Epigenetic Aging Biomarkers of Mild Cognitive Impairment, Alzheimer's Disease and Related Dementias, and Brain Aging

表观遗传年龄相对于实际年龄更高，被描述为表观遗传年龄加速(EAA)，表明 一个人的生理年龄比他们的年龄大。调查小组最近显示，监管局 与认知功能低下(如情景记忆、音素流利性)和脑白质减少有关 大脑总体积，支持EAA在认知和大脑健康中的作用。然而，尽管年龄是最大的风险 阿尔茨海默病和相关痴呆的因子(ADRD)--EAA与轻度认知障碍的关系 对损伤(MCI)、ADRD和脑老化的研究还很少。NIA 2020-2025年战略方向 研究目标包括了解“与衰老相关的变化的分子基础如何有助于 老年性痴呆的发展和病程及早期生物学和临床标记物的确定 检测认知功能减退、MCI和AD。为了实现这些目标，本项目的总体目标是澄清 嵌套病例队列中EAA与MCI、ADRD、成功认知老化和脑老化的关系 (n=2,836)在NIA资助的具有深刻表型、种族和民族多样性的妇女健康倡议范围内 记忆研究(突发奇想)。随着25年的跟踪至少将持续到2021年，Whims包含 详细的认知功能纵向测量数据；1336例严格查明的MCI事件 和ADRD；全基因组基因分型；以及大脑健康的纵向神经成像措施。作为创新的 这项研究的方面，使用来自两次研究访问的存储的血DNA的新的全基因组DNA甲基化数据14- 将产生相隔18年的时间，以检查地产代理监管局的变化。目标是：1)确定在多大程度上 EAA与MCI和ADRD的风险较高以及无认知障碍而存活到90岁的可能性较低相关 损害；2)确定EAA与总的和局部的脑体积减少相关的程度 以及增加总的脑室和白质病变体积；以及3)识别跨 在表观基因组关联研究中，基因组与这些认知和大脑结果相关。 种族/民族、载脂蛋白Eε4携带者、阿尔茨海默病多基因风险和心血管疾病相关性的缓和 疾病将被探索。这些发现将在表型良好的独立队列中复制和推广 拥有全基因组DNA甲基化以及认知和大脑结果数据的男性和女性。考虑到 病理生理学的ADRD过程可在症状出现前20年开始，了解 EAA作为一种衰老生物标记物，在疾病病程早期识别老年人是必要的，以潜在地预防 不可逆转的认知和功能衰退。这项研究还提供了一个独特的机会来确定年龄- MCI、ADRD和加速脑老化的相关表观遗传学机制可能作为 治疗的目标是促进晚年被保存的认知。重要的是，新的全基因组DNA 甲基化数据将丰富现有的WHIMS数据资源，并使未来能够对EAA和EWAS进行检查 与不同的衰老表型有关，从而在本研究之外产生广泛和持久的科学影响。

A higher epigenetic age relative to chronological age, described as ‘epigenetic age acceleration (EAA),’ indicates that an individual is biologically older than their years. The investigative team recently showed that EAA is associated with lower cognitive function (e.g., episodic memory, phonemic fluency) and lower white matter and total brain volumes, supporting a role of EAA in cognitive and brain health. Yet, while age is the strongest risk factor for Alzheimer’s disease and related dementias (ADRD), the association of EAA with mild cognitive impairment (MCI), ADRD, and brain aging is vastly understudied. The NIA’s 2020-2025 Strategic Directions for Research goals include understanding how “molecular bases of changes associated with aging contribute to the development and course of age-related dementia” and identifying “biological and clinical markers for early detection of cognitive decline, MCI, and AD.” Towards these goals, the overall objective of this project is to clarify the association of EAA with MCI, ADRD, successful cognitive aging, and brain aging in a nested case-cohort (N=2,836) within the deeply phenotyped, racially and ethnically diverse, NIA-funded Women’s Health Initiative Memory Study (WHIMS). With 25 years of follow-up that will continue at least through 2021, WHIMS contains detailed data on longitudinal measures of cognitive function; 1,336 incident cases of rigorously ascertained MCI and ADRD; genome-wide genotyping; and longitudinal neuroimaging measures of brain health. As an innovative aspect of this study, novel genome-wide DNA methylation data using stored blood DNA from two study visits 14- 18 years apart will be generated to examine changes in EAA. The Aims are to: 1) determine the extent to which EAA is associated with higher risk of MCI and ADRD and lower likelihood of survival to age 90 without cognitive impairment; 2) determine the extent to which EAA is associated with decreased total and regional brain volumes and increased total ventricular and white matter lesion volumes; and 3) identify epigenetic signatures across the genome associated with these cognitive and brain outcomes in epigenome-wide association studies (EWAS). Moderation of associations by race/ethnicity, APOE ε4 carriage, polygenic risk for AD, and cardiovascular disease will be explored. Findings will be replicated and extended in well-phenotyped, independent cohorts of men and women with data on genome-wide DNA methylation and cognitive and brain outcomes. Given that the pathophysiological ADRD process can begin up to 20 years before symptom onset, understanding the role of EAA as an aging biomarker identifying older adults early in the disease course is imperative to potentially prevent irreversible cognitive and functional decline. This study also presents a unique opportunity to identify age- associated epigenetic mechanisms of MCI, ADRD, and accelerated brain aging with potential to act as therapeutic targets to promote preserved cognition in late life. Importantly, the novel genome-wide DNA methylation data will enrich the existing WHIMS data resource and enable future examination of EAA and EWAS in relation to diverse phenotypes of aging, thereby having a broad and lasting scientific impact beyond this study.