. 2025 Jan 9;5(1):11.

doi: 10.1038/s43856-024-00682-w.

Consuming a modified Mediterranean ketogenic diet reverses the peripheral lipid signature of Alzheimer's disease in humans

Bryan J Neth^#¹, Kevin Huynh^#^{2

3}, Corey Giles^{2

3}, Tingting Wang², Natalie A Mellett², Thy Duong², Colette Blach⁴, Leyla Schimmel⁵, Thomas C Register⁶, Kaj Blennow⁷, Henrik Zetterberg^{7

8

9

10

11

12}, Richa Batra¹³, Annalise Schweickart¹³, Amanda Hazel Dilmore¹⁴, Cameron Martino¹⁴, Matthias Arnold^{5

15}, Jan Krumsiek¹³, Xianlin Han¹⁶, Pieter C Dorrestein¹⁷, Rob Knight¹⁸, Peter J Meikle^{2

3}, Suzanne Craft¹⁹, Rima Kaddurah-Daouk^{20

21

22}

Affiliations

¹ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
² Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, Australia.
³ Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Bundoora, VIC, Australia.
⁴ Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
⁵ Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.
⁶ Department of Pathology - Comparative Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA.
⁷ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁸ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁹ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
¹⁰ UK Dementia Research Institute at UCL, London, UK.
¹¹ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
¹² Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
¹³ Department of Physiology and Biophysics, Institute for Computational Biomedicine, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
¹⁴ Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
¹⁵ Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹⁶ Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
¹⁷ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
¹⁸ Departments of Pediatrics, Computer Science and Engineering, Bioengineering, University of California San Diego, La Jolla, CA, USA.
¹⁹ Department of Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA.
²⁰ Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA. rima.kaddurahdaouk@duke.edu.
²¹ Duke Institute of Brain Sciences, Duke University, Durham, NC, USA. rima.kaddurahdaouk@duke.edu.
²² Department of Medicine, Duke University, Durham, NC, USA. rima.kaddurahdaouk@duke.edu.

^# Contributed equally.

PMID: 39779882
PMCID: PMC11711287
DOI: 10.1038/s43856-024-00682-w

Consuming a modified Mediterranean ketogenic diet reverses the peripheral lipid signature of Alzheimer's disease in humans

Bryan J Neth et al. Commun Med (Lond). 2025.

. 2025 Jan 9;5(1):11.

doi: 10.1038/s43856-024-00682-w.

Authors

Affiliations

¹ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
² Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, Australia.
³ Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Bundoora, VIC, Australia.
⁴ Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
⁵ Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.
⁶ Department of Pathology - Comparative Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA.
⁷ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁸ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁹ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
¹⁰ UK Dementia Research Institute at UCL, London, UK.
¹¹ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
¹² Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
¹³ Department of Physiology and Biophysics, Institute for Computational Biomedicine, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
¹⁴ Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
¹⁵ Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹⁶ Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
¹⁷ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
¹⁸ Departments of Pediatrics, Computer Science and Engineering, Bioengineering, University of California San Diego, La Jolla, CA, USA.
¹⁹ Department of Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA.
²⁰ Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA. rima.kaddurahdaouk@duke.edu.
²¹ Duke Institute of Brain Sciences, Duke University, Durham, NC, USA. rima.kaddurahdaouk@duke.edu.
²² Department of Medicine, Duke University, Durham, NC, USA. rima.kaddurahdaouk@duke.edu.

^# Contributed equally.

PMID: 39779882
PMCID: PMC11711287
DOI: 10.1038/s43856-024-00682-w

Abstract

Background: Alzheimer's disease (AD) is a major neurodegenerative disorder with significant environmental factors, including diet and lifestyle, influencing its onset and progression. Although previous studies have suggested that certain diets may reduce the incidence of AD, the underlying mechanisms remain unclear.

Method: In this post-hoc analysis of a randomized crossover study of 20 elderly adults, we investigated the effects of a modified Mediterranean ketogenic diet (MMKD) on the plasma lipidome in the context of AD biomarkers, analyzing 784 lipid species across 47 classes using a targeted lipidomics platform.

