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) 的安全性和有效性： 一种治疗遗忘性轻度认知障碍（aMCI）的疗法。 KD 是一种非常低碳水化合物、高脂肪的饮食 由梅奥诊所开发，可有效治疗难治性癫痫。考虑到的几种机制 KD 功效的基础也与阿尔茨海默病 (AD) 的发病机制有关，包括 通过谷氨酸能抑制减少神经元过度兴奋，增强线粒体 代谢减少氧化应激，并抑制哺乳动物雷帕霉素靶点（MTOR）。每个 其中一些已被提议作为 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。人们对生酮饮食作为 AD 潜在治疗或预防策略的兴趣 临床前研究进一步推进，其中用酮诱导干预措施治疗的啮齿动物 AD 模型显示 减少淀粉样蛋白和/或 tau 蛋白病理，并提高记忆力。中链甘油三酯的研究 （MCT）补充剂或短期 KD 干预已报告参与者的记忆力有所改善 早期 AD，APOE 基因型调节的影响。使用 KD 的挑战包括合规性差 由于其限制性，以及由于高饱和脂肪和低植物营养素可能造成的长期健康风险 摄入量。改良地中海生酮饮食（MMKD）具有与传统生酮饮食相当的抑制癫痫发作的功效。 原来的 KD，但允许稍微增加碳水化合物的摄入量，以增加蔬菜和食物的摄入量 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、脑脊液 AD 生物标志物谱、线粒体功能和脑灌注 楔前叶和后扣带回区域。基于这些有希望的结果，拟议的研究将检查 对 120 名患有 aMCI 的成人进行 4 个月的 MMKD 与美国心脏协会饮食的效果比较。 我们将研究饮食对 AD 生物标志物、认知、新陈代谢的神经影像测量的影响， 血管功能和连接性，以及脑脊液/血液表观遗传、外泌体和组学标记。我们的研究将 通过以下几个重要方式扩展了先前的发现：1）使用 MMKD 而不是传统的 KD，这 有可能获得更大的长期合规性和健康益处； 2）增加饮食持续时间 干预措施和要研究的样本量； 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； 4) 检查关键治疗反应变量，例如 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 与 MMKD 干预相关的功效、可行性、安全性和潜在机制。如此一来，它将 提供重要信息来指导未来 III 期研究的设计并识别新型生物标志物 以及可能增强针对饮食和 AD 风险的精准医学方法的治疗目标。

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.