Physical Activity and Dementia: Mechanisms of Action

摘要 运动是最有希望在晚期对神经认知功能产生积极影响的方法之一 成人期。然而，尽管承认了这一点，但几个主要的知识差距排除了广泛开出处方的能力 为了预防或治疗认知障碍而进行的运动。此R35提案包括一系列创新和 潜在的开创性研究，将有助于运动和大脑领域的重大进展 健康。我们在这项提案中描述的研究将由几位非常有前途的初级科学家领导 在经验丰富和敬业的指导团队的支持下。概念性和科学性框架 对于本提案中描述的假设，围绕着演习领域面临的三个主要挑战展开 和认知老化：(1)我们对运动影响的机制了解很少 成年后期的认知功能，(2)我们对缓和或解释的因素认识不足 个体差异，对运动的反应，以及(3)我们不了解预测长期 锻炼行为的术语采用以及如何减少障碍和增强对那些发现 继续锻炼是很有挑战性的。尽管积极的生活方式有明显的好处，但大多数人无法满足 关于锻炼的公共健康建议。我们对预测和增强 长期从事运动，我们就越了解运动是否会影响高血压的发病率。 阿尔茨海默病与处方和保持运动的最佳实践 认知障碍的治疗。我们建议对银行数据进行二次分析，这些数据来自 严格和良好控制的监督运动随机临床试验(RCT)，并进行为期3年的 对这两项运动随机对照试验的570名参与者进行随访，以评估认知、心肺功能 体能和体力活动水平。特别是，我们建议研究运动是否会导致 心脏新陈代谢和睡眠测量中介运动对认知和大脑结果的好处。我们 还将针对运动主持人，包括载脂蛋白E基因和种族差异，以更好地描述 哪些个体差异变量会影响运动对大脑健康的影响程度。最后，我们 提出一个发现目标，该目标将利用我们对基因、 生理、大脑、认知和社会情绪水平，执行预测性建模以预测长期 采取行动(或阻碍长期收养的障碍)。简而言之，这项研究提案描述了一种 广泛而雄心勃勃的工作路线，将产生开创性和创新性的研究，以解决重大问题 在成年后期，我们对运动和大脑健康的理解存在差距。这些目标针对几个主要的 AD/ADRD由NIH确定的里程碑，并将使初级科学家担任领导角色，以推动该领域的发展 以有意义和开创性的方式前进。

Abstract Exercise is one of the most promising methods for positively influencing neurocognitive function in late adulthood. Yet, despite this recognition, several major knowledge gaps preclude the ability to broadly prescribe exercise to prevent or treat cognitive impairment. This R35 proposal includes a series of innovative and potentially groundbreaking studies that will contribute to major advancements in the field of exercise and brain health. The studies that we describe in this proposal would be led by several highly promising junior scientists with the support of an experienced and dedicated mentorship team. The conceptual and scientific framework for the hypotheses described in this proposal orbit around three major challenges facing the field of exercise and cognitive aging: (1) We have a poor understanding of the mechanisms by which exercise influences cognitive function in late adulthood, (2) We have a poor understanding of the factors that moderate, or explain individual variation in, the response to exercise, and (3) We do not understand the factors that predict long- term adoption of exercise behavior and how to reduce barriers and enhance incentives for individuals who find it challenging to continue to exercise. Despite the clear benefits of an active lifestyle, most people fail to meet public health recommendations for exercise. The more we know about the factors that predict and enhance long-term adoption of exercise, the more we will know about whether exercise influences incidence of Alzheimer’s Disease and best practices for prescribing and maintaining exercise for the prevention and treatment of cognitive impairment. We propose to conduct secondary analysis of banked data from two rigorous and well-controlled supervised exercise randomized clinical trials (RCTs) and to conduct a 3-year follow-up of >570 participants from both of these RCTs of exercise to assess cognitive, cardiorespiratory fitness, and physical activity levels. In particular, we propose to examine whether exercise-induced changes in cardiometabolic and sleep measures mediate exercise-derived benefits to cognitive and brain outcomes. We will also target moderators of exercise including APOE genotype and racial disparities to better characterize which individual difference variables influence the magnitude of effects of exercise on brain health. Finally, we propose a discovery aim that would leverage our rich measurement of participants at the genetic, physiological, brain, cognitive, and socioemotional levels to perform predictive modeling to forecast long-term adoption of exercise (or barriers prohibiting long-term adoption). In short, this research proposal describes a broad and ambitious line of work that will produce groundbreaking and innovative studies to address significant gaps in our understanding of exercise and brain health in late adulthood. The aims target several major AD/ADRD milestones identified by NIH and will position junior scientists in leadership roles to advance the field forward in significant and pioneering ways.