Results: Here we identified substantial changes in response to MMKD intervention, aside from metabolic changes associated with a ketogenic diet, we identified a a global elevation across all plasmanyl and plasmenyl ether lipid species, with many changes linked to clinical and biochemical markers of AD. We further validated our findings by leveraging our prior clinical studies into lipid related changeswith AD (n = 1912), and found that the lipidomic signature with MMKD was inversely associated with the lipidomic signature of prevalent and incident AD.

Conclusions: Intervention with a MMKD was able to alter the plasma lipidome in ways that contrast with AD-associated patterns. Given its low risk and cost, MMKD could be a promising approach for prevention or early symptomatic treatment of AD.

Plain language summary

Previous research has suggested that different diets might alter the risk of a person developing Alzheimer’s disease. We compared the blood of 20 older adults, some with memory impairment, following a change in diet. The two diets we compared were the Modified Mediterranean Ketogenic and American Heart Association Diets. The changes that were seen following consumption of the Mediterranean-ketogenic diet were the opposite to those typically seen in people with Alzheimer’s disease or those likely to develop it. These data suggest adopting this diet could potentially be a promising approach to slow down or prevent the development of Alzheimer’s disease. Aligning these results with previous larger clinical studies looking at lipids, we identified that these changes were opposite to what was typically seen in people with Alzheimer’s disease or those likely to develop it. As this diet was generally safe and inexpensive, this intervention could be a promising approach to mitigate some risk Alzheimer’s disease and help with early symptoms.

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Conflict of interest statement

Competing interests: Dr. Kaddurah-Daouk is an inventor on a series of patents on use of metabolomics for the diagnosis and treatment of CNS diseases and holds equity in Metabolon Inc., Chymia LLC and PsyProtix. JK holds equity in Chymia LLC and IP in PsyProtix and is cofounder of iollo. JK holds equity in Chymia LLC and IP in PsyProtix and is cofounder of iollo. Dr. Zetterberg has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). All other authors declare no competing interests.

Figures

**Fig. 1. Lipid class associations with the modified Mediterranean ketogenic diet (MMKD).**
a Forest plot highlighting significant lipid classes associated with the 6-week MMKD (n = 20) from a linear mixed model. Units are in fold change of lipid concentration from baseline with 95% confidence intervals. Light grey, uncorrected p value > 0.05, dark grey, uncorrected p value < 0.05, blue, Benjamini-Hochberg corrected p value < 0.05. **b–e** Relative concentration of each lipid class for each participant at baseline (grey) and follow-up (red). Horizontal bars represent mean concentration for baseline and follow up with 95% confidence intervals. Exact p-values and coefficients are in Supplementary Data 1.

**Fig. 2. Lipid species associations with the modified Mediterranean ketogenic diet (MMKD).**
a Associations of lipid species with 6-week MMKD (n = 20) obtained from a linear mixed model. Units are in fold change of lipid concentration from baseline with 95% confidence intervals. Light grey, corrected p value > 0.05, dark grey, Benjamini-Hochberg corrected p value < 0.05, blue, top 10 species ranked by p-value. **b–d** Volcano plot highlighting specific lipid classes associated with MMKD intervention, light grey circles, Benjamini-Hochberg corrected p value > 0.05, bolded grey circles, Benjamini-Hochberg corrected p value < 0.05, blue highlighted circles, class specific species that are Benjamini-Hochberg corrected p value < 0.05. FA: Fatty Acid, NL: Neutral Loss, Ox: Oxidized. For the spelling of lipid species abbreviations, see Fig. 1. Exact p values and coefficients are in Supplementary Data 2.

**Fig. 3. Differential plasma lipid response with the MMKD intervention based on subgroup interactions.**
A heatmap highlighting lipid associations with MMKD intervention (n = 20) stratified using an interaction term for cognitive group (a), *APOE* genotype (b) and sex (c). Reference denotes the unadjusted linear mixed model on lipid associations with MMKD intervention. Black diamonds, nominal p value < 0.05, black block, nominal interaction p value < 0.05. Both nominal and corrected p-values are in Supplementary Datas 3–5. APOE: Apolipoprotein E, CN: Cognitively Normal, MCI: Mild Cognitive Impairment, MMKD: Modified Mediterranean-Ketogenic Diet.

