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.

R01AG055122

2017-05-01

2023-04-30