Sex-Specific Genetic Drivers of Alzheimer's Disease Endophenotypes

阿尔茨海默病内表型的性别特异性遗传驱动因素

• 批准号: 10279214
• 负责人: Logan C Dumitrescu
• 金额: $ 91.06万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10279214
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloidosis; Autopsy; Biological; Biological Markers; Brain; Case-Control Studies; Cerebrospinal Fluid; Clinical; Cognitive; Cognitive aging; Data; Data Analyses; Data Set; Development; Diagnosis; Disease; Etiology; Female; Gene Expression; Generations; Genes; Genetic; Genetic Diseases; Genetic Markers; Genetic Variation; Genomics; Goals; Impaired cognition; Individual; Inflammatory; Injury; International; Laboratories; Language; Late Onset Alzheimer Disease; Lead; Longitudinal Studies; Measures; Memory; Nerve Degeneration; Neurobehavioral Manifestations; Neurofibrillary Tangles; Outcome; Pathology; Pathway interactions; Population; Positron-Emission Tomography; Prevention; Process; Public Health; Research; Risk; Severities; Sex Differences; Symptoms; Tauopathies; Time; Tissue-Specific Gene Expression; United States; Validation; Variant; Visuospatial; Woman; Work; X Chromosome; amyloid pathology; base; case control; clinical Diagnosis; cognitive change; effective intervention; endophenotype; executive function; gene function; genetic architecture; genetic association; genetic risk factor; genome wide association study; genome-wide; genome-wide analysis; hippocampal atrophy; human data; innovation; male; men; multiple omics; neuropathology; novel; personalized intervention; personalized therapeutic; precision medicine; sex; tau Proteins; therapeutic target; trait

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.

抽象的 随着人口老龄化，晚发性阿尔茨海默病（AD）正成为一个日益重要的公众问题 健康问题。 AD 对女性的影响尤为严重。在美国超过 500 万人口中 患有这种疾病的人中，三分之二是女性。患有 AD 的女性比患有 AD 的男性有更多的神经病理学症状 AD 具有更严重的认知症状和更严重的神经退行性变，表明该疾病 以不同的方式影响男性和女性的大脑。因此，关注 AD 中的性别差异对于推动 AD 的发展至关重要。 采取有效干预措施的领域。 AD 和 AD 相关的性别特异性遗传驱动因素的鉴定 内表型可以改变治疗的方式，并且是迈向治疗的关键一步 AD 的个性化干预措施。我们小组和其他人的研究已经开始揭示遗传 解释一些观察到的男性和女性之间差异的因素，特别是在 AD 方面 神经病理学和认知能力下降。为了推进该领域的发展，必须发现额外的遗传效应并 必须检查性别特异性损伤途径的潜在机制。该项目的目标 是识别和复制以性别特异性方式起作用的遗传效应，以驱动神经病理学 AD 的表现和临床进展。本提案将增进我们对性的理解 利用 30 项衰老和 AD 研究的数据，确定 AD 内表型的特定遗传因素 (n=33,740) 评估 AD 神经病理学和认知能力下降的遗传关联。这件事的结果 项目将突出新的候选途径，并开始通过以下方式表征机制的过程： 男性和女性之间的遗传变异会影响 AD 的风险和临床症状。性别- 确定的具体途径将提供治疗靶点并帮助该领域迈向个性化 考虑个人性别和神经病理学表现的干预措施。