Mediterranean Ketogenic Diet May Benefit Adults With Mild Cognitive Impairment

Adults with mild cognitive impairment who adhere to a high-fat modified Mediterranean ketogenic diet may reduce their risk for Alzheimer disease.

Adherence to a modified Mediterranean ketogenic diet may be beneficial in adults with mild cognitive impairment (MCI), according to findings from a small, longitudinal pilot study published in Alzheimer’s & Dementia.

The pathophysiologic events that lead to MCI remain to be elucidated, thus delaying the development of efficacious treatments for neurodegenerative disorders, such as Alzheimer disease (AD). It is well recognized that a number of systemic transformations, including inflammation, metabolic dysregulation, body compositional changes, and mitochondrial dysfunction, are observed throughout the progression of AD.

Realizing that gut microbiota is necessary for ketogenic diet-facilitated neuroprotection against seizures and bile acid modulation, researchers sought to explore the gut microbiota and metabolites associated with cognitive status by comparing a controlled ketogenic diet intervention with a low-fat diet intervention.

“The ketogenic diet (KD) is a candidate therapeutic for AD because of its ability to improve mitochondrial function and cerebral bioenergetics, enhance autophagy, and reduce oxidative stress,” according to the researchers.

Our results suggest that the MMKD may benefit adults with MCI through modulation of GABA levels and gut transit time.

The researchers enrolled individuals who were deemed to be at risk for AD, based on their cognitive and systemic metabolic dysfunction, or on objective/subjective memory issues at onset of the study. Participants received 1 of the following 2 diagnoses from a physician or neuropsychologist:

  • Cognitively normal with subjective memory issues, via use of the Alzheimer’s Disease Neuroimaging Initiative criteria
  • MCI, via use of the National Institute on Aging-Alzheimer’s Association guidelines for clinical diagnoses without referring to biomarker status

The researchers enrolled a total of 23 adults, 20 of whom completed the entire intervention. High-dimensional data according to 3 data layers were obtained and quantified in various assays:

  • Hundreds to thousands of microbes
  • Features of various foods
  • Metabolites

Individuals with prediabetes who were considered to be cognitively normal (n=11) or to have MCI (n=9) comprised the study enrollees. All of the participants were placed on either a low-fat American Heart Association diet or a high-fat modified Mediterranean ketogenic diet for 6 weeks. Following a 6-week washout, the participants all crossed over to the other diet.

Stool samples were obtained from all individuals at 5 different time points in the study, in an effort to evaluate participants’ microbiome and metabolome throughout the dietary interventions:

  • At the beginning of the first dietary intervention
  • At the end of the first dietary intervention
  • At the beginning of the second (crossover) dietary intervention
  • At the end of the second (crossover) dietary intervention
  • At 6 weeks after washout of the second dietary intervention

The researchers found that individuals with MCI who were on the modified Mediterranean ketogenic diet exhibited lower levels of GABA-producing microbes Alistipes sp. CAG:514 and GABA, along with higher levels of GABA-regulating microbes Akkermansia muciniphila.

In contrast, participants with curcumin in their diet exhibited lower levels of bile salt hydrolase-containing microbes, as well as an altered bile acid pool, which were suggestive of decreased gut motility.

Study limitations included its relatively brief intervention period and small sample size. Further, the low annotation rate of the untargeted metabolomics experiments left many of the key metabolites linked to a person’s cognitive status unannotated. Additionally, use of an untargeted metabolomics platform does not offer the level of classification of lipid metabolism and mitochondrial function that is available on a targeted platform.

“Our results suggest that the MMKD [modified Mediterranean ketogenic diet] may benefit adults with MCI through modulation of GABA levels and gut transit time,” the researchers concluded.

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Dilmore AH, Martino C, Neth BJ, et al; Alzheimer’s Gut Microbiome Project Consortium. Effects of a ketogenic and low-fat diet on the human metabolome, microbiome, and foodome in adults at risk for Alzheimer’s disease. Alzheimers Dement. Published online April 5, 2023. doi:10.1002/alz.13007