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.

项目总结