**Fig. 4. Inverse relationship between plasma lipid changes with MMKD intervention and signatures associated with Alzheimer’s disease.**
A scatter plot correlating lipid class associations with MMKD intervention and Alzheimer’s disease (data previously reported Huynh et al. 2020). a Lipid classes nominally associated with both MMKD and prevalent/existing AD (highlighted in blue, class totals, meta-analysis of both AIBL and ADNI) and b Lipid classes nominally associated with both MMKD and incident/future risk of AD (highlighted in red). Exact p-values and coefficients are in Supplementary Data 6. AD: Alzheimer’s Disease, Hex2Cer: Dihexosylceramide, Hex3Cer: Trihexosylceramide, LPE: Lysophosphatidylethanolamine, MMKD: Modified Mediterranean-Ketogenic Diet, NL: Neutral Loss, PC: Phosphatidylcholine, PE: Phosphatidylethanolamine, SHexCer: Sulfatide, TG: Triglyceride.

**Fig. 5. Correlated changes between plasma lipid totals (MMKD intervention) with Alzheimer’s disease risk factors, markers and outcomes.**
A Pearson correlation between changes in the total of each lipid class with changes in different biochemical, cognition and CSF markers. Black diamond, p < 0.05. n = 20 for all correlations except for weight (n = 17), fasting glucose (n = 17), fasting ketones (n = 16), I&D Story recall (n = 19), phosphorylated tau (n = 19), total tau (n = 19), amyloid ratio (n = 19), neurofilament light (n = 13), neurogranin (n = 9), ache (n = 13), bche (n = 13) and their ratio (n = 13). ADAS-COG12: Alzheimer’s Disease Assessment Scale-Cognitive, Cog: Cognition, CSF: Cerebrospinal Fluid, FCSRT: Free and Cued Selective Reminding Test, HbA1C: Hemoglobin A1c, HDL: High-Density Lipoprotein, I&D Story Recall: Immediate and Delayed Story Recall composite, LDL: Low-Density Lipoprotein, MMKD: Modified Mediterranean-Ketogenic Diet, VLDL: Very-Low-Density Lipoprotein. Exact coefficients are in Supplementary Data 7.

**Fig. 6. Correlated changes between plasma lipid species (MMKD intervention) with Alzheimer’s disease risk factors, markers and outcomes.**
Pearson correlation between changes in select lipid species with changes in different biochemical, cognition and CSF markers. Black diamond, p < 0.05. n = 20 for all correlations except for weight (n = 17), fasting glucose (n = 17), fasting ketones (n = 16), I&D Story recall (n = 19), phosphorylated tau (n = 19), total tau (n = 19), amyloid ratio (n = 19), neurofilament light (n = 13), neurogranin (n = 9), ache (n = 13), bche (n = 13) and their ratio (n = 13). AC: Acylcarnitine, ADAS-COG12: Alzheimer’s Disease Assessment Scale-Cognitive, CSF: Cerebrospinal Fluid, FCSRT: Free and Cued Selective Reminding Test, HbA1C: Hemoglobin A1c, HDL: High-Density Lipoprotein, I&D Story Recall: Immediate and Delayed Story Recall composite, LDL: Low-Density Lipoprotein, MMKD: Modified Mediterranean-Ketogenic Diet, TG: Triglyceride, PE: Phosphatidylethanolamine, VLDL: Very-Low-Density Lipoprotein. Exact coefficients are in Supplementary Data 7.

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References

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Consuming a modified Mediterranean ketogenic diet reverses the peripheral lipid signature of Alzheimer's disease in humans

Affiliations

Consuming a modified Mediterranean ketogenic diet reverses the peripheral lipid signature of Alzheimer's disease in humans

Authors

Affiliations

Abstract

Plain language summary

Conflict of interest statement

Figures

References

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Full Text Sources

Research Materials