Physical activity predictors of cognitive and brain health in the risk for Alzheimer's disease

摘要 阿尔茨海默氏病是一种进行性神经退行性疾病，导致大脑和神经系统的严重损失。 认知能力预计到2050年，阿尔茨海默病的患病率将超过1400万， 日益严重的公共卫生危机。研究可以减缓或预防阿尔茨海默氏症的疾病修饰干预措施 疾病是迫切需要的，包括可改变的生活方式行为，可以通过外周系统 增强阿尔茨海默病风险增加的人对认知能力下降的恢复机制。 最近的研究将有氧运动（PA）与增强脑血管功能和海马神经元功能联系起来。 神经发生，暗示支持易患阿尔茨海默病的大脑区域的途径。然而，结果 PA和阿尔茨海默病风险的相关性一直是混合的，可能是由于PA如何评估的差异， 从自我报告到行为到生理测量，以及外周血中的个体间差异。 对PA的全身生理反应。迫切需要确定不同的巴勒斯坦权力机构措施如何影响 大脑老化和临床前阿尔茨海默病风险的认知下降，并确定哪些PA标志物最能预测 阿尔茨海默病易感性的差异，因此基于大脑的机制可以有效地针对 基于PA的干预措施。我们计划评估270名居住在社区的老年人，年龄在70到84岁之间， 心肺适能的基线生理测量、来自可穿戴设备的PA的行为测量 加速度计，外周血神经源性（脑源性神经营养因子）和血管（内皮 祖细胞）标记物，以及运动挑战之前和之后的主观评级。 近期和终身的PA。将每隔18个月对参与者进行评估，以评估 与大脑皮层相关的记忆和额叶相关的执行认知功能，以及磁共振 脑结构、静息功能连接和白色物质完整性和高信号的成像扫描 损伤负荷。该队列将包括那些有和没有增加临床前阿尔茨海默病风险的人，定义如下 一级阿尔茨海默病家族史和主观记忆问题。该提案将解决 以下具体目标：研究PA的行为标记物如何预测以下方面的纵向变化：1） 认知功能和2）与阿尔茨海默病临床前风险相关的大脑结构和功能连接 评估PA的外周全身生理标志物如何预测认知的纵向变化 以及大脑结构和功能连接与阿尔茨海默病风险的关系;并确定 有氧运动的外周系统反应介导PA和纵向变化之间的关系， 大脑和认知在那些有和没有增加阿尔茨海默病的风险。通过评价一部小说， PA标志物的综合集，并测试它们对认知和大脑轨迹的影响， 阿尔茨海默病的风险，这一建议提供了一个独特的机会，以获得所需的关键数据，以帮助推进 努力开发有效的基于运动的干预措施，以预防阿尔茨海默病。

Abstract Alzheimer’s disease is a progressive neurodegenerative disorder leading to profound losses in brain and cognitive abilities. With a projected prevalence of over 14 million by 2050, Alzheimer’s disease represents a growing public health crisis. Research on disease modifying interventions that can slow or prevent Alzheimer’s disease is critically needed, including on modifiable lifestyle behaviors that can act through peripheral systemic mechanisms to enhance resilience against cognitive decline in those with increased risk for Alzheimer’s disease. Recent work has linked aerobic physical activity (PA) to enhanced cerebrovascular function and hippocampal neurogenesis, suggesting pathways to support brain regions vulnerable to Alzheimer’s disease. However, results relating PA and Alzheimer’s disease risk have been mixed, potentially due to differences in how PA is assessed, ranging from self-report to behavioral to physiological measures, as well as inter-individual variation in peripheral systemic physiological responses to PA. There is an urgent need to identify how different PA measures influence cognitive decline in brain aging and preclinical Alzheimer’s risk, and to determine which PA markers best predict differences in susceptibility to Alzheimer’s disease, so brain-based mechanisms can be effectively targeted for PA-based interventions. We plan to evaluate 270 community-dwelling older adults, ages 70 to 84, to obtain baseline physiological measures of cardiorespiratory fitness, behavioral measures of PA from wearable accelerometry, and peripheral blood neurogenic (brain-derived neurotrophic factor) and vascular (endothelial progenitor cells) markers assessed before and after an exercise challenge, together with subjective ratings of recent and lifelong PA. Participants will be evaluated at 18-month intervals to assess trajectories of decline in hippocampal-related memory and frontal-related executive cognitive functions, as well as magnetic resonance imaging scans of brain structure, resting functional connectivity, and white matter integrity and hyperintensity lesion load. The cohort will include those with and without increased preclinical Alzheimer’s disease risk, defined by first-degree Alzheimer’s disease family history and subjective memory concerns. This proposal will address the following specific aims: to investigate how behavioral markers of PA predict longitudinal change in 1) cognitive function and 2) brain structure and functional connectivity in relation to preclinical risk for Alzheimer’s disease; to evaluate how peripheral systemic physiological markers of PA predict longitudinal change in cognition and brain structure and functional connectivity in relation to Alzheimer’s disease risk; and to determine how the peripheral systemic response to aerobic exercise mediates the relation between PA and longitudinal changes in brain and cognition in those with and without increased Alzheimer’s disease risk. By evaluating a novel, comprehensive set of PA markers and testing their effects on trajectories of cognition and brain in relation to Alzheimer’s disease risk, this proposal provides a unique opportunity to obtain key data needed to help advance efforts in developing effective exercise-based interventions for Alzheimer’s disease prevention.