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

阿尔茨海默氏病引起的痴呆症影响着大约 560 万 65 岁以上的成年人，预计会造成一定的损失 未来 30 年从 $307B 升至 $1.5T。行为干预已显示出缓解的希望 神经退行性变和认知障碍。睡眠是一种可改变的健康行为，对认知至关重要 并随着年龄的增长和阿尔茨海默病而恶化。因此，优先考虑是否 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，卧床时间限制 干预措施可提高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 主要存在于前额叶连接中。前额叶与海马体连接的缩小 睡眠期间可能有助于保持支持记忆和认知功能的远程连接。在 在临床前阿尔茨海默病中，海马体的过度激活被认为具有兴奋毒性，并且已被证明 使神经元容易受到进一步 Aβ 沉积的影响。通过 SWA 缩小突触规模可能会减轻 阿尔茨海默病通过这些途径进展。拟议的研究将增加行为 以 Aβ 沉积为特征的老年人通过四个星期的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。我们将检查行为是否得到增强 SWA 减少海马过度激活，从而改善任务相关的前额叶海马 连接性、血浆 Aβ 水平和认知功能。这项研究探讨了是否有一个简单、可行、 可扩展的行为睡眠干预可改善兴奋性毒性的功能性神经影像指数， 阿尔茨海默病的病理生理学和认知表现。

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.