Effects of Successful OSA TreatmENT on Memory and AD BIomarkers in Older AduLts (ESSENTIAL)

阿尔茨海默病（AD）的患病率很高，预计还会增加。此外，流行病学数据 研究表明，约15%的AD风险可能归因于睡眠问题。阻塞性睡眠呼吸暂停（OSA）也是 常见于老年人（30-55%），我们之前的工作已经确定，认知正常的老年妇女 患有OSA的人患轻度认知障碍（MCI）或痴呆症的风险几乎是5年的两倍。 此外，我们还证明了：i.经气道正压通气（PAP）治疗的OSA患者， 血浆神经丝光（NfL）（神经损伤的标志物）的夜间增加，AD的趋势强烈， PAP停药后的特异性生物标志物（即Aβ40和Tau）; ii. OSA预测AD的纵向增加 生物标志物;和，iii. PAP治疗延迟了OSA患者MCI的发作。因此存在 强有力的证据表明OSA治疗可能是AD的重要预防策略。然而，在这方面， 用于治疗OSA以减缓认知下降和向AD进展的试验面临许多挑战。第一、 最有效的疗法（PAP）具有较差的依从性。第二个挑战是确定目标人群： 先前的试验针对患有MCI/AD的OSA患者，这些患者患有更晚期的疾病， 接受治疗第三个挑战是确定对睡眠中断敏感的认知测试，并与睡眠中断有关。 AD风险增加。(To OSA对离线处理阶段的捕获效应需要睡眠依赖性 记忆模式，其中信息的编码和回忆被睡眠期分开 有/没有OSA）。最后，一项持续时间足够长的随机试验来测试OSA治疗对 AD事件的风险是不可行的。我们提议的试验，成功的OSA治疗对记忆和 老年人的AD生物标志物（必需品）解决了这些挑战。Essential是一项为期5年的研究， 新诊断为OSA的认知正常老年人，年龄55-75岁，从4个良好的睡眠中招募 诊所。OSA患者（n=200）将被随机分配至：i）通过以下任何组合进行3个月OSA治疗： PAP、OAT和体位疗法可“有效”改善呼吸暂停低通气指数 (AHI)ii）在3个月的干预期结束时，一个等待名单对照组接受治疗。 有效治疗的个体（~150）和未治疗的个体（~100）将随访长达24个月 比较AHI的持续改善是否与更好的认知功能和AD相关 与未处理对照相比的生物标志物变化曲线。参与者将接受PSG，活动记录仪， 认知测试和基线、3个月和24个月时的抽血。我们的目标是：1）比较3个月的变化 随机分配至OSA治疗组和等待名单对照组的患者之间的血浆AD生物标志物（NfL、p-tau、Aβ） 2）比较OSA治疗组和对照组患者3个月认知功能的变化; 3)检查有效治疗的参与者在24个月内AHI是否持续降低， 未经治疗的对照组与AD生物标志物和认知的更好的24个月变化曲线相关。

The prevalence of Alzheimer disease (AD) is high and projected to increase. Further, epidemiological data suggests that ~15% of AD risk may be attributed to sleep problems. Obstructive sleep apnea (OSA) is also common among the elderly (30-55%), and our prior work has established that cognitively normal older women with OSA have nearly double the 5-year risk of developing mild cognitive impairment (MCI) or dementia. Further, we showed that: i. OSA patients treated with positive airway pressure (PAP) experienced significant overnight increases in plasma neurofilament light (NfL), a marker of neural injury, with strong trends for AD- specific biomarkers (i.e. Aβ40 and Tau) after PAP withdrawal; ii. OSA predicted longitudinal increases in AD biomarkers; and, iii. PAP treatment delayed the onset of MCI in subjects with reported OSA. There is therefore strong evidence suggesting that OSA treatment could be an important prevention strategy for AD. However, trials for treatment of OSA to slow cognitive decline and progression to AD face a number of challenges. First, the most effective therapy (PAP) has poor adherence. A second challenge is defining the target population: prior trials targeted OSA patients with MCI/AD, who have more advanced disease and could be less amenable to treatment. A third challenge is identifying cognitive testing that is sensitive to sleep disruption, and linked to increased AD risk. (To capture effects of OSA on the offline processing phase requires sleep-dependent memory paradigms, in which the encoding and recall of information are separated by a period of sleep with/without OSA). Finally, a randomized trial of sufficient duration to test the effects of treatment of OSA on risk of incident AD is not feasible. Our proposed trial, Effects of Successful OSA TreatmENT on Memory and AD BIomarkers in Older AduLts (ESSENTIAL), addresses these challenges. ESSENTIAL is a 5-year study of cognitively normal older adults with newly diagnosed OSA, ages 55-75, recruited from 4 well-established sleep clinics. OSA patients (n=200) will be randomized to either: i) a 3-month OSA treatment by any combination of PAP, OAT, and positional therapy that results in an “effective” improvement in the apnea-hypopnea index (AHI); ii) a waitlist control group to receive treatment at the conclusion of the 3-month intervention period. Effectively treated individuals (~150) and untreated individuals (~100) will then be followed for up to 24 months to compare whether sustained improvements in AHI are associated with better cognitive function and AD biomarker change profiles as compared to untreated controls. Participants will undergo PSG, actigraphy, cognitive tests, and blood draws at baseline, 3 and 24 months. Our aims are: 1) To compare 3-month change in plasma AD biomarkers (NfL, p-tau, Aβ) between those randomized to OSA treatment and wait-list control groups; 2) To compare 3-month change in cognition between the OSA treatment and wait-list control groups; 3) To examine if sustained reduction in AHI over 24 months among effectively treated participants versus untreated controls is associated with better 24-month change profiles for AD biomarkers and cognition.