Neural Mechanisms for Associations Between Fitness and Cognition in Aging

记忆功能下降不仅是健康老年人的常见抱怨。它也是一个主要指标 老年痴呆症（AD）载脂蛋白-E ε 4（APOE-ε4）等位基因是唯一明确确定的 一个迟发性AD的候选基因，与认知能力下降和脑功能减退的发病年龄较早相关。 萎缩尽管如此，APOE-ε4等位基因遗传并不能完全预测AD的发生，提示 可改变的生活方式因素，如身体活动（PA）和代谢健康指标， 随着年龄的增长，呼吸适应性（CRF）可能会影响认知轨迹。目前尚不清楚，如果 CRF改变了遗传风险增加的健康无症状老年人的神经网络完整性指数 对于AD。为了响应NOT-MH-21-175，我们将利用纵向高质量的功能，结构， 来自Lifespan Human Connectome Project Aging（HCP-Aging）数据集的弥散加权MR成像数据 以确定CRF对认知功能和人脑网络完整性的调节作用。我们将使用 两种创新的方法来研究CRF如何随着年龄的增长影响神经连接和大脑微观结构 以确定CRF在老年人中提供神经保护的潜在神经机制。我们还将 测试更大的CRF保护情景记忆表现，记忆网络连接， 大脑微结构的完整性免受APOE-β 4等位基因的有害影响。通过利用所有可用的 HCP-Aging数据集中的功能数据（增加我们工作的可重复性和影响力），我们将定义 海马皮层记忆系统内的神经网络完整性指数， 随着年龄的增长和认知能力的下降，包括网络隔离-一个网络内相关性的指数， 网络之间的相关性;和聚类系数-网络节点的邻居的分数， 彼此是邻居。我们还将利用高角分辨率扩散成像（HARDI）扩散- HCP提供的加权MRI方法，其在组织学上更有意义，对 与传统的扩散张量成像相比，我们将计算 灰质中的神经突密度指数和白色物质中的方向分散指数来检查关联 在CRF。我们假设CRF会调节年龄相关的情景记忆下降，神经功能减退， 网络连接性和神经突密度（以及与年龄相关的方向分散性增加）， CRF会随着年龄的增长而减弱。此外，我们假设高CRF会减弱 APOE-β 4等位基因和年龄对认知、网络连接和微结构完整性的影响 高CRF与低CRF ε4携带者随时间的结局。这个项目预计会产生很高的影响 通过使用高质量的神经影像学数据从HCP老化，并确定介质， CRF与老年人大脑健康之间的关系。这些机制的建立将为 在健康老龄化和AD遗传风险增加的人群中开展循证实践和预防工作。

Declining memory function is not only a common complaint of healthy aging adults. It is also a primary indicator of Alzheimer's disease (AD). The apolipoprotein-E epsilon4 (APOE-ε4) allele is the only clearly identified candidate gene for late-onset AD and is associated with an earlier age of onset of cognitive decline and brain atrophy. Nevertheless, APOE-ε4 allele inheritance is an imperfect predictor of who will develop AD, suggesting that modifiable lifestyle factors such as Physical Activity (PA), and metabolic health indicators such as Cardiorespiratory Fitness (CRF), might influence cognitive trajectory with age. It is not yet known, however, if CRF modifies indices of neural network integrity in healthy asymptomatic older adults at increased genetic risk for AD. In response to NOT-MH-21-175, we will utilize the longitudinal high-quality functional, structural, and diffusion-weighted MR imaging data from the Lifespan Human Connectome Project Aging (HCP-Aging) dataset to determine the moderating role of CRF on cognitive function and human brain network integrity. We will use two innovative approaches to examine how CRF impacts neural connectivity and brain microstructure with age to determine potential neural mechanisms whereby CRF provides neuroprotection in older adults. We will also test the hypothesis that greater CRF protects episodic memory performance, memory network connectivity, and brain microstructural integrity from the harmful impacts of the APOE-4 allele. By leveraging all available functional data in the HCP-Aging dataset (increasing the reproducibility and impact of our work), we will define indices of neural network integrity within the hippocampal cortical memory system that are known to decrease with age and cognitive decline, including network segregation – an index of within-network correlations compared to between-network correlations; and the clustering coefficient - the fraction of a network node's neighbors that are neighbors to each other. We will also utilize the high angular resolution diffusion imaging (HARDI) diffusion- weighted MRI methods provided by the HCP, which are more histologically meaningful and sensitive to underlying tissue microstructure and function than traditional diffusion tensor imaging. We will calculate the Neurite Density Index in gray matter and the Orientation Dispersion Index in white matter to examine associations with CRF. We hypothesize CRF will moderate the relationship of age-related decline in episodic memory, neural network connectivity, and neurite density (and age-related increases in orientation dispersion) such that High CRF will attenuate the reduction with age. Moreover, we hypothesize that High CRF will attenuate the combined impact of the APOE-4 allele and age on the cognitive, network connectivity, and microstructural integrity outcomes in High CRF versus Low CRF ε4-carriers over time. This project is expected to have a high impact through the use of high-quality neuroimaging data from the HCP-Aging, and the determination of mediators of the association between CRF and brain health in older adults. Substantiating these mechanisms will inform evidence-based practice and prevention efforts in healthy aging and those at increased genetic risk for AD.