproductive period could positively predict MMSE score (β = 0.112) and negative prediction of the number of parities (β = -0.449); the number of parities could negatively predict MMSE score (β = -0.851) as well. Conclusions: Longer duration of reproductive period, directly or through lower number of pregnancies/parities indirectly, lowers the risk of dementia in late life. Neurology Neurosurgery reproductive period estrogen exposure parity pregnancy cognitive impairment dementia Figures Figure 1 Figure 2 Figure 3 Background Epidemiologic studies have for years consistently proved that women comprise more than half of people suffering cognitive impairment (CI), regardless of traditional risk factors we known (age, ethnicity, low education, hypertension, diabetes, dyslipidemia, and alcohol consumption et. al.) [ 1 , 2 ]. Several pre-clinical and human studies for early prediction for dementia have pointed menopause transition as a major modified factor for females [ 3 ]. During the average human menstrual cycle, women experience sharply increase in 17β-estradiol and progesterone [ 4 ]. The production of sex hormones surging during pregnancy, particularly [ 5 ]. Later in life, women experience a steep decline in sex hormone production during the transition to menopause [ 6 ]. Animal studies offer unambiguous evidence that sex hormone regulates the hippocampal morphology and prefrontal cortex pyramidal neurons, which express estrogen receptors (ER-α), to affect memory performance [ 7 ]. Meanwhile, neuroprotective and neurotrophic effects of estrogen, including inhibition of amyloid-β (Aβ) formation [ 8 ], stimulation of cholinergic activity [ 9 ], protection against oxidative stress [ 10 ], and increase of cerebral blood flow [ 11 ], improve the cognitive performance in human and animals. Numbers of epidemiologic studies identify that reproductive factors play an important role in the cognitive performance in old females. Shorter reproductive period and higher number of parities are associated increase risk of cognitive impairment in late life [ 12 ], while the putative associations among longer reproductive period, number of pregnancies and cognitive performance are controversial [ 13 , 14 ]. Most research has been conducted in the western population, few information on rural elder women in northern China. Previous studies indicate shorter duration of reproductive periods in Chinese women, with older age at menarche and lower age at menopause than that of white women [ 15 ]. Two population-based studies in northern China report that longer duration of reproductive period is associated with better cognitive performance [ 16 , 17 ], the same result is found among Singapore Chinese women [ 12 ]. Therefore, studies in rural northern Chinese women are still needed. Currently, few studies have examined the associations among reproductive period, the number of parities, and risk of dementia in rural northern Chinese females. We conducted a large population-based cross-section investigation from rural northern China to evaluate the association between reproductive factors with the risk of dementia in women who with natural menopause. We hypothesize longer reproductive period is related to lower risk of dementia in late life directly, as well as through lower number of parities indirectly. Methods Participants This cross-sectional study enrolled participants ≥ 65 years of age in 112 community primary health care centers selected from 949 villages in the rural Ji County in northern China between April 2019 and January 2020. The local medical practitioner in each village (who had worked there for over 5 years) was involved in identifying all individuals aged ≥ 65 years based on the date of birth provided on the residence certificate. A face-to-face questionnaire-based survey was conducted by senior MD students or medical staff in the local panel health centers, a neurologist with special expertise in cognitive impairment to re-review the data in each region. All interviewers and experts received the same one-week training on collecting information (consisting demography, lifestyles, medical history, reproductive factors), neuropsychological assessment and diagnosis, and participated in a retraining course every 2 months. Figure 1 showed the flow chart of study enrollment and exclusion. The total number of female participants aged ≥ 65 years in these communities was 4,951; however, due to refusal (n = 89), death (n = 5), migration (n = 2), hearing loss (n = 53), aphasia (n = 4) or mental disorders (including definite depression, anxiety, n = 37), totally 4,791 completed the interview. Because of 123 participants with surgical menopause history and 363 participants with uncompleted reproductive information, 486 records were excluded, and 4,275 records were analyzed finally. The study was approved by the Committee for Medical Research Ethics at Tianjin Huanhu Hospital and the Tianjin Health Bureau, and we confirm that all methods were performed in accordance with the relevant guidelines and regulations. Measures In this study, all female participants had menopause already. Reproductive factors were collected in the reproductive history section, including age at menarche, age at menopause (natural or surgical), number of pregnancies, and number of parities. Reproductive period was calculated as age at menopause minus age at menarche. Information on other covariates was collected via the questionnaires, including age, education, marital status (single, married, divorced, widowed), occupation (manual worker, none-manual worker), living states (with spouse, with children, alone, others). History of smoking, drinking, as well as physician’s diagnosis of stroke, diabetes mellitus (DM), heart disease, and hypertension. Cognitive assessment Cognitive assessment was conducted using the Chinese Mini-Mental State Examination (C-MMSE) [ 18 ], the Clinical Dementia Rating (CDR) scale [ 19 ], and the Activities of Daily Living (ADL) scale [ 20 ]. Participants with C-MMSE score below the cutoff points (17, 20 and 24 points for participants of illiteracy, primary school and higher education) [ 21 ]. In this study, we diagnosed dementia based of the Diagnostic and Statistical Manual of Mental Disorders Ⅴ criteria (DSM-5) [ 22 ]. All dementias underwent physical examination, and neuroimaging examination [magnetic resonance imaging (MRI) or computed tomography (CT)], 11 C-PIB PET scan and a 18 F-FDG PET scan for those difficult to diagnose if possible. The detailed design was described in a previous study [ 23 ]. Data analysis We calculated descriptive statistics for continuous variables (age, education, and reproductive factors), student t test was used for continuous variables consistent with normal distribution and nonparametric test for non-normal applications. χ2 tests for categorical variables (marital states, occupation, living status, lifestyles, and comorbidities). In order to evaluate the crude age-, pregnancy-, and parity- specific prevalence of dementia by reproductive period, we divided age (65–69 years, 70–74 years, 75–79 years, ≥ 80 years), the number of pregnancy (0, 1–2, 3–4, and ≥ 5), the number of parity (0, 1–2, 3–4, and ≥ 5) into categorical variables. To avoid interaction effect, we classified age at menarche (≤ 15, 16–17, ≥ 18), age at menopause (≤ 46, 47–49, 50–52, ≥ 53), and reproductive period (≤ 30, 31–33, 34–36, ≥ 37) as well. Logistic regression and Spearman linear correlation analysis were used to estimate the association or interaction between reproductive factors and dementia. In adjusted models, the age and education were calculated. All data were analyzed using IBM SPSS Statistics for Windows (Version 25.0; IBM Corp., Armonk, N.Y. USA). P-values < 0.05 were considered statistically significant. Results General characteristics of participants Among the 4275 natural postmenopausal women, the mean (SD) age was 74.21 (5.72) years, and 486 (11.4%) were assessed to have dementia. The general characteristics of participants were presented in Table 1 . Compared to those without dementia, women with dementia were significantly older; with lower education; in widowed/divorced; manual workers; fewer living with spouse; more with stroke history; were significantly older at menarche and younger at menopause; had significantly shorter duration of reproductive period; and had more pregnancies and parities. Table 1 General characteristics of participants Characteristics Overall Dementia p-value a Yes No Num. 4275 486 3789 Age (years, mean, SD) 74.32 ± 5.72 77.32 ± 6.15 73.94 ± 5.54 < 0.001 Education (years, mean, SD) 4.90 ± 4.41 3.50 ± 4.24 5.08 ± 4.40 < 0.001 Marital status (n, %) < 0.001 Single 7 (0.2) 1 (0.2) 6 (0.2) Married 3078 (72.0) 304 (62.6) 2774 (73.2) Divorced 48 (1.1) 2 (0.4) 46 (1.2) Widowed 1142 (26.7) 179 (36.8) 963 (25.4) Occupation (n, %) 0.040 Manual worker 2471 (57.8) 302 (62.1) 2169 (57.2) None-manual worker 1804 (42.2) 184 (37.9) 1620 (42.8) Living states (n, %) < 0.001 With spouse 2714 (63.5) 256 (52.3) 2460 (64.9) With children 998 (23.3) 167 (34.4) 831 (21.9) Alone 521 (12.2) 59 (12.1) 462 (12.2) Others 42 (1.0) 6 (1.2) 36 (1.0) Lifestyles (n, %) Smoking (yes) 296 (6.9) 22 (4.5) 170 (4.5) 0.968 Drinking (yes) 192 (4.5) 12 (2.5) 137 (3.6) 0.194 Comorbidities (yes, n, %) Stroke 434 (10.2) 85 (17.5) 349 (9.2) < 0.001 DM 684 (16.0) 82 (16.9) 602 (15.9) 0.577 Heart disease 755 (17.7) 100 (20.6) 655 (17.3) 0.076 Hypertension 2285 (53.5) 265 (54.5) 2020 (53.3) 0.613 Reproductive factors (mean, SD) Age at menarche (years) 16.36 ± 2.25 16.64 ± 2.37 16.33 ± 2.24 0.004 Age at menopause (years) 49.33 ± 4.52 48.63 ± 4.70 49.41 ± 4.49 < 0.001 Reproductive period (years) 32.97 ± 5.03 31.99 ± 5.26 33.08 ± 4.99 < 0.001 Num. of pregnancies 3.19 ± 1.45 3.52 ± 1.63 3.15 ± 1.42 < 0.001 Num. of parities 2.60 ± 1.20 3.08 ± 1.45 2.54 ± 1.15 < 0.001 Num., the number of samples; SD, standard deviation; DM, diabetes mellitus. a compared between dementia with non-dementia. Association between reproductive