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

本申请提出了一项第二阶段研究，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)的方法。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，有效治疗难治性癫痫。几种被认为是 潜在的KD疗效也与阿尔茨海默病(AD)的发病机制有关，包括 谷氨酸能抑制、线粒体增强降低神经元的超兴奋性 减少氧化应激的代谢，并抑制哺乳动物的雷帕霉素靶标(MTOR)。每个人 其中已被认为是AD病理过程的调节器，如-淀粉样蛋白聚集和 Tau蛋白过度磷酸化。人们一直对KD作为AD的潜在治疗或预防策略感兴趣 在临床前研究中，用酮诱导干预治疗的啮齿动物AD模型显示 减少淀粉样蛋白和/或tau病理，并改善记忆性能。中链甘油三酯的研究 (MCT)补充剂或短期KD干预报告了患有以下疾病的参与者的记忆改善 早期阿尔茨海默病，这种效应受载脂蛋白E基因的调节。KD使用面临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导致的长期健康风险 入口处。改进的地中海生酮饮食(MMKD)具有与 最初的KD，但允许略微较高的碳水化合物摄入量，以增加蔬菜和 水果，强调健康的脂肪和蛋白质，如橄榄油和鱼。在试点工作中，我们展示了6周 MMKD改善小鼠记忆、脑脊液AD生物标志物分布、线粒体功能和脑血流灌注 楔前和后扣带回区域。基于这些有希望的结果，拟议的研究将审查 对120例成人急性心肌梗死患者进行为期4个月的MMKD与美国心脏协会饮食的比较。 我们将调查饮食对AD生物标志物、认知、代谢神经成像指标的影响， 血管功能和连通性，以及脑脊液/血液表观遗传学、外显体和基因组标记。我们的研究将 通过以下几个重要方式扩展先前的发现：1)使用MMKD而不是传统的KD，这 有更大的长期依从性和健康益处的潜力；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；以及4)检查关键的治疗反应变量，如 载脂蛋白E基因、淀粉样蛋白阳性和代谢状态可为精确医学方法提供信息 饮食处方。拟议的研究将通过提供丰富的数据来扩展先前的工作 与MMKD干预相关的有效性、可行性、安全性和潜在机制。因此，它将 提供重要信息以指导未来第三阶段研究的设计和确定新的生物标记物 和治疗靶点，可能会加强饮食和AD风险的精准医学方法。

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 -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.