Abstract: Background At present, research on the associations between female reproductive factors and dementia-related plasma biomarkers remains insufficient, and few studies have focused on the linear and nonlinear association patterns between them. Existing findings are inconsistent. Objective To explore the associations between female reproductive factors, including number of children, age at first childbirth, age at last childbirth, age at menarche, age at menopause, and reproductive span, and four dementia-related plasma biomarkers, including tau, amyloid-β (Aβ)42, Aβ40, and the Aβ42/Aβ40 ratio, so as to provide biomarker-level evidence for sex specific mechanisms underlying dementia in women and a theoretical basis for early prevention strategies for dementia. Methods This study combined data from the Pingyin cohort and the UK Biobank and included a total of 824 eligible postmenopausal women. Information on reproductive factors was collected by self-report, and plasma biomarker levels were measured using the single molecule array (Simoa) assay. After adjustment for relevant covariates, multivariable linear regression and nonlinear analytical methods were used to explore the linear and nonlinear associations between reproductive factors and dementia-related biomarkers. Results Among the 824 postmenopausal women, the mean age was (59.3±6.8) years. Multivariable linear regression analysis showed that, compared with nulliparous women, women with one child (β=11.30, 95%CI=3.420 to 19.100, P=0.005) and two children (β=7.50, 95%CI=1.21 to 13.80, P=0.020) had significantly increased Aβ40 levels; women with one child (β=-0.005,95%CI=-0.009 to -0.002, P=0.005) and two children (β=-0.004, 95%CI=-0.007 to -0.001, P=0.005) had significantly decreased Aβ42/Aβ40 ratios. Compared with women whose age at first childbirth was 0-25 years, women whose age at first childbirth was 26-30 years had significantly increased Aβ42 levels (β=0.327, 95%CI=0.018 to 0.637, P=0.038) and Aβ40 levels (β=7.49,95%CI=1.21 to 13.80, P=0.020). Age at last childbirth was significantly associated only with the Aβ42/Aβ40 ratio; compared with women whose age at last childbirth was 0-25 years, women whose age at last childbirth was >35 years had a significantly increased Aβ42/Aβ40 ratio (β=0.005, 95%CI=0.010 to 0.009, P=0.016). Compared with women whose age at menarche was 0-12 years, women whose age at menarche was >15 years had significantly increased Aβ40 levels (β=8.140, 95%CI=1.250 to 15.000, P=0.021); for each 1-standard deviation increase in age at menarche, Aβ40 levels increased by an average of 6.374 ng/ L (β=6.374, 95%CI=3.597 to 9.152, P<0.001). Compared with women whose age at menopause was 0-45 years, women whose age at menopause was >50 years had significantly decreased Aβ40 levels (β=-8.870, 95%CI=-17.000 to -0.720, P=0.033); for each 1-standard deviation increase in age at menopause, both Aβ42 levels (β=-0.148, 95%CI=-0.294 to -0.003, P=0.046) and Aβ40 levels (β=-4.942, 95%CI=-8.016 to -1.867, P=0.002) decreased significantly. Compared with women whose age at menopause was 0-45 years, women whose age at menopause was >50 years had significantly decreased Aβ40 levels (β=-7.860,95%CI=-14.000 to -1.730, P=0.033); for each 1-standard deviation increase in reproductive span, both Aβ42 levels (β=-0.187,95%CI=-0.345 to -0.030, P=0.020) and Aβ40 levels (β=-6.981, 95%CI=-10.285 to -3.677, P<0.001) decreased significantly.Nonlinear analysis showed that there were significant nonlinear associations between reproductive factors and dementia-related biomarkers, particularly for Aβ40 and the Aβ42/Aβ40 ratio. Conclusion This study found that female reproductive factors were significantly associated with dementia-related plasma biomarkers in both linear and nonlinear patterns. Higher number of children, first childbirth at 26-30 years, later age at menarche, later age at menopause, and longer reproductive span were all associated with changes in dementia-related biomarkers. Future studies should pay attention to the potential associations between reproductive factors and dementia risk in women, so as to provide new theoretical evidence for developing precise early prevention and intervention strategies.

