Modified Ketogenic Diet Effects on Alzheimer's Disease Biomarkers and Cognition in Mild Cognitive Impairment

本申请提出了一项II期研究，以确定生酮饮食（KD）的安全性和疗效， 用于遗忘型轻度认知障碍（aMCI）的疗法。KD是一种非常低碳水化合物，高脂肪的饮食 由马约诊所开发，有效治疗难治性癫痫。几种机制被认为 潜在的KD功效也与阿尔茨海默病（AD）的发病机制有关，包括 通过谷氨酸能抑制降低神经元的过度兴奋性，增强线粒体 在一些实施方案中，本发明的化合物具有降低的氧化应激的代谢和抑制雷帕霉素的哺乳动物靶标（MTOR）。每个 已经提出这些中的一种作为AD病理过程的调节剂，例如β-淀粉样蛋白聚集和 tau蛋白过度磷酸化。对KD作为AD的潜在治疗或预防策略的兴趣已经 进一步通过临床前研究，其中用酮诱导干预治疗的啮齿动物AD模型显示， 淀粉样蛋白和/或tau病变较少，以及改善的记忆性能。中链甘油三酯的研究 (MCT)补充剂或短期KD干预报告了参与者的记忆改善， 早期AD，受APOE基因型调节。使用KD的挑战包括依从性差 由于其限制性的性质，以及由于高饱和脂肪和低植物营养素而可能的长期健康风险， 摄入改良地中海生酮饮食（MMKD）的癫痫发作抑制功效与 但允许略高的碳水化合物消耗，以允许增加蔬菜的摄入量， 水果，并强调健康的脂肪和蛋白质，如橄榄油和鱼。在试点工作中，我们表明，6周 MMKD改善了记忆、CSF AD生物标志物谱、线粒体功能和脑灌注， 楔前叶和后扣带区。基于这些令人鼓舞的结果，拟议的研究将审查 4个月MMKD与美国心脏协会饮食在120名aMCI成人中的效果比较。 我们将研究饮食对AD生物标志物、认知、代谢的神经影像学指标的影响， 血管功能和连通性，以及CSF/血液表观遗传、外泌体和组学标记物。我们的研究将 通过以下几种重要方式扩展了以前的发现：1）使用MMKD而不是传统的KD， 具有更大的长期依从性和健康益处的潜力; 2）增加饮食的持续时间 干预和样本量进行研究; 3）检查饮食影响的潜在机制， 产生新的生物标志物和治疗靶点;以及4）检查关键的治疗反应变量， APOE基因型、淀粉样蛋白阳性和代谢状态可以为精准医学方法提供信息， 饮食处方拟议的研究将通过提供有关 有效性、可行性、安全性和与MMKD干预相关的潜在机制。因此， 为指导未来III期研究的设计和识别新的生物标志物提供重要信息 以及可能增强针对饮食和AD风险的精准医学方法的治疗靶点。

This application proposes a Phase II study to determine the safety and efficacy of a ketogenic diet (KD) as a therapy for amnestic mild cognitive impairment (aMCI). The KD is a very low carbohydrate, high fat diet developed by the Mayo Clinic, that effectively treats refractory epilepsy. Several mechanisms thought to underlie KD efficacy have also been implicated in the pathogenesis of Alzheimer's disease (AD), including reduction of neuronal hyperexcitability through glutamatergic inhibition, enhancement of mitochondrial metabolism with reduced oxidative stress, and inhibition of the mammalian target of rapamycin (MTOR). Each of these has been proposed as a modulator of AD pathological processes such as β-amyloid aggregation and tau hyperphosphorylation. Interest in the KD as a potential treatment or prevention strategy for AD has been furthered by preclinical studies in which rodent AD models treated with ketone-inducing interventions showed less amyloid and/or tau pathology, and improved memory performance. Studies of medium chain triglyceride (MCT) supplements or a short-term KD intervention have reported memory improvement in participants with early AD, an effect moderated by APOE genotype. Challenges to the use of the KD include poor compliance due to its restrictive nature, and possible long term health risks due to high saturated fat and low phytonutrient intake. The modified Mediterranean ketogenic diet (MMKD) has comparable seizure-inhibiting efficacy to the original KD but allows slightly higher carbohydrate consumption to permit increased intake of vegetables and fruits, and emphasizes healthy fats and proteins such as olive oil and fish. In pilot work, we show that a 6 week MMKD improved memory, CSF AD biomarker profiles, mitochondrial function, and brain perfusion in precuneus and posterior cingulate regions. Based on these promising results, the proposed study will examine the effects of a 4-month MMKD compared with an American Heart Association diet in 120 adults with aMCI. We will investigate diet effects on AD biomarkers, on cognition, on neuroimaging measures of metabolism, vascular function and connectivity, and on CSF/blood epigenetic, exosome, and omic markers. Our study will extend previous findings in several important ways by: 1) using a MMKD rather than a traditional KD, which has the potential for greater long-term compliance and health benefits; 2) increasing the duration of the diet intervention and the sample size to be studied; 3) examining potential mechanisms of diet effects that may result in new biomarkers and therapeutic targets; and 4) examining key treatment response variables such as APOE genotype, amyloid positivity and metabolic status that could inform precision medicine approaches to dietary prescription. The proposed study will extend previous work by providing rich data regarding the efficacy, feasibility, safety, and underlying mechanisms associated with MMKD intervention. As such, it will provide important information to guide the design of a future Phase III study and to identify novel biomarkers and therapeutic targets that may enhance precision medicine approaches to diet and AD risk.