Therapeutic potential of a modified Mediterranean ketogenic diet in reversing the peripheral lipid signature of Alzheimer’s disease

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. In this randomized crossover study of 20 elderly adults, we investigated the effects of a modified Mediterranean ketogenic diet (MMKD) on the plasma lipidome, analyzing 784 lipid species across 47 classes. We identified substantial changes in response to intervention, notably a global elevation across all plasmanyl and plasmenyl ether lipid species among others, with many changes linked with changes to clinical and biochemical markers of AD. Leveraging our prior clinical studies on AD (n = 1,912), we found that MMKD was inversely associated with the lipidomic signature of prevalent and incident AD. Given its low risk and cost, MMKD could be a promising approach for prevention or early symptomatic treatment of AD. ### Competing Interest Statement Conflict of interest Dr. Kaddurah-Daouk in 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). ### Clinical Trial NCT02984540 ### Funding Statement Acknowledgments and Funding Samples were provided by Wake Forest Alzheimer's Disease Research Center (WFADRC) supported by (P30AG049638) and associated laboratory staff, the Hartman Family Foundation, and the Roena B. Kulynych Center for Memory and Cognition Research. We would like to acknowledge the contributions of the Wake Forest Clinical and Translational Science Institute which is supported by the National Center for Advancing Translational Sciences (NCATS) through National Institutes of Health grant UL1TR001420. Additional support was provided by the Swedish Research Council and Swedish State Support for Clinical Research (ALFGBG) and laboratory technicians at Sahlgrenska University Hospital, Molndal, Sweden. Metabolomics data is provided by the Alzheimer's Gut Microbiome Project (AGMP) or the Alzheimer's Disease Metabolomics Consortium (ADMC) funded wholly or in part by the following grants and supplements thereto: NIA R01AG046171, RF1AG051550, RF1AG057452, R01AG059093, RF1AG058942, U01AG061359, U19AG063744 and FNIH: #DAOU16AMPA awarded to Dr. Kaddurah-Daouk at Duke University in partnership with a large number of academic institutions. As such, the investigators within the AGMP and the ADMC, not listed specifically in this publication's author's list, provided data along with its pre-processing and prepared it for analysis, but did not participate in analysis or writing of this manuscript. A listing of AGMP Investigators can be found at . A complete listing of ADMC investigators can be found at: . Dr. Huynh is supported by a National Health and Medical Research Council (NHMRC) investigator grant (1197190). JK and RB are supported by the National Institute of Aging of the National Institutes of Health under awards 1U19AG063744 and R01AG069901-01. RB is also supported by Alzheimer's association award AARFD-22-974775. Dr. Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018 and #2019-02397), the European Union's Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen for Gamla Tjanarinnor, Hjarnfonden, Sweden (#FO2022-0270), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme-Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Samples were provided by Wake Forest Alzheimer's Disease Research Center. Clinical data can be requested from the National Alzheimer's Coordinating Center (). The protocol was approved by the Wake Forest Institutional Review Board, and written informed consent was obtained from all participants and/or their study partners. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Samples were provided by Wake Forest Alzheimer's Disease Research Center. Clinical data can be requested from the National Alzheimer's Coordinating Center ().