Key words: Dementia, Female, Reproductive factors, Cognitive function, Plasma proteins

摘要： 背景 目前关于女性生殖因素与痴呆相关血浆生物标志物的研究尚不充分，且鲜少关注二者间的线性与非线性关联特征，现有研究结论缺乏一致性。目的 探讨女性生殖因素（子女数量、初产年龄、末产年龄、初潮年龄、绝经年龄及生育期长度）与4种痴呆相关血浆生物标志物[Tau蛋白、β淀粉样蛋白（Aβ）42蛋白、Aβ40蛋白及Aβ42/Aβ40比值]之间的关联，为女性痴呆发病的性别特异性机制提供生物标志物层面的证据，进而为痴呆的早期预防策略提供理论依据。方法 本研究结合平阴队列数据和UKB数据，共纳入824名符合条件的已绝经女性为研究对象。采用自我报告方式收集生殖因素信息，通过数字式单分子免疫阵列分析法（Simoa）法检测血浆生物标志物水平，校正相关协变量后，通过多元线性回归和非线性分析方法，探索各生殖因素与痴呆生物标志物的线性及非线性关联。结果 824名已绝经女性平均年龄（59.3±6.8）岁。多元线性回归分析结果显示，与无子女女性相比，子女数量为1个（β=11.30，95%CI=3.420~19.100，P=0.005）、2个（β=7.50，95%CI=1.21~13.80，P=0.020）的女性Aβ40蛋白水平显著升高；子女数量为1个（β=-0.005，95%CI=-0.009~-0.002，P=0.005）、2个（β=-0.004，95%CI=-0.007~-0.001，P=0.005）的女性Aβ42/Aβ40比值显著降低。与0~25岁初产女性相比，26~30岁初产女性的Aβ42蛋白水平（β=0.327，95%CI=0.018~0.637，P=0.038）与Aβ40蛋白水平（β=7.49，95%CI=1.21~13.80，P=0.020）均显著升高。末产年龄仅与Aβ42/Aβ40比值存在显著关联，与0~25岁末产女性相比，末产年龄>35岁的女性Aβ42/Aβ40比值显著升高（β=0.005，95%CI=0.010~0.009，P=0.016）。与0~12岁初潮女性相比，初潮年龄>15岁的女性Aβ40蛋白水平显著升高（β=8.140，95%CI=1.250~15.000，P=0.021）；且初潮年龄每增加1个标准差，Aβ40蛋白水平平均升高6.374 ng/L（β=6.374，95%CI=3.597~9.152，P<0.001）。与0~45岁绝经女性相比，>50岁绝经女性的Aβ40蛋白水平显著降低（β=-8.870，95%CI=-17.000~-0.720，P=0.033）；绝经年龄每增加1个标准差，Aβ42蛋白水平（β=-0.148，95%CI=-0.294~-0.003，P=0.046） 与 Aβ40 蛋 白水平（β=-4.942，95%CI=-8.016~-1.867，P=0.002）均显著降低。与 0~45 岁绝经女性相比，>50 岁绝经女性的Aβ40蛋白水平显著降低（β=--7.860，95%CI=-14.000~-1.730，P=0.033）；生育期长度每增加1个标准差，Aβ42蛋白水平（β=-0.187，95%CI=-0.345~-0.030，P=0.020）与Aβ40蛋白水平（β=-6.981，95%CI=-10.285~-3.677，P<0.001）均显著降低。非线性分析表明，生育因素与痴呆生物标志物之间呈现显著的非线性关系，尤其在Aβ40蛋白和Aβ42/Aβ40比值方面。结论 本研究发现，女性的生育因素与痴呆相关血浆生物标志物之间存在显著的线性和非线性关联。较多子女、26~30岁初产、初潮年龄较晚、绝经年龄较晚和较长生育期均与痴呆相关生物标志物的改变存在关联。未来应关注生育因素与女性痴呆风险的潜在关联，为制定精准的早期预防干预策略提供新的理论依据。

关键词: 痴呆, 女性, 生殖因素, 认知功能, 血浆蛋白