Introduction. Comprehensive treatment of Alzheimer's disease and related dementias (ADRD) requires not only pharmacologic treatment but also management of existing medical conditions and lifestyle modifications including diet, cognitive training, and exercise. The Coaching for Cognition in Alzheimer's (COCOA) trial was a prospective randomized controlled trial (RCT) to test the hypothesis that a remotely coached multimodal lifestyle intervention would improve early-stage Alzheimer's disease (AD). AD results from the interplay of multiple interacting dysfunctional biological systems. Specific causes of AD differ between individuals. Personalized, multimodal therapies are needed to best prevent and treat AD. COCOA collected psychometric, clinical, lifestyle, genomic, proteomic, metabolomic and microbiome data at multiple timepoints across two years for each participant. These data enable systems-biology analyses. We report analyses of the first COCOA data freeze. This analysis includes an evaluation of the effect of the intervention on outcome measures. It also includes systems analyses to identify molecular mediators that convey the effect of personalized multimodal lifestyle interventions on amelioration of cognitive trajectory. Methods. A total of 55 participants with early-stage AD from Southern California were randomized into two parallel arms. Arm 1 (control; N=24) received standard of care. Arm 2 (intervention; N=31) also received telephonic personalized coaching for multiple lifestyle interventions including diet, exercise, and cognitive training. COCOA's overarching aim was to gather dense molecular data from an AD cohort to improve understanding of pathophysiology and advance treatment. For the RCT, COCOA's objective was to test the hypothesis that the Memory Performance Index (MPI) trajectory would be better in the intervention arm than in the control arm. The Functional Assessment Staging Test (FAST) was assessed for a secondary outcome. Assessments were blinded. The nature of the intervention precluded participant blinding. Results. The intervention arm ameliorated 2.6 ± 0.8 MPI points (p = 0.0007; N = 48) compared to the control arm over the two-year intervention. Top-ranked candidate mediators included: albumin, propionylcarnitine, sphingomyelin, hexadecanedioate, acetylkynurenine, tiglylcarnitine, IL18R1, palmitoyl-sphingosine-phosphoethanolamine, acetyltryptophan, and IL17D. These individual molecules implicated inflammatory and nitrogen/tryptophan metabolism pathways. No important adverse events or side effects were observed. Conclusions. Clinical trials should include frequent assessment of dense data to maximize knowledge gained. Such knowledge is useful not only in testing a primary hypothesis, but also in advancing basic biological and pathophysiological knowledge, understanding mechanisms explaining trial results, generating synergistic knowledge tangential to preconceived hypotheses, and refining interventions for clinical translation. Data from every trial should allow an intervention to be refined and then tested in future trials, driving iterative improvement. Multimodal lifestyle interventions are effective for ameliorating cognitive decline and may have an effect size larger than pharmacological interventions. Effects may be molecularly idiosyncratic; personalization of interventions is important. Dietary changes and exercise are likely to be beneficial components of multimodal interventions in many individuals. Remote coaching is an effective intervention for early stage ADRD. Remote interventions were effective during the COVID pandemic.

中文翻译：

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阿尔茨海默病的多模式干预导致血液中反映的多方面全身效应并改善功能和认知结果

介绍。阿尔茨海默病和相关痴呆症 (ADRD) 的综合治疗不仅需要药物治疗，还需要管理现有的医疗状况和改变生活方式，包括饮食、认知训练和锻炼。阿尔茨海默病认知指导 (COCOA) 试验是一项前瞻性随机对照试验 (RCT)，旨在检验远程指导的多模式生活方式干预将改善早期阿尔茨海默病 (AD) 的假设。AD 是多个相互作用的功能失调的生物系统相互作用的结果。AD的具体原因因人而异。需要个性化的多模式疗法来最好地预防和治疗 AD。COCOA 收集了心理测量学、临床、生活方式、基因组学、蛋白质组学、每位参与者在两年内多个时间点的代谢组学和微生物组数据。这些数据使系统生物学分析成为可能。我们报告了对第一次 COCOA 数据冻结的分析。该分析包括评估干预对结果测量的影响。它还包括系统分析，以确定传达个性化多模式生活方式干预对改善认知轨迹的影响的分子介质。方法。来自南加州的 55 名早期 AD 参与者被随机分为两个平行组。第 1 组（对照；N=24）接受标准护理。第 2 组（干预；N=31）还接受了针对多种生活方式干预的电话个性化辅导，包括饮食、锻炼和认知训练。可可' 我们的首要目标是从 AD 队列中收集密集的分子数据，以提高对病理生理学的理解和推进治疗。对于 RCT，COCOA 的目标是检验干预组的记忆性能指数 (MPI) 轨迹优于对照组的假设。功能评估分期测试 (FAST) 被评估为次要结果。评估是盲目的。干预的性质排除了参与者的盲法。结果。与对照组相比，干预组在两年干预期间改善了 2.6 ± 0.8 MPI 点（p = 0.0007；N = 48）。排名靠前的候选介质包括：白蛋白、丙酰肉碱、鞘磷脂、十六烷二酸酯、乙酰犬尿氨酸、替格肉碱、IL18R1、棕榈酰-鞘氨醇-磷酸乙醇胺、乙酰色氨酸和 IL17D。这些单个分子涉及炎症和氮/色氨酸代谢途径。没有观察到重要的不良事件或副作用。结论。临床试验应包括对密集数据的频繁评估，以最大限度地获得知识。这些知识不仅有助于检验主要假设，而且有助于推进基本的生物学和病理生理学知识，理解解释试验结果的机制，产生与先入为主的假设相切的协同知识，以及改进临床转化的干预措施。每项试验的数据都应允许对干预措施进行改进，然后在未来的试验中进行测试，从而推动迭代改进。多模式生活方式干预可有效改善认知能力下降，并且可能比药物干预具有更大的效果。影响可能是分子异质的；干预的个性化很重要。饮食改变和锻炼可能是许多人多模式干预的有益组成部分。远程辅导是早期 ADRD 的有效干预措施。在 COVID 大流行期间，远程干预是有效的。