characteristics and dementia Figure 2 showed age- (Fig. 2 A), pregnancy- (Fig. 2 B), and parity- (Fig. 2 C) specific prevalence of dementia by reproductive period. After we adjusted for age and education in Table 2 , compared with women who had menarche before 15 years old, the odds ratio (OR) (95% Confidence interval, 95% CI) was 1.404 (1.077–1.831) for participants who had menarche after 17 years old. And women with older age of menopause than 46 years showed less likely to be dementia, the ORs were 0.662 (95% CI, 0.483–0.909), 0.740 (95% CI, 0.564–0.972), and 0.584 (95% CI, 0.419–0.813) for the age of 47–49 years, 50–52 years, and ≥ 53 years, respectively. There were 0.757 (95% CI, 0.568–1.009), 0.698 (95% CI, 0.524–0.929), and 0.708 (95% CI, 0.525–0.955) times to get dementia for women who experienced reproductive periods with 31–33 years, 34–36 years, and ≥ 37 years, respectively, as compared with ≤ 30 years. While we didn’t find significant difference among pregnancy- and parity- subgroups. Table 2 Association between reproductive characteristics and dementia Reproductive characteristics Overall Dementia Crude Adjusted b Yes No p-value a OR (95% CI) p-value OR (95% CI) p-value Age at menarche (years, mean, SD) ≤ 15 1413 (35.2) 118 (29.8) 1295 (35.8) 0.018 1.00 (Ref.) -- 1.00 (Ref.) -- 16–17 1354 (33.7) 122 (30.8) 1232 (34.0) 0.192 1.087 (0.834–1.416) 0.538 1.046 (0.797–1.372) 0.747 ≥ 18 1247 (31.1) 156 (39.4) 1091 (30.2) < 0.001 1.569 (1.219–2.020) < 0.001 1.404 (1.077–1.831) 0.012 Age at menopause (years, mean, SD) ≤ 46 878 (22.2) 112(29.6) 766 (21.4) < 0.001 1.00 (Ref.) -- 1.00 (Ref.) -- 47–49 859 (21.7) 73 (19.3) 786 (21.9) 0.238 0.635 (0.465–0.867) 0.004 0.662 (0.483–0.909) 0.011 50–52 1395 (35.2) 131 (34.7) 1264 (35.3) 0.807 0.709 (0.542–0.926) 0.030 0.740 (0.564–0.972) 0.044 ≥ 53 828 (20.9) 62 (16.4) 766 (21.4) < 0.001 0.554 (0.400-0.767) 0.001 0.584 (0.419–0.813) 0.002 Reproductive period (years, mean, SD) ≤ 30 1143 (28.5) 144 (36.4) 999 (27.6) < 0.001 1.00 (Ref.) -- 1.00 (Ref.) -- 31–33 917 (22.8) 87 (22.0) 830 (22.9) 0.666 0.727 (0.549–0.964) 0.027 0.757 (0.568–1.009) 0.057 34–36 1042 (25.9) 88 (22.2) 954 (26.4) 0.075 0.640 (0.484–0.846) 0.002 0.698 (0.524–0.929) 0.014 ≥ 37 914 (22.8) 77 (19.4) 837 (23.1) 0.098 0.638 (0.477–0.854) 0.003 0.708 (0.525–0.955) 0.024 Num. of pregnancies (n, %) 0 42 (1.0) 7 (1.5) 35 (1.0) 0.281 NA NA 1–2 1395 (34.2) 165 (35.5) 1230 (34.1) 0.540 1.00 (Ref.) -- 1.00 (Ref.) -- 3–4 1998 (49.0) 212 (45.6) 1786 (49.4) 0.118 NA NA ≥ 5 642 (15.7) 81 (17.4) 561 (15.5) 0.293 NA NA Num. of parities (n, %) 0 58 (1.4) 9 (1.9) 49 (1.3) 0.319 NA NA 1–2 2195 (53.5) 256 (54.8) 1939 (53.4) 0.555 1.00 (Ref.) -- 1.00 (Ref.) -- 3–4 1557 (38.0) 160 (34.3) 1397 (38.5) 0.079 NA NA ≥ 5 290 (7.1) 42 (9.0) 248 (6.8) 0.086 NA NA Num., the number of samples; SD, standard deviation; ORs, odds ratios; CI, confidence interval; Ref., reference. a compared between dementia with non-dementia; b adjusted age and education. Table 3 showed the correlation coefficients between reproductive factors and MMSE score. Larger number of pregnancies (r = -0.123) or parities (r = -0.217), older age of menarche (r = -0.092), younger age of menopause (r = 0.103) and shorter duration of reproductive period (r = 0.131) were correlated with lower MMSE scores, as well as poorer cognitive performance. Reproductive period could positively predict MMSE score (β = 0.112, p < 0. 001) and negative prediction of the number of parities (β = -0.449, p < 0. 001); the number of parities could negatively predict MMSE score (β = -0.851, p < 0. 001) as well. The results indicated that the number of parities had mediating effect on MMSE scores (Fig. 3 A). Similarly, the number of pregnancies also established mediating effect on MMSE score (Fig. 3 B). Table 3 Correlation coefficients of reproductive factors and MMSE score Num. of pregnancies Num. of parities Age at menarche Age at menopause Reproductive period MMSE Num. of pregnancies -- Num. of parities 0.737** -- Age at menarche 0.032* 0.130** -- Age at menopause − 0.038* − 0.077** 0.018 -- Reproductive period − 0.055** − 0.137** − 0.447** 0.859** -- MMSE score − 0.123** − 0.217** − 0.092** 0.103** 0.131** -- MMSE, Mini Mental State Examination; * p < 0.05; ** p < 0.001 Discussion Consistent with our original hypothesis, the longer duration of reproductive period, directly or through lower number of pregnancies/parities indirectly, was positive related to lower risk of dementia in late life. This population-based cross-sectional study of rural females with natural menopause, were generally consistent with previous studies that have examined the relationship of the reproductive period on cognitive profile [ 24 , 25 ]. Traditionally, the duration of reproductive period was defined as the period extending from age at menarche to age at menopause in years. We found that the average age at menarche in rural old females was 16.36 (2.25), which was consistent with old women in Eastern China (16.8 ± 1.7 years old) [ 17 ]. While the age of menarche was younger in developed countries. French women showed younger age at first menses (13.1 ± 1.6 years old), older age at menopause (49.5 ± 5.4 years old), and average 36.6 (5.6) years of reproductive period [ 26 ]. The Japanese women with CI began menstruating at 14.4 (1.7) years old, which was later than normal women [ 14 ] whereas earlier than rural women in northern China. The international age at natural menopause was 44.6–55 years [ 27 ], several reports suggested the age was 54 in Europe, 51.4 in North America, and 48.6 in Latin America, and 51.1 in Asia [ 15 ]. In our study, the average age at menopause (49.33 ± 4.52 years of age) was consistent with previous studies in Eastern China (49.3 ± 4.2 years of age) and France (49.5 ± 5.4). It was reported that the mean age of natural menopause among Jordanian women was younger (48.5 ± 5.0) [ 28 ], with 7.8% of the women experienced early menopause (40–44 years of age), and 21.1% with late menopause (> 52 years of age). What’s more, later age at menarche and younger age at menopause were associated with poor cognitive performance [ 13 , 16 ], and our findings were generally consistent with these studies. Most previous studies had been conducted among Western females to investigate the relationship between reproductive periods with risk of cognitive function and dementia, while evidence among Asian populations is limited. Reproductive period, an indicator of endogenous estrogen exposure, lasted shorter in Chinese women (32.97 ± 5.03 in our study; 34.5 ± 4.3 in Guangzhou province; and 32.5 ± 4.7 in Zhejiang province) than those living in dependent countries (36.6 ± 5.6 in ESPRIT study from France, 35.1 ± 5.2 in the Rotterdam Study from Netherlands, and 34.9 ± 4.5 in the Prospective Population Study of Women from Gothenburg, Sweden). In other words, old females in rural northern China had shorter period of endogenous estrogen exposure, which might lead to poor cognitive performance and increase the risk of dementia. Three population-based studies had supported that shorter reproductive period was significantly associated with worse cognitive function among Chinese women [ 12 , 16 , 17 ]. The Japan Public Health Center-based Prospective Study also showed longer exposure to endogenous estrogen may have a protective effect against cognitive impairment. Women with a reproductive period ≥ 38 years had a significantly lower risk of cognitive impairment (OR = 0.62, 95% CI, 0.40–0.96) compared with those with ≤ 33 years [ 14 ]. The putative association between hormones and cognitive performance is controversial. An observational study in Switzerland, including 44 women receiving IVF, showed that estradiol didn’t have a significant short-term effect on cognitive function [ 29 ]. While in a retrospective analysis with 164 surgical-menopause women (the mean time since menopause was 11.3 ± 7.4 years) performed frontal lobe dysfunction and couldn’t be improved by hormone therapy usage [ 30 ]. A Cochrane systematic review of clinical trials concluded that hormone replacement therapy (HRT) did not prevent cognitive decline in postmenopausal women[ 31 ], and some observational studies also reported null or opposite [ 13 , 32 , 33 ] associations[ 34 ]. In a population-based prospective cohort (The Singapore Chinese Health Study), women with 39 years. When comparing to women with 39–44 years reproductive period, women with 35–38 years had no significant difference on the increased risk of dementia [ 35 ]. In ESPRIT study, longer reproductive period had association with better verbal fluency, instead of better global cognition, though the age at first menses was negatively associated with visual memory and psychomotor speed performance [ 26 ]. Longer reproductive period was associated with increased risk of all-cause dementia and Alzheimer’s disease in all models, particularly in aging people [ 34 ]. We also found that more pregnancies and parities were associated with lower MMSE scores, especially among women with shorter duration of reproductive period. Previous studies indicated that parous women had shorter reproductive periods and lower level of estradiol than nulliparous women, and thus greater parity could lead to an overall lower levels of lifetime estrogen exposure [ 36 , 37 ]. These findings had been proved in many studies [ 38 – 41 ]. Women with higher number of pregnancies had indirectly relate to higher estro-progestinic exposure. We proposed that it is the increase of progesterone or estrogens level – and not the estrogens decrease, in other words, the dramatic changes in estrogen and progesterone during and after parity, play a role in cognitive impairment. Women with greater parity might lead to lower circulating estrogen over lifetime than women with fewer parity or nulliparity. In our analysis of interaction among the number of pregnancies/parities, reproductive period and dementia, reproductive period positively predicted cognitive performance. And the number of pregnancies/parities, as