Sex-Specific Genetic Drivers of Alzheimer's Disease Endophenotypes

摘要 随着人口老龄化，晚发性阿尔茨海默病（AD）正成为越来越重要的公众 健康问题。AD对妇女的影响尤为严重。在美国超过500万的人口中 患有这种疾病的人中，三分之二是妇女。女性AD患者的神经病理学比男性AD患者多。 AD，有更严重的认知症状，和更严重的神经退行性变，表明这种疾病 影响男性和女性大脑的方式不同因此，关注AD中的性别差异对于 实地进行有效干预。AD及其相关疾病性别特异性遗传驱动因子的鉴定 内源性表型可能会改变治疗的方式， 针对AD的个性化干预。我们小组和其他人的研究已经开始揭示基因 解释男性和女性之间观察到的一些差异的因素，特别是在AD方面 神经病理学和认知能力下降。为了推动这一领域的发展，必须发现更多的遗传效应， 必须研究性别特异性损伤途径的潜在机制。本项目的目标 是识别和复制以性别特异性方式起作用的遗传效应， AD的表现和临床进展。本提案将推进我们对性的理解- 通过利用来自30项衰老和AD研究的数据， （n= 33，740），以评估与AD神经病理学和认知功能下降的遗传相关性。这场 项目将突出新的候选途径，并通过以下方式开始表征机制的过程 男性和女性之间的遗传变异影响AD的风险和临床症状。做爱- 确定的特定途径将提供治疗靶点，并有助于将该领域推向个性化， 干预措施，考虑到个人的性别和神经病理表现。

Abstract As the population ages, late-onset Alzheimer’s disease (AD) is becoming an increasingly important public health issue. AD disproportionately affects women. Of the more than 5 million people in the United States afflicted with this disease, two-thirds are women. Women with AD have more neuropathology than men with AD, have more severe cognitive symptoms, and more severe neurodegeneration, suggesting that the disease affects male and female brains in different ways. Thus, a focus on sex differences in AD is essential to move the field towards effective interventions. The identification of sex-specific genetic drivers of AD and AD-related endophenotypes could transform the way treatments are administered and be a critical step towards personalized interventions for AD. Research from both our group and others has begun to uncover genetic factors that explain some of the observed differences between males and females, specifically in terms of AD neuropathology and cognitive decline. To advance the field, additional genetic effects must be discovered and the underlying mechanisms of sex-specific pathways of injury must be examined. The objective of this project is to identify and replicate genetic effects that act in a sex-specific manner to drive the neuropathological presentation and clinical progression of AD. The present proposal will advance our understanding of sex- specific genetic contributors to AD endophenotypes by leveraging data from 30 studies of aging and AD (n=33,740) to assess genetic associations with AD neuropathology and cognitive decline. The outcome of this project will highlight new candidate pathways and begin the process of characterizing the mechanisms by which genetic variation among males and females affects the risk and clinical symptoms of AD. The sex- specific pathways identified will offer therapeutic targets and help move the field towards personalized interventions that consider an individual’s sex and neuropathological presentation.