Understanding the relationship between female reproductive span and dementia risk

点击翻译按钮获取中文摘要

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.