Randomized crossover trial of a modified ketogenic diet in Alzheimer’s disease

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Abstract

Background

Brain energy metabolism is impaired in Alzheimer’s disease (AD), which may be mitigated by a ketogenic diet. We conducted a randomized crossover trial to determine whether a 12-week modified ketogenic diet improved cognition, daily function, or quality of life in a hospital clinic of AD patients.

Methods

We randomly assigned patients with clinically confirmed diagnoses of AD to a modified ketogenic diet or usual diet supplemented with low-fat healthy-eating guidelines and enrolled them in a single-phase, assessor-blinded, two-period crossover trial (two 12-week treatment periods, separated by a 10-week washout period). Primary outcomes were mean within-individual changes in the Addenbrookes Cognitive Examination - III (ACE-III) scale, AD Cooperative Study - Activities of Daily Living (ADCS-ADL) inventory, and Quality of Life in AD (QOL-AD) questionnaire over 12 weeks. Secondary outcomes considered changes in cardiovascular risk factors and adverse effects.

Results

We randomized 26 patients, of whom 21 (81%) completed the ketogenic diet; only one withdrawal was attributed to the ketogenic diet. While on the ketogenic diet, patients achieved sustained physiological ketosis (12-week mean beta-hydroxybutyrate level: 0.95 ± 0.34 mmol/L). Compared with usual diet, patients on the ketogenic diet increased their mean within-individual ADCS-ADL (+ 3.13 ± 5.01 points, P = 0.0067) and QOL-AD (+ 3.37 ± 6.86 points, P = 0.023) scores; the ACE-III also increased, but not significantly (+ 2.12 ± 8.70 points, P = 0.24). Changes in cardiovascular risk factors were mostly favourable, and adverse effects were mild.

Conclusions

This is the first randomized trial to investigate the impact of a ketogenic diet in patients with uniform diagnoses of AD. High rates of retention, adherence, and safety appear to be achievable in applying a 12-week modified ketogenic diet to AD patients. Compared with a usual diet supplemented with low-fat healthy-eating guidelines, patients on the ketogenic diet improved in daily function and quality of life, two factors of great importance to people living with dementia.

Trial registration

This trial is registered on the Australia New Zealand Clinical Trials Registry, number ACTRN12618001450202. The trial was registered on August 28, 2018.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13195-021-00783-x.

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Most cited references 38

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The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

Guy M McKhann, David S. Knopman, Howard Chertkow … (2011)

The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia. Copyright © 2011. Published by Elsevier Inc.

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Validation of the Addenbrooke's Cognitive Examination III in Frontotemporal Dementia and Alzheimer's Disease

Sharpley Hsieh, Samantha Schubert, Christopher Hoon … (2013)

Background/Aims: The aims of this study were to validate the newly developed version of the Addenbrooke's Cognitive Examination (ACE-III) against standardised neuropsychological tests and its predecessor (ACE-R) in early dementia. Methods: A total of 61 patients with dementia (frontotemporal dementia, FTD, n = 33, and Alzheimer's disease, AD, n = 28) and 25 controls were included in the study. Results: ACE-III cognitive domains correlated significantly with standardised neuropsychological tests used in the assessment of attention, language, verbal memory and visuospatial function. The ACE-III also compared very favourably with its predecessor, the ACE-R, with similar levels of sensitivity and specificity. Conclusion: The results of this study provide objective validation of the ACE-III as a screening tool for cognitive deficits in FTD and AD.

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Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline.

Parminder Raina, Pasqualina L. Santaguida, Afisi Ismaila … (2008)

