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.

项目摘要/摘要体育活动（PA）已被列为承诺干预措施，以延迟或防止阿尔茨海默氏症疾病（AD）和相关痴呆症（ADRD），但是大多数研究都使用自我报告的PA。我们的初步数据表明，在老年妇女中，较高量的加速度计中等至有力强度PA和步骤/天与严格调整事件的较低风险有关损害（MCI）和ADRD。但是，PA会影响ADRD风险的分子机制不清楚。血浆蛋白质组是识别PA的分子机制的有希望的目标因为蛋白质调节生物学过程，捕获疾病机制，并可能确定干预措施目标。机器学习（ML）方法已应用于推导PA蛋白质组学特征，蛋白质组学衰老时钟和ADRD蛋白质组学时钟。但是，很少有研究系统地应用并比较了ML 推导PA蛋白质组学特征的方法。这项研究的目的是增强我们对 PA，蛋白质组学及其与ADRD的关系。我建议利用NIA资助的研究（RF1AG079149）将使用Somascan平台测量约7,000个临床相关的等离子体蛋白和等离子体AD 生物标志物在2,836例（n = 1,336例MCI/ADRD病例）中的妇女中，从收集的样本中种族/种族的妇女健康计划（WHI）记忆研究（WHI）记忆研究（WHI） 1995-1998（n = 2,836）和2012 - 2013年后的14-18年（n = 1,000; 500事件MCI/ADRD案件）和对收集的研究 2012 - 2014年的加速度计中有6,489名妇女，包括RF1AG079149中的1,000名WHIMS妇女。 WHIMS包含纵向年度认知评估，并在27岁以上进行了严格调整的MCI/痴呆症多年后续行动。在R00阶段，我提议从600个黑色获得AD病理的血浆生物标志物和西班牙裔/拉丁裔女性。研究结果将在动脉粥样硬化风险中复制社区研究将发现扩展到男女。我们的目标是：（1A）应用和比较ML方法为了得出PA蛋白质组学特征，（1B）检查PA蛋白质组学特征的重叠，蛋白质组学衰老时钟和ADRD蛋白质组学时钟，（1C）将PA蛋白质组学特征与MCI/ADRD和认知相关联功能，（2）确定与PA相关的血浆蛋白在我们观察到的PA-MCI/ADRD中的作用关联，（3）确定PA（自我报告和加速度计）和PA-的关联黑色，西班牙裔/拉丁裔和白人妇女的相关血浆蛋白与血浆AD生物标志物。这研究将进一步了解将PA，衰老和ADRD连接的分子机制的理解。加法会对OPACH的血浆AD生物标志物数据将通过更广泛的研究对与衰老相关的表型有关的加速度计和AD病理。