part of a mediation model, played negative predictive role on cognition; that is, reproductive period would be mediated by the number of pregnancies/parities, had indirect effects of cognitive performance for older women. The shorter reproductive period could increase the risk of dementia by non-parous or greater pregnancies/parities in elderly women. Later age at menarche (≥ 17 years), earlier age at menopause (< 40 years), shorter reproductive span (< 30 years) increased the risks of fractures [ 42 ] and age-related hearing decline [ 43 ] as well. The main strength of our study was the large population in rural northern China, and detailed collection of information on participants (demographic, dietary, lifestyle factors, and medical history) to investigate the association and interaction between reproductive and dementia. Nevertheless, several limitations should be noted. As research on reproductive factors and dementia continues, more and more risk factors needed to be investigated, including those affecting dementia and reproduction. The second is recall bias. Because of the self-report information was retrospective, the information of participants might be inaccurate due to their age, while previous studies suggested that age at menarche, age at menopause, the number of brain fast /parities could still be reliable over many years [ 44 , 45 ]. Another is the lack of objective biomarkers. In this cross-sectional study, hormone levels and Aβ levels were not measured, and dementia was not classified as subtypes, which required further analysis and exploration of the data. Conclusions The duration of reproductive period is shorter for women living in rural northern China. Longer duration of reproductive period, directly or through lower number of pregnancies/parities indirectly, lowers the risk of dementia in late life. We call for more awareness for the adverse effects of reproductive factors on women's brain health, particular in rural regions. Declarations Acknowledgments Not applicable. Authors’ contributions JG: Conceptualization, Formal analysis, Investigation, Writing-original draft, Writing - review & editing. SL: Conceptualization, Formal analysis, Investigation, Methodology, Visualization, and Funding. XW: Conceptualization, Data curation, Investigation, Methodology, Writing - review & editing. ZC, XD, FW, WH, and HZ: Investigation. ZS: Resources, Supervision. YJ: Conceptualization, Methodology, Project administration, Resources, Supervision, Validation, and Funding. All authors read and approved the final manuscript. Funding Funding was provided by the National Key Research and Development Program of China [grant number 2016YFC1306305] from YJ, and Research Project of Tianjin Nursing Association [grant number tjhlky2020YB05] from SL. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate The present study was approved by the Committee for Medical Research Ethics at Tianjin Huanhu Hospital and the Tianjin Health Bureau (ID: 2019-40). And all subjects gave written informed consent before enrollment. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. References Association. As. 2019 Alzheimer's disease facts and figures. Alzheimer's & Dementia. 2019;15 3:321-87; doi: https://doi.org/10.1016/j.jalz.2019.01.010 . Neu SC, Pa J, Kukull W, Beekly D, Kuzma A, Gangadharan P, et al. Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA neurology. 2017;74 10:1178-89; doi: 10.1001/jamaneurol.2017.2188. Brinton RD, Yao J, Yin F, Mack WJ, Cadenas E. 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Nihon Ronen Igakkai Zasshi. 1992;29 11:841-8. Zhang MY, Katzman R, Salmon D, Jin H, Cai GJ, Wang ZY, et al. The prevalence of dementia and Alzheimer's disease in Shanghai, China: impact of age, gender, and education. Ann Neurol. 1990;27 4:428-37; doi: 10.1002/ana.410270412. Arbanas G. Diagnostic and statistical manual of mental disorders (DSM-5). Alcoholism and Psychiatry Research. 2015;51:61-4. Ji Y, Shi Z, Zhang Y, Liu S, Liu S, Yue W, et al. Prevalence of dementia and main subtypes in rural northern China. Dementia and geriatric cognitive disorders. 2015;39 5-6:294-302; doi: 10.1159/000375366. Tierney MC, Ryan J, Ancelin ML, Moineddin R, Rankin S, Yao C, et al. Lifelong estrogen exposure and memory in older postmenopausal women. Journal of Alzheimer's disease : JAD. 2013;34 3:601-8; doi: 10.3233/jad-122062. Kuh D, Cooper R, Moore A, Richards M, Hardy R. Age at menopause and lifetime cognition: Findings from a British birth cohort study. Neurology. 2018;90 19:e1673-e81; doi: 10.1212/WNL.0000000000005486. Ryan J, Carrière I, Scali J, Ritchie K, Ancelin ML. Life-time estrogen exposure and cognitive functioning in later life. Psychoneuroendocrinology. 2009;34 2:287-98; doi: 10.1016/j.psyneuen.2008.09.008. Thomas F, Renaud F, Benefice E, de Meeüs T, Guegan JF. International variability of ages at menarche and menopause: patterns and main determinants. Human biology. 2001;73 2:271-90; doi: 10.1353/hub.2001.0029. Bustami M, Matalka KZ, Elyyan Y, Hussein N, Hussein N, Abu Safieh N, et al. Age of Natural Menopause Among Jordanian Women and Factors Related to Premature and Early Menopause. Risk management and healthcare policy. 2021;14:199-207; doi: 10.2147/rmhp.S289851. Leeners B, Krüger T, Geraedts K, Tronci E, Mancini T, Ille F, et al. Cognitive function in association with high estradiol levels resulting from fertility treatment. Hormones and behavior. 2021;130:104951; doi: 10.1016/j.yhbeh.2021.104951. Orprayoon N, Santibenchakul S, Hemrungrojn S, Phutrakool P, Kengsakul M, Jaisamrarn U, et al. Effect of surgical menopause and frontal lobe cognitive function. Climacteric. 2021:1-9; doi: 10.1080/13697137.2020.1867529. Lethaby A, Hogervorst E, Richards M, Yesufu A, Yaffe K. Hormone replacement therapy for cognitive function in postmenopausal women. The Cochrane database of systematic reviews. 2008;2008 1:Cd003122; doi: 10.1002/14651858.CD003122.pub2. Low LF, Anstey KJ, Jorm AF, Rodgers B, Christensen H. Reproductive period and cognitive function in a representative sample of naturally postmenopausal women aged 60–64 years. Climacteric. 2005;8 4:380-9; doi: 10.1080/13697130500345240. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. Jama. 2003;289 20:2651-62; doi: 10.1001/jama.289.20.2651. Najar J, Östling S, Waern M, Zettergren A, Kern S, Wetterberg H, et al. Reproductive period and dementia: A 44-year longitudinal population study of Swedish women. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2020;16 8:1153-63; doi: 10.1002/alz.12118. Gilsanz P, Lee C, Corrada MM, Kawas CH, Quesenberry CP, Jr., Whitmer RA. Reproductive period and risk of dementia in a diverse cohort of health care members. Neurology. 2019;92 17:e2005-e14; doi: 10.1212/wnl.0000000000007326. Bernstein L, Pike MC, Ross RK, Judd HL, Brown JB, Henderson BE. Estrogen and sex hormone-binding globulin levels in nulliparous and parous women. Journal of the National Cancer Institute. 1985;74 4:741-5. Dorgan JF, Reichman ME, Judd JT, Brown C, Longcope C, Schatzkin A, et al. Relationships of age and reproductive characteristics with plasma estrogens and androgens in premenopausal women. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 1995;4 4:381-6. Rasgon NL, Magnusson C, Johansson AL, Pedersen NL, Elman S, Gatz M. Endogenous and exogenous hormone exposure and risk of cognitive impairment in Swedish twins: a preliminary study. Psychoneuroendocrinology. 2005;30 6:558-67; doi: 10.1016/j.psyneuen.2005.01.004. Bae JB, Lipnicki DM, Han JW, Sachdev PS, Kim TH, Kwak KP, et al. Parity and the risk of incident dementia: a COSMIC study. Epidemiology and psychiatric sciences. 2020;29:e176; doi: 10.1017/s2045796020000876. Ptok U, Barkow K, Heun R. Fertility and number of children in patients with Alzheimer's disease. Archives of women's mental health. 2002;5 2:83-6; doi: 10.1007/s00737-002-0142-6. Colucci M, Cammarata S, Assini A, Croce R, Clerici F, Novello C, et al. The number of pregnancies is a risk factor for Alzheimer's disease. Eur J Neurol. 2006;13 12:1374-7; doi: 10.1111/j.1468-1331.2006.01520.x. Yoo JE, Shin DW, Han K, Kim D, Yoon JW, Lee DY. Association of Female Reproductive Factors With Incidence of Fracture Among Postmenopausal Women in Korea. JAMA Netw Open. 2021;4 1:e2030405; doi: 10.1001/jamanetworkopen.2020.30405. Suh MJ, Oh SK, Lee SB, Kim SH. Effects of endogenous and exogenous oestrogen exposure on hearing level in postmenopausal women: A cross-sectional study. Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery. 2020; doi: 10.1111/coa.13685. Must A, Phillips SM, Naumova EN, Blum M, Harris S, Dawson-Hughes B, et al. Recall of early menstrual history and menarcheal body size: after 30 years, how well do women remember? Am J Epidemiol. 2002;155 7:672-9; doi: 10.1093/aje/155.7.672. Bean JA, Leeper JD, Wallace RB, Sherman BM, Jagger H. Variations in the reporting of menstrual histories. Am J Epidemiol. 1979;109 2:181-5; doi: 10.1093/oxfordjournals.aje.a112673. