Plasma proteomic signatures of physical activity and Alzheimer's disease and related dementias

项目摘要/摘要 体力活动(PA)已被列为延缓或预防阿尔茨海默氏症的有前途的干预措施 疾病(AD)和相关痴呆(ADRD)，然而大多数研究使用自我报告的PA。我们的预赛 数据显示，在老年女性中，测量到的中等到剧烈的加速计数量更高 强度PA和步数/天与较低的严格判断事件轻微认知风险相关 损害(MCI)和ADRD。然而，PA影响ADRD风险的分子机制 都不清楚。血浆蛋白质组是研究PA分子机制的一个有前景的靶点 因为蛋白质调节生物过程，捕捉疾病机制，并可能识别干预 目标。机器学习(ML)方法已被应用于获得PA蛋白质组签名、蛋白质组老化 时钟和ADRD蛋白质组时钟。然而，很少有研究系统地应用和比较ML 获得PA蛋白质组特征的方法。这项研究的目的是增进我们对 PA，蛋白质组学，以及它们与ADRD的关系。我建议利用NIA资助的一项研究(RF1AG079149) 将使用SOMAscan平台测量约7,000种临床相关的血浆蛋白和血浆AD 在一个2,836例(n=1,336例MCI/ADRD病例)的病例队列中的生物标志物在富有表型和 种族/民族多元化妇女健康倡议(WHI)记忆研究(Whims)来自收集的样本 1995-1998年(n=2,836)和14-18年后的2012-2013年(n=1,000；500起MCI/ADRD病例)和 WHI客观体力活动与心血管健康(OPACH；R01HL105065)研究，收集 2012年至2014年对6489名女性进行了加速测量，其中包括RF1AG079149中1000名突发奇想的女性。 Whims包含一年一度的纵向认知评估和对27岁以上MCI/痴呆症的严格裁决 多年的跟踪调查。在R00阶段，我建议从600个Black中获得AD病理的血浆生物标记物 以及西班牙裔/拉丁裔OPACH女性。研究结果将在#年动脉粥样硬化风险中重复 社区研究旨在将研究结果推广到男性和女性。我们的目标是：(1)应用和比较最大似然方法 为了获得PA蛋白质组特征，(1b)检查PA蛋白质组特征的重叠、蛋白质组老化 时钟和ADRD蛋白质组时钟，(1c)PA蛋白质组特征与MCI/ADRD和认知 功能，(2)确定PA相关血浆蛋白在我们观察到的PA-MCI/ADRD中的作用 关联，以及(3)确定PA(自报告和加速度计测量)和PA- 黑人、西班牙裔/拉丁裔和白人女性中血浆蛋白与血浆AD生物标记物的相关性。这 研究将促进对PA、衰老和ADRD之间联系的分子机制的理解。加法 将血浆AD生物标记物数据转移到OPACH将产生持久的影响，使更广泛的研究能够 加速计量学和AD病理与衰老相关表型的关系。

PROJECT SUMMARY/ABSTRACT Physical activity (PA) has been listed as a promising intervention to delay or prevent Alzheimer’s disease (AD) and related dementias (ADRD), however most studies used self-reported PA. Our preliminary data show that, among older women, higher amounts of accelerometer-measured moderate to vigorous intensity PA and steps/day are associated with lower risk of rigorously adjudicated incident mild cognitive impairment (MCI) and ADRD. However, the molecular mechanisms through which PA influences ADRD risk are unclear. The plasma proteome is a promising target for identifying the molecular mechanisms of PA because proteins regulate biological processes, capture disease mechanisms, and may identify intervention targets. Machine learning (ML) methods have been applied to derive PA proteomic signatures, proteomic aging clocks, and ADRD proteomic clocks. However, few studies have systematically applied and compared ML methods to derive PA proteomic signatures. The objective of this research is to enhance our understanding of PA, proteomics, and how they relate to ADRD. I propose leveraging an NIA-funded study (RF1AG079149) that will use the SOMAscan platform to measure ~7,000 clinically relevant plasma proteins and plasma AD biomarkers in a case cohort of 2,836 (n=1,336 incident MCI/ADRD cases) women in the richly phenotyped and racially/ethnically diverse Women’s Health Initiative (WHI) Memory Study (WHIMS) from samples collected in 1995-1998 (n=2,836) and 14-18 years later in 2012-2013 (n=1,000; 500 incident MCI/ADRD cases) and the WHI Objective Physical Activity and Cardiovascular Health (OPACH; R01HL105065) study which collected accelerometry in 2012-2014 among 6,489 women, including the 1,000 WHIMS women in RF1AG079149. WHIMS contains longitudinal annual cognitive assessments and rigorously adjudicated MCI/dementia over 27 years of follow-up. In the R00 phase, I propose obtaining plasma biomarkers of AD pathology from 600 Black and Hispanic/Latina OPACH women. Study results will be replicated in the Atherosclerosis Risk in Communities study to extend findings to men and women. Our Aims are: (1a) Apply and compare ML methods to derive PA proteomic signatures, (1b) Examine the overlap of PA proteomic signatures, proteomic aging clocks, and ADRD proteomic clocks, (1c) Relate PA proteomic signatures with MCI/ADRD and cognitive functioning, (2) Determine the role of PA-associated plasma proteins in our observed PA-MCI/ADRD associations, and (3) Determine the associations of PA (self-reported and accelerometer-measured) and PA- associated plasma proteins with plasma AD biomarkers among Black, Hispanic/Latina, and White women. This research will advance understanding of the molecular mechanisms linking PA, aging, and ADRD. The addition of plasma AD biomarker data to OPACH will have an enduring impact by enabling broader studies of accelerometry and AD pathology in relation to aging-related phenotypes.