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

Matthew C L Phillips, Laura M Deprez, Grace M N Mortimer, Deborah K J Murtagh, Stacey McCoy, Ruth Mylchreest, Linda J Gilbertson, Karen M Clark, Patricia V Simpson, Eileen J McManus, Jee-Eun Oh, Satish Yadavaraj, Vanessa M King, Avinesh Pillai, Beatriz Romero-Ferrando, Martijn Brinkhuis, Bronwyn M Copeland, Shah Samad, Shenyang Liao, Jan A C Schepel

Journal: Alzheimer's research & therapy 2021;13(1):51

PMID: 33622392

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Plain Language Summary

Most people with dementia have Alzheimer’s disease (AD), a disorder that characteristically results in progressive cognitive and functional decline. Brain energy metabolism is impaired in AD. Ketogenic diets can theoretically mitigate impaired brain energy metabolism in AD, leading to improved cognition, daily function, or quality of life. Ketogenic diets are high-fat, low-carbohydrate diets that shift the body towards fat metabolism. The aim of this study was to determine whether a 12-week modified ketogenic diet was well-tolerated and improved cognition, daily function, or quality of life in a hospital clinic of AD patients. This study is a single-phase, assessor-blinded, two-period randomised crossover trial. Participants (n=26) were randomised (1:1 allocation) to a modified ketogenic diet (intervention diet) or their usual diet supplemented with low-fat healthy-eating guidelines and optional recipes (control diet). Results show that high rates of retention and adherence are achievable by following 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. Furthermore, changes in cardiovascular risk factors were mostly favourable and adverse effects were mild. Authors conclude that ketogenic diets may hold promise as viable and effective treatment strategies in AD, but larger and longer studies are needed in order to draw definitive conclusions.

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.

Address: Department of Neurology, Waikato Hospital, Hamilton, New Zealand. [email protected].; Department of Neurology, Waikato Hospital, Hamilton, New Zealand.; Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands.; Healthy Kitchen Christchurch Ltd, Hamilton, New Zealand.; Department of Dietetics Services, Waikato Hospital, Hamilton, New Zealand.; Department of Neurology, Waikato Hospital, Hamilton, New Zealand.; LINC Mental Health Services, Tauranga Hospital, Tauranga, New Zealand.; Department of Statistics, University of Auckland, Auckland, New Zealand.; Mental Health Services for Older People, Waikato Hospital, Hamilton, New Zealand.; Mental Health Services for Older People, Tauranga Hospital, Tauranga, New Zealand.; Older Persons and Rehabilitation Service, Waikato Hospital, Hamilton, New Zealand.

DOI: 10.1186/s13195-021-00783-x