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-562858","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":29757895,"identity":"6acc95f9-d918-405b-a598-d0ad498f93ee","order_by":0,"name":"Jinghuan Gan","email":"","orcid":"","institution":"Beijing Tian Tan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jinghuan","middleName":"","lastName":"Gan","suffix":""},{"id":29757896,"identity":"a634c794-b3fd-49b2-a636-221827fd8361","order_by":1,"name":"Zhichao Chen","email":"","orcid":"","institution":"Beijing Tian Tan 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Ji","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwklEQVRIiWNgGAWjYBACxmYYi72x8cEH0rTwHG42nEGafRLpbdIcxChkbucxfFzw67A9/8yHDdIMDHZyug0EHcZjbDyz73DijNuJDcYFDMnGZgcIazGT5u05nMAA1JI8g+FA4jZitdjL3zzYcJiHaC08Pw4zbrjB2NhMpBa2YmPehvTEjWcSmxlnGBDhF8P+wxsf8/yxtpc7fvz5jw8VdnKEtTRwGDAwtsG4BgSUg4A8A/sDBoY/RKgcBaNgFIyCkQsAz+1Dxpj0GoIAAAAASUVORK5CYII=","orcid":"","institution":"Beijing Tian Tan Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yong","middleName":"","lastName":"Ji","suffix":""}],"badges":[],"createdAt":"2021-05-26 13:44:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-562858/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-562858/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":9856164,"identity":"ccfc236b-0cb2-4ffc-8da0-1576ba4b581e","added_by":"auto","created_at":"2021-06-01 19:55:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":26892,"visible":true,"origin":"","legend":"Flowchart of this study.","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-562858/v1/e00ac19fa9bcf2754b222bdd.png"},{"id":9855862,"identity":"da158b82-e82d-4316-8c12-c4292dd77b80","added_by":"auto","created_at":"2021-06-01 19:52:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":22736,"visible":true,"origin":"","legend":"Specific prevalence rates of dementia by quartile of reproductive period","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-562858/v1/aa74d2b41dd0cf2a849c18af.png"},{"id":9856165,"identity":"be2a9ae5-5c7c-4ef2-abac-3a978a8fd190","added_by":"auto","created_at":"2021-06-01 19:55:44","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":20364,"visible":true,"origin":"","legend":"Mediating effect models of pregnancy/parity between reproductive period and dementia in elderly women MMSE, Mini Mental State Examination; *p \u003c 0.05; **p \u003c 0.001","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-562858/v1/b9b98a7139f0b7b39131fce3.png"},{"id":14253980,"identity":"f1a4048a-8c9d-404f-a4ba-7e3528787ed6","added_by":"auto","created_at":"2021-10-05 10:14:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":690211,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-562858/v1/53232cc5-07eb-40f4-a634-556a8bb7651e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eReproductive Factors and Risk of Dementia in Natural Postmenopausal Women: a Cross-sectional Study\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eEpidemiologic studies have for years consistently proved that women comprise more than half of people suffering cognitive impairment (CI), regardless of traditional risk factors we known (age, ethnicity, low education, hypertension, diabetes, dyslipidemia, and alcohol consumption et. al.) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Several pre-clinical and human studies for early prediction for dementia have pointed menopause transition as a major modified factor for females [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDuring the average human menstrual cycle, women experience sharply increase in 17β-estradiol and progesterone [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The production of sex hormones surging during pregnancy, particularly [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Later in life, women experience a steep decline in sex hormone production during the transition to menopause [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Animal studies offer unambiguous evidence that sex hormone regulates the hippocampal morphology and prefrontal cortex pyramidal neurons, which express estrogen receptors (ER-α), to affect memory performance [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Meanwhile, neuroprotective and neurotrophic effects of estrogen, including inhibition of amyloid-β (Aβ) formation [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], stimulation of cholinergic activity [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], protection against oxidative stress [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], and increase of cerebral blood flow [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], improve the cognitive performance in human and animals. Numbers of epidemiologic studies identify that reproductive factors play an important role in the cognitive performance in old females. Shorter reproductive period and higher number of parities are associated increase risk of cognitive impairment in late life [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], while the putative associations among longer reproductive period, number of pregnancies and cognitive performance are controversial [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMost research has been conducted in the western population, few information on rural elder women in northern China. Previous studies indicate shorter duration of reproductive periods in Chinese women, with older age at menarche and lower age at menopause than that of white women [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Two population-based studies in northern China report that longer duration of reproductive period is associated with better cognitive performance [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], the same result is found among Singapore Chinese women [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Therefore, studies in rural northern Chinese women are still needed.\u003c/p\u003e \u003cp\u003eCurrently, few studies have examined the associations among reproductive period, the number of parities, and risk of dementia in rural northern Chinese females. We conducted a large population-based cross-section investigation from rural northern China to evaluate the association between reproductive factors with the risk of dementia in women who with natural menopause. We hypothesize longer reproductive period is related to lower risk of dementia in late life directly, as well as through lower number of parities indirectly.\u003c/p\u003e "},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eParticipants\u003c/h2\u003e\n\u003cp\u003eThis cross-sectional study enrolled participants\u0026thinsp;\u0026ge;\u0026thinsp;65 years of age in 112 community primary health care centers selected from 949 villages in the rural Ji County in northern China between April 2019 and January 2020. The local medical practitioner in each village (who had worked there for over 5 years) was involved in identifying all individuals aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years based on the date of birth provided on the residence certificate. A face-to-face questionnaire-based survey was conducted by senior MD students or medical staff in the local panel health centers, a neurologist with special expertise in cognitive impairment to re-review the data in each region. All interviewers and experts received the same one-week training on collecting information (consisting demography, lifestyles, medical history, reproductive factors), neuropsychological assessment and diagnosis, and participated in a retraining course every 2 months.\u003c/p\u003e\n\u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e showed the flow chart of study enrollment and exclusion. The total number of female participants aged\u0026thinsp;\u0026ge;\u0026thinsp;65 years in these communities was 4,951; however, due to refusal (n\u0026thinsp;=\u0026thinsp;89), death (n\u0026thinsp;=\u0026thinsp;5), migration (n\u0026thinsp;=\u0026thinsp;2), hearing loss (n\u0026thinsp;=\u0026thinsp;53), aphasia (n\u0026thinsp;=\u0026thinsp;4) or mental disorders (including definite depression, anxiety, n\u0026thinsp;=\u0026thinsp;37), totally 4,791 completed the interview. Because of 123 participants with surgical menopause history and 363 participants with uncompleted reproductive information, 486 records were excluded, and 4,275 records were analyzed finally. The study was approved by the Committee for Medical Research Ethics at Tianjin Huanhu Hospital and the Tianjin Health Bureau, and we confirm that all methods were performed in accordance with the relevant guidelines and regulations.\u003c/p\u003e\n\u003ch2\u003eMeasures\u003c/h2\u003e\n\u003cp\u003eIn this study, all female participants had menopause already. Reproductive factors were collected in the reproductive history section, including age at menarche, age at menopause (natural or surgical), number of pregnancies, and number of parities. Reproductive period was calculated as age at menopause minus age at menarche.\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eInformation on other covariates was collected via the questionnaires, including age, education, marital status (single, married, divorced, widowed), occupation (manual worker, none-manual worker), living states (with spouse, with children, alone, others). History of smoking, drinking, as well as physician\u0026rsquo;s diagnosis of stroke, diabetes mellitus (DM), heart disease, and hypertension.\u003c/p\u003e\n\u003ch2\u003eCognitive assessment\u003c/h2\u003e\n\u003cp\u003eCognitive assessment was conducted using the Chinese Mini-Mental State Examination (C-MMSE) [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e], the Clinical Dementia Rating (CDR) scale [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e], and the Activities of Daily Living (ADL) scale [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]. Participants with C-MMSE score below the cutoff points (17, 20 and 24 points for participants of illiteracy, primary school and higher education) [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. In this study, we diagnosed dementia based of the Diagnostic and Statistical Manual of Mental Disorders Ⅴ criteria (DSM-5) [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. All dementias underwent physical examination, and neuroimaging examination [magnetic resonance imaging (MRI) or computed tomography (CT)], \u003csup\u003e11\u003c/sup\u003eC-PIB PET scan and a \u003csup\u003e18\u003c/sup\u003eF-FDG PET scan for those difficult to diagnose if possible. The detailed design was described in a previous study [\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003eData analysis\u003c/h2\u003e\n\u003cp\u003eWe calculated descriptive statistics for continuous variables (age, education, and reproductive factors), student t test was used for continuous variables consistent with normal distribution and nonparametric test for non-normal applications. \u0026chi;2 tests for categorical variables (marital states, occupation, living status, lifestyles, and comorbidities).