Slow-wave sleep enhancement in those at risk for Alzheimer's disease: Links with memory, excitotoxicity, and plasma A-beta

阿尔茨海默病引起的痴呆症影响大约560万65岁以上的成年人，预计会产生费用 在未来30年内从3070亿美元增加到1.5万亿美元。行为干预已显示出减轻 神经退化和认知障碍。睡眠是一种可改变的健康行为，对认知至关重要 并随着年龄增长和老年痴呆症而恶化因此，应优先审查 改善睡眠可以改变阿尔茨海默病的病理生理学和认知功能。我们的研究表明 更深、更巩固的睡眠与记忆和执行功能呈正相关， 这些过程背后的网络。我们的初步研究证实， 干预增加睡眠效率和非快速眼动慢波活动（SWA），并建议 SWA的增加与认知功能的改善有关。SWA反映突触缩小 主要是在前额叶的连接中。前额叶与海马体的联系缩小 在睡眠期间，可能有助于保持支持记忆和认知功能的长距离连接。在 在临床前阿尔茨海默病中，海马的过度激活被认为是兴奋性毒性的，并且显示 使神经元更容易受到Aβ沉积的影响。通过SWA的突触降尺度可以减轻 阿尔茨海默病的发展通过这些途径。拟议的研究将在行为上增加 以Aβ沉积为特征的老年人通过4周卧床时间限制的睡眠深度（SWA） 以及与阿尔茨海默病风险相关的多种因素。我们将研究行为增强是否 SWA减少海马过度激活，导致任务相关的前额叶-海马 连接性、血浆Aβ水平和认知功能。本研究旨在探讨一种简单、可行、 并且可扩展的行为睡眠干预改善了兴奋性毒性的功能性神经成像指数， 阿尔茨海默病的病理生理学和认知能力。

Dementia caused by Alzheimer’s disease affects approximately 5.6M adults over age 65, with costs expected to rise from $307B to $1.5T over the next 30 years. Behavioral interventions have shown promise for mitigating neurodegeneration and cognitive impairments. Sleep is a modifiable health behavior that is critical for cognition and deteriorates with advancing age and Alzheimer’s disease. Thus, it is a priority to examine whether improving sleep modifies Alzheimer’s disease pathophysiology and cognitive function. Our research suggests that deeper, more consolidated sleep is positively associated with memory and executive functions and networks that underlie these processes. Our preliminary studies confirm that time-in-bed restriction interventions increase sleep efficiency and non-rapid eye movement slow-wave activity (SWA) and suggest that increases in SWA are associated with improved cognitive function. SWA reflects synaptic downscaling predominantly among prefrontal connections. Downscaling of prefrontal connections with the hippocampus during sleep may help to preserve the long-range connections that support memory and cognitive function. In pre-clinical Alzheimer’s disease, hyperactivation of the hippocampus is thought to be excitotoxic and is shown to leave neurons vulnerable to further Aβ deposition. Synaptic downscaling through SWA may mitigate the progression of Alzheimer’s disease through these pathways. The proposed study will behaviorally increase sleep depth (SWA) through four weeks of time-in-bed restriction in older adults characterized on Aβ deposition and multiple factors associated with Alzheimer’s disease risk. We will examine whether behaviorally enhanced SWA reduces hippocampal hyperactivation, leading to improved task-related prefrontal-hippocampal connectivity, plasma Aβ levels, and cognitive function. This research addresses whether a simple, feasible, and scalable behavioral sleep intervention improves functional neuroimaging indices of excitotoxicity, Alzheimer’s pathophysiology, and cognitive performance.