Epigenetic Age Acceleration as a Biomarker of Early Life Adversity and Mid-life Cognitive Function

摘要 早年生活中的逆境影响了美国三分之二的儿童，并可能对健康产生持久的影响 认知老化，干扰早期认知能力的获得，并导致更早、更陡峭 中年时认知功能下降。理论模型表明，早年生活中的逆境改变了生理 在认知健康的广泛领域下的压力调节系统。早期生命的生物效应 因此，逆境可以作为高度新颖的生物标志物，其独特的优势是可以在 认知障碍。在中年、认知障碍发作之前甚至是中年时识别生物标志物 神经退行性疾病，如阿尔茨海默病和相关的痴呆，可以提供可操作的 改善早期发现的信息，以及在后期延迟、逆转或预防这些情况的努力- 生活。这项建议将研究早期生活中的逆境是否会改变一种新的认知功能生物标记物 寿命，表观遗传年龄，人类组织和细胞因DNA甲基化而产生的生物年龄的指数 并预示着晚年的认知障碍。现有的数据和生物样品将被用来检查 女性早年逆境对表观遗传年龄的影响及其与中年认知功能的关系 生长发育研究(N=173；MAGE=39.47)，一项关于儿童影响的30年前瞻性队列研究 性虐待。正在积极收集有关女性成长和发展研究的数据， 使用公认的、基于表现的方法检查儿童性虐待对认知功能的影响 测量工作记忆、抑制控制、流体推理和接受性语言。海流 应用程序将利用这一机会，为儿童如何 性虐待嵌入在甲基组中，会影响中年的认知功能。DNA和全基因组 DNA甲基化的变异将通过全血来表征。胞嘧啶353位的DNA甲基化- 跨越甲基组的鸟嘌呤部位将被用来量化表观遗传年龄，并检查其与儿童的关系 性虐待。中介模型将测试糖皮质激素重塑是否发生在16年 跟随儿童性虐待可以解释中年表观遗传年龄的加速。的可变甲基化区域 还将检查受儿童性虐待影响的甲基组，以确定哪些区域具有最强的 中年的风险和保护与认知功能的关系。表观遗传年龄和其他既定风险， 包括认知功能、多基因风险评分、教育程度、社会经济地位和终生 暴露在应激事件中，将被包括在统计模型中，以检验增加的预测能力 从这些认知功能的分子分析中获得，超越了已知的风险。遵循以下建议 由国家老龄化研究所提出的这项建议将测试表观遗传年龄作为认知能力的独特生物标记物 在经历了早年的逆境之后，在中年时识别那些认知障碍风险最高的人，并 晚年衰退。

ABSTRACT Early life adversity affects two-thirds of all children in the U.S. and can have a lasting impact on healthy cognitive aging, interfering with the acquisition of cognitive abilities in early life and leading to earlier, steeper declines in cognitive function at mid-life. Theoretical models specify that early life adversity alters biological stress-mediating systems underlying broad domains of cognitive health. The biological effects of early life adversity can therefore serve as highly novel biomarkers with the unique advantage of being detected prior to cognitive impairment. Identifying biomarkers at mid-life, prior to the onset of cognitive impairment or even neurodegenerative diseases such as Alzheimer's Disease and related dementias, can provide actionable information to improve early detection and efforts at delaying, reversing, or preventing these conditions in late- life. This proposal will examine whether early life adversity alters a novel biomarker of cognitive function at mid- life, epigenetic age, an index of the biological age of human tissues and cells derived from DNA methylation and predictive of cognitive impairment in late-life. Existing data and biospecimens will be used to examine the impact of early life adversity on epigenetic age and its relation to cognitive function at mid-life in the Female Growth and Development Study (N=173; Mage=39.47), a 30-year prospective cohort study of the impact of child sexual abuse. Active data collection with the Female Growth and Development Study is underway and examining the impact of child sexual abuse on cognitive function using well-established, performance-based measures of working memory, inhibitory control, fluid reasoning, and receptive language. The current application would capitalize on this opportunity by advancing comprehensive biological models for how child sexual abuse is embedded in the methylome to affect cognitive function at mid-life. DNA and genome-wide variation in DNA methylation will be characterized through whole blood. DNA methylation at 353 cytosine- guanine sites across the methylome will be used to quantify epigenetic age and examine its relation with child sexual abuse. Mediation models will test whether glucocorticoid remodeling occurring in the sixteen years following child sexual abuse explains accelerations in epigenetic age at mid-life. Variably methylated regions of the methylome affected by child sexual abuse will also be examined to identify regions that have the strongest risk and protective relations with cognitive function at mid-life. Epigenetic age and other established risks, including a cognitive function polygenic risk score, educational attainment, socioeconomic status, and lifetime exposure to stressful events, will be included in statistical models to examine the increased predictive power gained from these molecular analyses of cognitive function beyond known risks. Following recommendations by the National Institute on Aging, this proposal will test epigenetic age as a unique biomarker of cognitive function at mid-life following early life adversity to identify those at greatest risk for cognitive impairment and decline in late-life.