\u003c/p\u003e\n\u003cp\u003eIn order to evaluate the crude age-, pregnancy-, and parity- specific prevalence of dementia by reproductive period, we divided age (65\u0026ndash;69 years, 70\u0026ndash;74 years, 75\u0026ndash;79 years, \u0026ge; 80 years), the number of pregnancy (0, 1\u0026ndash;2, 3\u0026ndash;4, and \u0026ge;\u0026thinsp;5), the number of parity (0, 1\u0026ndash;2, 3\u0026ndash;4, and \u0026ge;\u0026thinsp;5) into categorical variables. To avoid interaction effect, we classified age at menarche (\u0026le;\u0026thinsp;15, 16\u0026ndash;17, \u0026ge; 18), age at menopause (\u0026le;\u0026thinsp;46, 47\u0026ndash;49, 50\u0026ndash;52, \u0026ge; 53), and reproductive period (\u0026le;\u0026thinsp;30, 31\u0026ndash;33, 34\u0026ndash;36, \u0026ge; 37) as well. Logistic regression and Spearman linear correlation analysis were used to estimate the association or interaction between reproductive factors and dementia. In adjusted models, the age and education were calculated.\u003c/p\u003e\n\u003cp\u003eAll data were analyzed using IBM SPSS Statistics for Windows (Version 25.0; IBM Corp., Armonk, N.Y. USA). P-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eGeneral characteristics of participants\u003c/h2\u003e\n\u003cp\u003eAmong the 4275 natural postmenopausal women, the mean (SD) age was 74.21 (5.72) years, and 486 (11.4%) were assessed to have dementia. The general characteristics of participants were presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Compared to those without dementia, women with dementia were significantly older; with lower education; in widowed/divorced; manual workers; fewer living with spouse; more with stroke history; were significantly older at menarche and younger at menopause; had significantly shorter duration of reproductive period; and had more pregnancies and parities.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eGeneral characteristics of participants\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eCharacteristics\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eOverall\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eDementia\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003ep-value \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eYes\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNum.\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4275\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e486\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3789\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge (years, mean, SD)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e74.32\u0026thinsp;\u0026plusmn;\u0026thinsp;5.72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e77.32\u0026thinsp;\u0026plusmn;\u0026thinsp;6.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e73.94\u0026thinsp;\u0026plusmn;\u0026thinsp;5.54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eEducation (years, mean, SD)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.90\u0026thinsp;\u0026plusmn;\u0026thinsp;4.41\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.50\u0026thinsp;\u0026plusmn;\u0026thinsp;4.24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.08\u0026thinsp;\u0026plusmn;\u0026thinsp;4.40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMarital status (n, %)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSingle\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (0.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (0.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (0.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMarried\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3078 (72.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e304 (62.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2774 (73.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDivorced\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48 (1.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (0.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46 (1.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWidowed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1142 (26.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e179 (36.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e963 (25.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eOccupation (n, %)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.040\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eManual worker\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2471 (57.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e302 (62.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2169 (57.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNone-manual worker\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1804 (42.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e184 (37.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1620 (42.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLiving states (n, %)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWith spouse\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2714 (63.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e256 (52.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2460 (64.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWith children\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e998 (23.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e167 (34.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e831 (21.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAlone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e521 (12.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e59 (12.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e462 (12.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOthers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42 (1.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (1.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36 (1.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLifestyles (n, %)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSmoking (yes)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e296 (6.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (4.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e170 (4.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.968\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDrinking (yes)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e192 (4.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (2.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e137 (3.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.194\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eComorbidities (yes, n, %)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eStroke\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e434 (10.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e85 (17.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e349 (9.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDM\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e684 (16.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e82 (16.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e602 (15.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.577\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHeart disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e755 (17.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100 (20.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e655 (17.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.076\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHypertension\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2285 (53.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e265 (54.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2020 (53.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.613\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eReproductive factors (mean, SD)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge at menarche (years)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.36\u0026thinsp;\u0026plusmn;\u0026thinsp;2.25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.64\u0026thinsp;\u0026plusmn;\u0026thinsp;2.37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.33\u0026thinsp;\u0026plusmn;\u0026thinsp;2.24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.004\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge at menopause (years)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49.33\u0026thinsp;\u0026plusmn;\u0026thinsp;4.52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48.63\u0026thinsp;\u0026plusmn;\u0026thinsp;4.70\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49.41\u0026thinsp;\u0026plusmn;\u0026thinsp;4.49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eReproductive period (years)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32.97\u0026thinsp;\u0026plusmn;\u0026thinsp;5.03\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31.99\u0026thinsp;\u0026plusmn;\u0026thinsp;5.26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33.08\u0026thinsp;\u0026plusmn;\u0026thinsp;4.99\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNum. of pregnancies\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.19\u0026thinsp;\u0026plusmn;\u0026thinsp;1.45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.52\u0026thinsp;\u0026plusmn;\u0026thinsp;1.63\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.15\u0026thinsp;\u0026plusmn;\u0026thinsp;1.42\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNum. of parities\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.60\u0026thinsp;\u0026plusmn;\u0026thinsp;1.20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.08\u0026thinsp;\u0026plusmn;\u0026thinsp;1.45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.54\u0026thinsp;\u0026plusmn;\u0026thinsp;1.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eNum., the number of samples; SD, standard deviation; DM, diabetes mellitus.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003e compared between dementia with non-dementia.