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

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $1,068,699

## Abstract

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 imp...

## Key facts

- **NIH application ID:** 10134977
- **Project number:** 5R01AG055122-04
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** SUZANNE CRAFT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,068,699
- **Award type:** 5
- **Project period:** 2017-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134977

## Citation

> US National Institutes of Health, RePORTER application 10134977, Modified Ketogenic Diet Effects on Alzheimer's Disease Biomarkers and Cognition in Mild Cognitive Impairment (5R01AG055122-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10134977. Licensed CC0.

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