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

体力活动和阿尔茨海默氏病及相关痴呆症的血浆蛋白质组特征

基本信息

批准号：
10724140
负责人：
Steve Nguyen
金额：
$ 10.36万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10724140
关键词：
Acceleration Accelerometer Adult Aging Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer’s disease biomarker Amyloid beta-42 Atherosclerosis Risk in Communities Biological Biological Aging Biological Markers Biological Process Black race Brain Data Dementia Disease Disease Outcome Engineering Environment Etiology Funding Glial Fibrillary Acidic Protein Goals Health Hispanic Impaired cognition Intervention Latina Light Link Long-Term Effects Machine Learning Measures Mediating Medicine Memory Mentorship Molecular Molecular Profiling Outcome Pathway interactions Patient Self-Report Phase Phenotype Physical activity Plasma Plasma Proteins Proteins Proteome Proteomics Research Resources Risk Role Sampling Studies Strategic Planning Threonine Training United States National Academy of Sciences United States National Institutes of Health Woman Women&apos s Health adjudication cardiovascular health clinically relevant cognitive function cognitive testing cohort dementia risk ethnic diversity follow-up insight machine learning method men mild cognitive impairment moderate-to-vigorous physical activity mortality multiple chronic conditions neurofilament neuropathology novel older women prevent programs prospective proteomic signature racial diversity tau-1 vigorous intensity

项目摘要

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.

项目概要/摘要体力活动 (PA) 已被列为延缓或预防阿尔茨海默病的一种有前景的干预措施疾病（AD）和相关痴呆（ADRD），但大多数研究使用我们的初步报告的 PA。数据显示，在老年女性中，通过加速度计测量的中度至剧烈运动的数量较多强度 PA 和步数/天与严格判定的轻度认知事件的较低风险相关然而，PA 影响 ADRD 风险的分子机制。血浆蛋白质组是鉴定 PA 分子机制的一个有希望的目标。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机器学习 (ML) 方法已应用于推导 PA 蛋白质组特征、蛋白质组老化。然而，很少有研究系统地应用和比较机器学习。获得 PA 蛋白质组学特征的方法本研究的目的是增强我们对 PA 蛋白质组学特征的理解。 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 种临床相关血浆蛋白和血浆 AD 研究人员对 2,836 名女性病例组（n=1,336 例 MCI/ADRD 病例）中的生物标志物进行了研究，这些女性来自表型丰富且种族/族裔多元化女性健康倡议 (WHI) 记忆研究 (WHIMS)，样本收集于 1995-1998 年（n=2,836）和 14-18 年后的 2012-2013 年（n=1,000；500 起 MCI/ADRD 病例）以及 WHI 目标体力活动与心血管健康 (OPACH; R01HL105065) 研究收集了 2012 年至 2014 年，对 6,489 名女性进行了加速度测量，其中包括 RF1AG079149 中的 1,000 名 WHIMS 女性。 WHIMS 包含纵向年度认知评估和严格判定的 27 岁以上 MCI/痴呆症在 R00 阶段，我建议从 600 Black 中获取 AD 病理学的血浆生物标志物。西班牙裔/拉丁裔 OPACH 女性的研究结果将在动脉粥样硬化风险中得到复制。社区研究将研究结果扩展到男性和女性，我们的目标是：(1a) 应用和比较机器学习方法。为了获得 PA 蛋白质组特征，(1b) 检查 PA 蛋白质组特征、蛋白质组老化的重叠时钟和 ADRD 蛋白质组时钟，(1c) 将 PA 蛋白质组特征与 MCI/ADRD 和认知联系起来 (2) 确定 PA 相关血浆蛋白在我们观察到的 PA-MCI/ADRD 中的作用 (3) 确定 PA（自我报告和加速度计测量）和 PA- 的关联黑人、西班牙裔/拉丁裔和白人女性的血浆蛋白与血浆 AD 生物标志物相关。研究将促进对 PA、衰老和 ADRD 之间的分子机制的理解。向 OPACH 收集血浆 AD 生物标志物数据将通过开展更广泛的研究来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。