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003eAssociation between reproductive characteristics and dementia\u003c/h2\u003e\n\u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e showed age- (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA), pregnancy- (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB), and parity- (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC) specific prevalence of dementia by reproductive period.\u003c/p\u003e\n\u003cp\u003eAfter we adjusted for age and education in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, compared with women who had menarche before 15 years old, the odds ratio (OR) (95% Confidence interval, 95% CI) was 1.404 (1.077\u0026ndash;1.831) for participants who had menarche after 17 years old. And women with older age of menopause than 46 years showed less likely to be dementia, the ORs were 0.662 (95% CI, 0.483\u0026ndash;0.909), 0.740 (95% CI, 0.564\u0026ndash;0.972), and 0.584 (95% CI, 0.419\u0026ndash;0.813) for the age of 47\u0026ndash;49 years, 50\u0026ndash;52 years, and \u0026ge;\u0026thinsp;53 years, respectively. There were 0.757 (95% CI, 0.568\u0026ndash;1.009), 0.698 (95% CI, 0.524\u0026ndash;0.929), and 0.708 (95% CI, 0.525\u0026ndash;0.955) times to get dementia for women who experienced reproductive periods with 31\u0026ndash;33 years, 34\u0026ndash;36 years, and \u0026ge;\u0026thinsp;37 years, respectively, as compared with \u0026le;\u0026thinsp;30 years. While we didn\u0026rsquo;t find significant difference among pregnancy- and parity- subgroups.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eAssociation between reproductive characteristics and dementia\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eReproductive characteristics\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eOverall\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eDementia\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eCrude\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eAdjusted \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eYes\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e \u003csup\u003e\u003cstrong\u003ea\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eOR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eOR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge at menarche (years, mean, SD)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026le;\u0026thinsp;15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1413 (35.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e118 (29.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1295 (35.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.018\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00 (Ref.)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00 (Ref.)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16\u0026ndash;17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1354 (33.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e122 (30.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1232 (34.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.192\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.087 (0.834\u0026ndash;1.416)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.538\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.046 (0.797\u0026ndash;1.372)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.747\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1247 (31.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e156 (39.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1091 (30.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.569 (1.219\u0026ndash;2.020)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.404 (1.077\u0026ndash;1.831)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.012\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge at menopause (years, mean, SD)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026le;\u0026thinsp;46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e878 (22.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e112(29.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e766 (21.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00 (Ref.)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00 (Ref.)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47\u0026ndash;49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e859 (21.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e73 (19.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e786 (21.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.238\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.635 (0.465\u0026ndash;0.867)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.004\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.662 (0.483\u0026ndash;0.909)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.011\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u0026ndash;52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1395 (35.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e131 (34.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1264 (35.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.807\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.709 (0.542\u0026ndash;0.926)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.030\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.740 (0.564\u0026ndash;0.972)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.044\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;53\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e828 (20.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e62 (16.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e766 (21.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.554 (0.400-0.767)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.584 (0.419\u0026ndash;0.813)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.002\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eReproductive period (years, mean, SD)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026le;\u0026thinsp;30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1143 (28.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e144 (36.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e999 (27.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00 (Ref.)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00 (Ref.)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31\u0026ndash;33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e917 (22.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e87 (22.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e830 (22.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.666\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.727 (0.549\u0026ndash;0.964)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.027\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.757 (0.568\u0026ndash;1.009)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.057\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34\u0026ndash;36\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1042 (25.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e88 (22.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e954 (26.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.075\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.640 (0.484\u0026ndash;0.846)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.002\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.698 (0.524\u0026ndash;0.929)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.014\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e914 (22.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e77 (19.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e837 (23.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.098\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.638 (0.477\u0026ndash;0.854)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.003\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.708 (0.525\u0026ndash;0.955)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.024\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNum. of pregnancies (n, %)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e42 (1.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e7 (1.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e35 (1.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.281\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u0026ndash;2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1395 (34.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e165 (35.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1230 (34.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.540\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00 (Ref.)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00 (Ref.)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u0026ndash;4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1998 (49.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e212 (45.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1786 (49.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.118\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e642 (15.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e81 (17.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e561 (15.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.293\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNum. of parities (n, %)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e58 (1.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e9 (1.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e49 (1.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.319\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u0026ndash;2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2195 (53.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e256 (54.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1939 (53.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.555\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00 (Ref.)