Understanding the relationship between female reproductive span and dementia risk

项目总结 尽管有强有力的证据表明阿尔茨海默病和相关痴呆(ADRD)存在性别差异，但 这种差异背后的机制仍然知之甚少。考虑到生殖荷尔蒙是 大脑结构和功能性别差异的决定因素，我们假设影响 终生生殖激素暴露(特别是雌激素暴露)对于理解 ADRD在女性中的发展。这项拟议的研究的目标是利用瑞典人现有的数据 双胞胎登记处-世界上最大的以人口为基础的双胞胎登记处之一-为了了解 女性生育史与环境之间的遗传和环境关系 阿德勒。在目标1中，我们将使用传统的和新的数据分析方法来阐明 女性生殖寿命与ADRD之间的关系是由于共同的遗传和环境因素造成的。 ADRD的遗传分析，以及由此引申出来的任何寻求确定遗传程度的分析 与ADRD重叠，由于ADRD的相对风险因年龄而显著不同，这一事实变得更加复杂。我们 将开发一种具有遗传信息的生存分析方法来估计遗传和环境 ADRD的决定因素，以及遗传和环境与生殖跨度的相关性。在目标2中，我们 将测试女性生殖跨度是否改变了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影响。 受体，进而调节下游基因的表达。我们假设由于这个原因 机制，ADRD的遗传率将作为女性生殖跨度的函数而变化。在《目标3》中，我们将 确定关键的女性健康因素--口服避孕药的使用、产次、手术绝经和激素 替代疗法--影响生殖周期和ADRD之间的联系。我们假设 这些因素对了解女性一生的健康至关重要，它们将通过以下方式影响ADRD风险 改变终生雌激素暴露的程度。这项提议将促进实地对 女性生殖史如何通过提供第一个遗传信息来促进ADRD的病因学 双生子发育期女性生育期与ADRD的关系分析 对ADRD的遗传信息分析至关重要的分析方法，检验新的假说 关于终生雌激素暴露是否会影响ADRD的遗传和环境决定因素， 最终确定女性生育史的共同因素如何影响两者之间的关系 生殖广度和ADRD。美国国立卫生研究院把重点放在了研究人员治疗性的必要性上 作为一个生物变量，并侧重于那些导致健康和疾病性别差异的因素。 拟议的研究通过审查女性生育史的影响直接面对这一问题--a 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.