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

项目总结/摘要 身体活动（PA）已被列为一种有希望的干预措施，以延迟或预防阿尔茨海默氏症 疾病（AD）和相关痴呆（ADRD），但大多数研究使用自我报告的PA。我们的初步 数据显示，在老年妇女中，加速计测量的中度到剧烈的 强度PA和步数/天与严格判定的轻度认知事件风险降低相关 （1）轻度认知障碍（MCI）和ADRD。然而，PA影响ADRD风险的分子机制 不清楚。血浆蛋白质组是研究PA发病机制的重要靶点 因为蛋白质调节生物过程，捕获疾病机制，并可能识别干预措施， 目标的机器学习（ML）方法已被应用于获得PA蛋白质组特征、蛋白质组老化、蛋白质组学特征和蛋白质组学特征。 时钟和ADRD蛋白质组学时钟。然而，很少有研究系统地应用和比较ML 方法来获得PA蛋白质组签名。这项研究的目的是为了提高我们对 PA，蛋白质组学，以及它们与ADRD的关系。我建议利用一项由NIA资助的研究（RF 1AG 079149）， 将使用SOMAscan平台测量约7，000种临床相关血浆蛋白和血浆AD 在2，836例（n= 1，336例MCI/ADRD病例）病例队列中， 种族/民族多样化的妇女健康倡议（WHI）记忆研究（WHIMS）从收集的样本， 1995-1998年（n= 2，836）和14-18年后的2012-2013年（n= 1，000; 500例MCI/ADRD病例）， WHI客观体力活动和心血管健康（OACH; R 01 HL 105065）研究，收集了 2012-2014年，在6,489名女性中进行了加速测量，包括RF 1AG 079149中的1,000名WHIMS女性。 WHIMS包含纵向年度认知评估和27岁以上严格裁定的MCI/痴呆 多年的后续。在R 00阶段，我建议从600名黑人中获得AD病理学的血浆生物标志物。 和西班牙裔/拉丁裔OPACH女性。研究结果将在动脉粥样硬化风险中重复， 社区研究将调查结果扩展到男性和女性。我们的目标是：（1a）应用和比较ML方法 （1b）检查PA蛋白质组签名的重叠，蛋白质组老化， （1c）将PA蛋白质组学特征与MCI/ADRD和认知功能相关 （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（自我报告的和加速度计测量的）和PA的关联。 在黑人、西班牙裔/拉丁裔和白色女性中，将血浆蛋白与血浆AD生物标志物相关联。这 这项研究将促进对PA、衰老和ADRD相关分子机制的理解。添加 将血浆AD生物标志物数据与OPACH数据相结合将产生持久的影响， 加速测量和AD病理学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.