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00 (Ref.)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u0026ndash;4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1557 (38.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e160 (34.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1397 (38.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.079\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e290 (7.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e42 (9.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e248 (6.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.086\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"9\"\u003eNum., the number of samples; SD, standard deviation; ORs, odds ratios; CI, confidence interval; Ref., reference.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"9\"\u003ea compared between dementia with non-dementia; b adjusted age and education.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e showed the correlation coefficients between reproductive factors and MMSE score. Larger number of pregnancies (r = -0.123) or parities (r = -0.217), older age of menarche (r = -0.092), younger age of menopause (r\u0026thinsp;=\u0026thinsp;0.103) and shorter duration of reproductive period (r\u0026thinsp;=\u0026thinsp;0.131) were correlated with lower MMSE scores, as well as poorer cognitive performance. Reproductive period could positively predict MMSE score (\u0026beta;\u0026thinsp;=\u0026thinsp;0.112, p\u0026thinsp;\u0026lt;\u0026thinsp;0. 001) and negative prediction of the number of parities (\u0026beta; = -0.449, p\u0026thinsp;\u0026lt;\u0026thinsp;0. 001); the number of parities could negatively predict MMSE score (\u0026beta; = -0.851, p\u0026thinsp;\u0026lt;\u0026thinsp;0. 001) as well. The results indicated that the number of parities had mediating effect on MMSE scores (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA). Similarly, the number of pregnancies also established mediating effect on MMSE score (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCorrelation coefficients of reproductive factors and MMSE score\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNum. of\u003c/p\u003e\n\u003cp\u003epregnancies\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNum. of\u003c/p\u003e\n\u003cp\u003eparities\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAge at\u003c/p\u003e\n\u003cp\u003emenarche\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAge at\u003c/p\u003e\n\u003cp\u003emenopause\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eReproductive period\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMMSE\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNum. of pregnancies\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNum. of parities\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.737**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge at menarche\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.032*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.130**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge at menopause\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;\u0026thinsp;0.038*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;\u0026thinsp;0.077**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.018\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eReproductive period\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;\u0026thinsp;0.055**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;\u0026thinsp;0.137**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;\u0026thinsp;0.447**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.859**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMMSE score\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;\u0026thinsp;0.123**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;\u0026thinsp;0.217**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026minus;\u0026thinsp;0.092**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.103**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.131**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\"\u003eMMSE, Mini Mental State Examination; *\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05; **\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":" \u003cp\u003eConsistent with our original hypothesis, the longer duration of reproductive period, directly or through lower number of pregnancies/parities indirectly, was positive related to lower risk of dementia in late life.\u003c/p\u003e \u003cp\u003eThis population-based cross-sectional study of rural females with natural menopause, were generally consistent with previous studies that have examined the relationship of the reproductive period on cognitive profile [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Traditionally, the duration of reproductive period was defined as the period extending from age at menarche to age at menopause in years. We found that the average age at menarche in rural old females was 16.36 (2.25), which was consistent with old women in Eastern China (16.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 years old) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. While the age of menarche was younger in developed countries. French women showed younger age at first menses (13.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6 years old), older age at menopause (49.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.4 years old), and average 36.6 (5.6) years of reproductive period [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The Japanese women with CI began menstruating at 14.4 (1.7) years old, which was later than normal women [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] whereas earlier than rural women in northern China. The international age at natural menopause was 44.6\u0026ndash;55 years [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], several reports suggested the age was 54 in Europe, 51.4 in North America, and 48.6 in Latin America, and 51.1 in Asia [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In our study, the average age at menopause (49.33\u0026thinsp;\u0026plusmn;\u0026thinsp;4.52 years of age) was consistent with previous studies in Eastern China (49.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2 years of age) and France (49.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.4). It was reported that the mean age of natural menopause among Jordanian women was younger (48.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], with 7.8% of the women experienced early menopause (40\u0026ndash;44 years of age), and 21.1% with late menopause (\u0026gt;\u0026thinsp;52 years of age). What\u0026rsquo;s more, later age at menarche and younger age at menopause were associated with poor cognitive performance [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], and our findings were generally consistent with these studies.\u003c/p\u003e \u003cp\u003eMost previous studies had been conducted among Western females to investigate the relationship between reproductive periods with risk of cognitive function and dementia, while evidence among Asian populations is limited. Reproductive period, an indicator of endogenous estrogen exposure, lasted shorter in Chinese women (32.97\u0026thinsp;\u0026plusmn;\u0026thinsp;5.03 in our study; 34.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3 in Guangzhou province; and 32.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7 in Zhejiang province) than those living in dependent countries (36.6\u0026thinsp;\u0026plusmn;\u0026thinsp;5.6 in ESPRIT study from France, 35.1\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2 in the Rotterdam Study from Netherlands, and 34.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5 in the Prospective Population Study of Women from Gothenburg, Sweden). In other words, old females in rural northern China had shorter period of endogenous estrogen exposure, which might lead to poor cognitive performance and increase the risk of dementia. Three population-based studies had supported that shorter reproductive period was significantly associated with worse cognitive function among Chinese women [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The Japan Public Health Center-based Prospective Study also showed longer exposure to endogenous estrogen may have a protective effect against cognitive impairment. Women with a reproductive period\u0026thinsp;\u0026ge;\u0026thinsp;38 years had a significantly lower risk of cognitive impairment (OR\u0026thinsp;=\u0026thinsp;0.62, 95% CI, 0.40\u0026ndash;0.96) compared with those with \u0026le;\u0026thinsp;33 years [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe putative association between hormones and cognitive performance is controversial. An observational study in Switzerland, including 44 women receiving IVF, showed that estradiol didn\u0026rsquo;t have a significant short-term effect on cognitive function [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. While in a retrospective analysis with 164 surgical-menopause women (the mean time since menopause was 11.3\u0026thinsp;\u0026plusmn;\u0026thinsp;7.4 years) performed frontal lobe dysfunction and couldn\u0026rsquo;t be improved by hormone therapy usage [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. A Cochrane systematic review of clinical trials concluded that hormone replacement therapy (HRT) did not prevent cognitive decline in postmenopausal women[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], and some observational studies also reported null or opposite [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] associations[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. In a population-based prospective cohort (The Singapore Chinese Health Study), women with \u0026lt;\u0026thinsp;35 reproductive years were 1.28 (95% CI, 1.11\u0026ndash;1.48) times to get cognitive impairment compared with women with 35\u0026ndash;39 reproductive years (Ref.), whereas