The effectiveness of the 5 U.S. Food and Drug Administration-approved pharmacologic therapies for dementias in achieving clinically relevant improvements is unclear. To review the evidence for the effectiveness of cholinesterase inhibitors (donepezil, galantamine, rivastigmine, and tacrine) and the neuropeptide-modifying agent memantine in achieving clinically relevant improvements, primarily in cognition, global function, behavior, and quality of life, for patients with dementia. Cochrane Central Register of Controlled Trials, MEDLINE, PREMEDLINE, EMBASE, Allied and Complementary Medicine Database, CINAHL, AgeLine, and PsycINFO from January 1986 through November 2006. English-language randomized, controlled trials were included in the review if they evaluated pharmacologic agents for adults with a diagnosis of dementia, did not use a crossover design, and had a quality score of at least 3 on the Jadad scale. Data were extracted on study characteristics and outcomes, including adverse events. Effect sizes were calculated and data were combined when appropriate. 96 publications representing 59 unique studies were eligible for this review. Both cholinesterase inhibitors and memantine had consistent effects in the domains of cognition and global assessment, but summary estimates showed small effect sizes. Outcomes in the domains of behavior and quality of life were evaluated less frequently and showed less consistent effects. Most studies were of short duration (6 months), which limited their ability to detect delay in onset or progression of dementia. Three studies directly compared different cholinesterase inhibitors and found no differences in cognition and behavior. Limitations of available studies included short duration, inclusion of only patients with mild to moderate Alzheimer disease, poor reporting of adverse events, lack of clear definitions for statistical significance, limited evaluation of behavior and quality-of-life outcomes, and limited direct comparison of different treatments. Treatment of dementia with cholinesterase inhibitors and memantine can result in statistically significant but clinically marginal improvement in measures of cognition and global assessment of dementia.

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Author and article information

Contributors

Matthew C. L. Phillips:

ORCID: http://orcid.org/0000-0003-4183-7766

Matthew.Phillips@waikatodhb.health.nz

Journal

Journal ID (nlm-ta): Alzheimers Res Ther

Journal ID (iso-abbrev): Alzheimers Res Ther

Title: Alzheimer's Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1758-9193

Publication date (Electronic): 23 February 2021

Publication date PMC-release: 23 February 2021

Publication date Collection: 2021

Volume: 13

Electronic Location Identifier: 51

Affiliations

[1 ]GRID grid.413952.8, ISNI 0000 0004 0408 3667, Department of Neurology, , Waikato Hospital, ; Hamilton, New Zealand

[2 ]GRID grid.5012.6, ISNI 0000 0001 0481 6099, Faculty of Psychology and Neuroscience, , Maastricht University, ; Maastricht, The Netherlands

[3 ]Healthy Kitchen Christchurch Ltd, Hamilton, New Zealand

[4 ]GRID grid.413952.8, ISNI 0000 0004 0408 3667, Department of Dietetics Services, , Waikato Hospital, ; Hamilton, New Zealand

[5 ]GRID grid.416922.a, ISNI 0000 0004 0621 7630, LINC Mental Health Services, , Tauranga Hospital, ; Tauranga, New Zealand

[6 ]GRID grid.9654.e, ISNI 0000 0004 0372 3343, Department of Statistics, , University of Auckland, ; Auckland, New Zealand

[7 ]GRID grid.413952.8, ISNI 0000 0004 0408 3667, Mental Health Services for Older People, , Waikato Hospital, ; Hamilton, New Zealand

[8 ]GRID grid.416922.a, ISNI 0000 0004 0621 7630, Mental Health Services for Older People, , Tauranga Hospital, ; Tauranga, New Zealand

[9 ]GRID grid.413952.8, ISNI 0000 0004 0408 3667, Older Persons and Rehabilitation Service, , Waikato Hospital, ; Hamilton, New Zealand

Author information

Matthew C. L. Phillips http://orcid.org/0000-0003-4183-7766

Article

Publisher ID: 783

DOI: 10.1186/s13195-021-00783-x

PMC ID: 7901512

PubMed ID: 33622392

SO-VID: 744907b3-55e9-4082-a328-90cc9f76c86a

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 18 September 2020

Date accepted : 3 February 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001529, Waikato Medical Research Foundation;

Award ID: 300

Custom metadata

ScienceOpen disciplines: Neurology

Keywords: alzheimer’s disease,ketogenic diet,randomized crossover trial,cognition,daily function,quality of life

Data availability:

ScienceOpen disciplines: Neurology

Keywords: alzheimer’s disease, ketogenic diet, randomized crossover trial, cognition, daily function, quality of life

Randomized crossover trial of a modified ketogenic diet in Alzheimer’s disease

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Karger: Neurology and Neuroscience

Most cited references 38

The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

Validation of the Addenbrooke's Cognitive Examination III in Frontotemporal Dementia and Alzheimer's Disease

Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline.

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