Understanding the relationship between female reproductive span and dementia risk

了解女性生育期与痴呆风险之间的关系

• 批准号: 10301699
• 负责人: Matthew S Panizzon
• 金额: $ 22.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301699
• 关键词: Accounting; Age; Age at Menarche; Alzheimer' s disease related dementia; Binding; Biological; Biological Markers; Brain; Breast Feeding; Contraceptive Usage; Cost of Illness; Data; Data Analyses; Data Analytics; Data Set; Development; Disease; ESR1 gene; ESR2 gene; Early identification; Environmental Risk Factor; Estrogens; Etiology; Event; Exposure to; Female; Genes; Genetic; Genetic Risk; Goals; Health; Heritability; Hormone Receptor; Hormone replacement therapy; Hormones; Individual; Intervention; Knowledge; Life; Life Cycle Stages; Longevity; Measures; Menopause; Methods; Nature; Operative Surgical Procedures; Oral Contraceptives; Phenotype; Physiological; Pregnancy; Prevalence; Prevention strategy; Proxy; Public Health; Registries; Relative Risks; Reproductive History; Research; Research Personnel; Role; Sex Differences; Statistical Methods; Stress; Structure; Survival Analysis; Symptoms; Techniques; Testing; Therapeutic Intervention; Twin Multiple Birth; United States; United States National Institutes of Health; Woman; Women' s Health; aging brain; analytical method; dementia risk; economic impact; gene environment interaction; genetic analysis; health difference; innovation; insight; middle age; novel; parity; population based; programs; reproductive; reproductive hormone; sex; years of life lost

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.

项目摘要 尽管有充分的证据表明阿尔茨海默氏病和相关痴呆症（ADRD）有性别差异，但 这种差异背后的机制仍然知之甚少。鉴于复制激素是中心 决定性别差异在大脑结构和功能方面的决定因素，我们假设影响影响的因素 终生生殖骑马暴露（尤其是雌激素暴露）对于理解 妇女的ADRD的发展。拟议的研究的目的是利用瑞典的现有数据 双胞胎注册表是世界上最大的基于人群的双胞胎注册机构之一 - 为了了解 遗传和环境关系是女性复制史与 adrd。在AIM 1中，我们将使用常规和新的数据分析方法来阐明 女性生殖跨度与ADRD之间的关联是由于共同的遗传和环境因素引起的。 ADRD的遗传分析，并通过扩展任何旨在确定遗传程度的分析 与ADRD重叠的事实使ADRD的重叠变得复杂，即ADRD的相对风险按年龄急剧急剧下降。我们 将开发一种普遍的信息生存分析方法来估计遗传和环境 ADRD的决定因素，以及与生殖跨度的遗传和环境相关性。在AIM 2中，我们 将测试女性生殖跨度是否修改了ADRD的遗传和环境决定者。 雌激素原发性繁殖激素通过与激素结合发挥其身体影响 接收器又调节了下游基因的表达。我们假设是这样 机理，ADRD的遗传力将随着女性生殖跨度的函数而变化。在AIM 3中，我们将 确定关键女性的健康因素如何 - 口服避孕药，奇偶校验，手术更年期和马匹 替代疗法 - 影响复制跨度与ADRD之间的关联。我们假设这一点 这些因素对于了解整个生命周期的妇女健康至关重要，将影响ADRD的风险 修改寿命雌激素暴露的程度。该提议将提高该领域对 女性生殖历史如何通过提供第一个遗传信息来促进ADRD的病因 分析在双胞胎中进行的女性复制跨度与ADRD之间的关系 对ADRD的遗传信息分析必不可少的分析方法，测试了新的假设 关于寿命雌激素暴露是否影响ADRD的遗传和环境决定者 最终确定女性生殖历史共同的因素如何影响 生殖跨度和ADRD。 NIH对研究人员的治疗性需要重视 作为生物学变量，并专注于导致健康和疾病性别差异的因素。 拟议的研究直接通过检查女性复制史的影响来面对这个问题 - 妇女健康的主要确定者是生命的危险。