no significant findings among women with \u0026gt;\u0026thinsp;39 years. When comparing to women with 39\u0026ndash;44 years reproductive period, women with 35\u0026ndash;38 years had no significant difference on the increased risk of dementia [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. In ESPRIT study, longer reproductive period had association with better verbal fluency, instead of better global cognition, though the age at first menses was negatively associated with visual memory and psychomotor speed performance [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Longer reproductive period was associated with increased risk of all-cause dementia and Alzheimer\u0026rsquo;s disease in all models, particularly in aging people [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe also found that more pregnancies and parities were associated with lower MMSE scores, especially among women with shorter duration of reproductive period. Previous studies indicated that parous women had shorter reproductive periods and lower level of estradiol than nulliparous women, and thus greater parity could lead to an overall lower levels of lifetime estrogen exposure [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. These findings had been proved in many studies [\u003cspan additionalcitationids=\"CR39 CR40\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Women with higher number of pregnancies had indirectly relate to higher estro-progestinic exposure. We proposed that it is the increase of progesterone or estrogens level \u0026ndash; and not the estrogens decrease, in other words, the dramatic changes in estrogen and progesterone during and after parity, play a role in cognitive impairment. Women with greater parity might lead to lower circulating estrogen over lifetime than women with fewer parity or nulliparity. In our analysis of interaction among the number of pregnancies/parities, reproductive period and dementia, reproductive period positively predicted cognitive performance. And the number of pregnancies/parities, as part of a mediation model, played negative predictive role on cognition; that is, reproductive period would be mediated by the number of pregnancies/parities, had indirect effects of cognitive performance for older women. The shorter reproductive period could increase the risk of dementia by non-parous or greater pregnancies/parities in elderly women. Later age at menarche (\u0026ge;\u0026thinsp;17 years), earlier age at menopause (\u0026lt;\u0026thinsp;40 years), shorter reproductive span (\u0026lt;\u0026thinsp;30 years) increased the risks of fractures [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] and age-related hearing decline [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e] as well.\u003c/p\u003e \u003cp\u003eThe main strength of our study was the large population in rural northern China, and detailed collection of information on participants (demographic, dietary, lifestyle factors, and medical history) to investigate the association and interaction between reproductive and dementia. Nevertheless, several limitations should be noted. As research on reproductive factors and dementia continues, more and more risk factors needed to be investigated, including those affecting dementia and reproduction. The second is recall bias. Because of the self-report information was retrospective, the information of participants might be inaccurate due to their age, while previous studies suggested that age at menarche, age at menopause, the number of brain fast /parities could still be reliable over many years [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Another is the lack of objective biomarkers. In this cross-sectional study, hormone levels and Aβ levels were not measured, and dementia was not classified as subtypes, which required further analysis and exploration of the data.\u003c/p\u003e "},{"header":"Conclusions","content":" \u003cp\u003eThe duration of reproductive period is shorter for women living in rural northern China. Longer duration of reproductive period, directly or through lower number of pregnancies/parities indirectly, lowers the risk of dementia in late life. We call for more awareness for the adverse effects of reproductive factors on women's brain health, particular in rural regions.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJG: Conceptualization, Formal analysis, Investigation, Writing-original draft, Writing - review \u0026amp; editing. SL: Conceptualization, Formal analysis, Investigation, Methodology, Visualization, and Funding. XW: Conceptualization, Data curation, Investigation, Methodology, Writing - review \u0026amp; editing. ZC, XD, FW, WH, and HZ: Investigation. ZS: Resources, Supervision. YJ: Conceptualization, Methodology, Project administration, Resources, Supervision, Validation, and Funding. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunding was provided by the National Key Research and Development Program of China [grant number 2016YFC1306305] from YJ, and Research Project of Tianjin Nursing Association [grant number tjhlky2020YB05] from SL.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present study was approved by the Committee for Medical Research Ethics at Tianjin Huanhu Hospital and the Tianjin Health Bureau (ID: 2019-40). And all subjects gave written informed consent before enrollment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAssociation. As. 2019 Alzheimer's disease facts and figures. Alzheimer's \u0026amp; Dementia. 2019;15 3:321-87; doi: \u003ca href=\"https://doi.org/10.1016/j.jalz.2019.01.010\"\u003ehttps://doi.org/10.1016/j.jalz.2019.01.010\u003c/a\u003e.\u003c/li\u003e\n\u003cli\u003eNeu SC, Pa J, Kukull W, Beekly D, Kuzma A, Gangadharan P, et al. Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. 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Journal of Alzheimer's disease : JAD. 2013;34 3:601-8; doi: 10.3233/jad-122062.\u003c/li\u003e\n\u003cli\u003eKuh D, Cooper R, Moore A, Richards M, Hardy R. Age at menopause and lifetime cognition: Findings from a British birth cohort study. Neurology. 2018;90 19:e1673-e81; doi: 10.1212/WNL.0000000000005486.\u003c/li\u003e\n\u003cli\u003eRyan J, Carri\u0026egrave;re I, Scali J, Ritchie K, Ancelin ML. Life-time estrogen exposure and cognitive functioning in later life. Psychoneuroendocrinology. 2009;34 2:287-98; doi: 10.1016/j.psyneuen.2008.09.008.\u003c/li\u003e\n\u003cli\u003eThomas F, Renaud F, Benefice E, de Mee\u0026uuml;s T, Guegan JF. International variability of ages at menarche and menopause: patterns and main determinants. Human biology. 2001;73 2:271-90; doi: 10.1353/hub.2001.0029.\u003c/li\u003e\n\u003cli\u003eBustami M, Matalka KZ, Elyyan Y, Hussein N, Hussein N, Abu Safieh N, et al. 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Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology \u0026amp; Cervico-Facial Surgery. 2020; doi: 10.1111/coa.13685.\u003c/li\u003e\n\u003cli\u003eMust A, Phillips SM, Naumova EN, Blum M, Harris S, Dawson-Hughes B, et al. Recall of early menstrual history and menarcheal body size: after 30 years, how well do women remember? Am J Epidemiol. 2002;155 7:672-9; doi: 10.1093/aje/155.7.672.\u003c/li\u003e\n\u003cli\u003eBean JA, Leeper JD, Wallace RB, Sherman BM, Jagger H. Variations in the reporting of menstrual histories. Am J Epidemiol. 1979;109 2:181-5; doi: 10.1093/oxfordjournals.aje.a112673.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"reproductive period, estrogen exposure, parity, pregnancy, cognitive impairment, dementia ","lastPublishedDoi":"10.21203/rs.3.rs-562858/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-562858/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eWomen comprise more than half of people suffering cognitive impairment. This study aims to evaluate the association or interaction between reproductive factors and the risk of dementia in Chinese women with natural menopause.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThe cross-sectional study was conducted in 112 community primary health care centers in rural northern China between April 2019 and January 2020. A total of 4,275 women aged ≥ 65 years who had natural menopause were included. Reproductive factors were recorded by self-report. Reproductive period was calculated as age at menopause minus age at menarche.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eCompared to those without dementia, women with dementia were significantly older at menarche and younger at menopause; had significantly shorter duration of reproductive period; and had more pregnancies and parities. There were 0.757, 0.698, and 0.708 times to get dementia for women who experienced reproductive periods with 31-33 years, 34-36 years, and ≥ 37 years, respectively, as compared with ≤ 30 years. Reproductive period could positively predict MMSE score (β = 0.112) and negative prediction of the number of parities (β = -0.449); the number of parities could negatively predict MMSE score (β = -0.851) as well.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eLonger duration of reproductive period, directly or through lower number of pregnancies/parities indirectly, lowers the risk of dementia in late life.\u003c/p\u003e","manuscriptTitle":"Reproductive Factors and Risk of Dementia in Natural Postmenopausal Women: a Cross-sectional Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-06-01 19:52:42","doi":"10.21203/rs.3.rs-562858/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"86725628-0608-4fd9-8923-933697203cec","owner":[],"postedDate":"June 1st, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":4694792,"name":"Neurology"},{"id":4694793,"name":"Neurosurgery"}],"tags":[],"updatedAt":"2021-10-05T10:14:14+00:00","versionOfRecord":[],"versionCreatedAt":"2021-06-01 19:52:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-562858","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-562858","identity":"rs-562858","version":["v1"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}