Understanding the relationship between female reproductive span and dementia risk

项目摘要 尽管有强有力的证据表明阿尔茨海默病和相关痴呆症（ADRD）存在性别差异， 这种差异背后的机制仍然知之甚少。鉴于生殖激素是 大脑结构和功能的性别差异的决定因素，我们假设， 终生生殖激素暴露（特别是雌激素暴露）对于了解 在女性中发展ADRD。拟议研究的目标是利用瑞典的现有数据， 双胞胎登记处-世界上最大的人口为基础的双胞胎登记处之一-为了了解 遗传和环境关系是女性生殖史和 ADRD。在目标1中，我们将使用传统和新的数据分析方法来阐明 女性生育期与ADRD之间的关联是由于共同的遗传和环境因素。 ADRD的遗传分析，以及任何试图确定遗传程度的分析， 与ADRD重叠，由于ADRD的相对风险随年龄变化而显着变化的事实而变得复杂。我们 将开发一种遗传信息生存分析方法，以估计遗传和环境 ADRD的决定因素，以及遗传和环境与生育期的相关性。在目标2中， 将测试女性生育期是否会改变ADRD的遗传和环境决定因素。 生殖激素如雌激素主要通过与激素结合来发挥其生理作用 受体，这反过来又调节下游基因的表达。我们假设由于这个原因 ADRD的遗传率将随着女性生育年限的变化而变化。在目标3中，我们 确定关键的妇女健康因素--口服避孕药的使用、产次、手术绝经和激素 替代疗法-影响生育期和ADRD之间的关联。我们假设 这些因素对于了解女性在整个生命周期中的健康状况至关重要，将通过以下方式影响ADRD风险： 改变了一生雌激素暴露的程度。这一建议将促进该领域对以下问题的理解： 女性生殖史如何通过提供第一个遗传学信息来促进ADRD的病因学 分析女性生育年限与ADRD的关系， 分析方法是必不可少的遗传知情分析ADRD，测试新的假设 关于终生雌激素暴露是否影响ADRD的遗传和环境决定因素， 最后确定女性生殖史的共同因素如何影响 繁殖期和ADRD。美国国立卫生研究院已经把重点放在研究人员需要对待性 作为一个生物变量，并侧重于那些因素，有助于性别差异的健康和疾病。 这项拟议中的研究直接面对这一问题，通过检查女性生殖史的影响， 女性晚年健康的主要决定因素-ADRD风险。

PROJECT SUMMARY Despite robust evidence for a sex difference in Alzheimer’s disease and related dementias (ADRD), the mechanisms behind this difference remain poorly understood. Given that reproductive hormones are a central determinant of sex differences in brain structure and function, we hypothesize that factors that influence lifetime reproductive hormone exposure (in particular estrogen exposure) are critical to understanding the development of ADRD in women. The goal of the proposed study is to utilize existing data from the Swedish Twin Registry – one of the largest population-based twin registries in the world – in order to understand the genetic and environmental relationships underlying the association between female reproductive history and ADRD. In Aim 1 we will use conventional and new data analytic methods to elucidate the degree to which the association between female reproductive span and ADRD is due to shared genetic and environmental factors. The genetic analysis of ADRD, and by extension any analysis which seeks to determine the degree of genetic overlap with ADRD, is complicated by the fact that the relative risk of ADRD varies dramatically by age. We will develop a genetically-informative survival analysis method to estimate the genetic and environmental determinants of ADRD, as well as genetic and environmental correlations with reproductive span. In Aim 2, we will test whether female reproductive span modifies the genetic and environmental determinants of ADRD. Reproductive hormones like estrogen primarily exert their physiological influence by binding to hormone receptors, which in turn modulate the expression of downstream genes. We hypothesize that due to this mechanism, the heritability of ADRD will vary as a function of female reproductive span. In Aim 3, we will determine how key women’s health factors – oral contraceptive use, parity, surgical menopause, and hormone replacement therapy – impact the association between reproductive span and ADRD. We hypothesize that these factors, which are crucial to understanding women’s health across the lifespan, will impact ADRD risk by modifying the degree of lifetime estrogen exposure. This proposal will advance the field’s understanding of how female reproductive history contributes to the etiology of ADRD by providing the first genetically-informed analysis of the relationship between female reproductive span and ADRD conducted in twins, developing analytic methods that are essential to genetically-informed analysis of ADRD, testing novel hypotheses regarding whether lifetime estrogen exposure influences the genetic and environmental determinants of ADRD, and finally determining how factors common to female reproductive history influence the relationship between reproductive span and ADRD. The NIH has placed a major emphasis on the need for researchers to treat sex as a biological variable, and to focus on those factors that contribute to sex differences in health and disease. The proposed study directly confronts this issue by examining the impact of female reproductive history – a major determinant of women’s health later in life – on ADRD risk.