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

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.

Keywords: Alzheimer’s disease; Cognition; Daily function; Ketogenic diet; Quality of life; Randomized crossover trial.

Fig. 1

Patient flow, showing all exclusions and withdrawals

Fig. 2

Mean weekly blood (a) glucose and (b) ketone (beta-hydroxybutyrate) levels for all randomized patients (n = 26 for ketogenic diet, n = 26 for usual diet). For patients with weeks containing partial data, the days containing data were used to calculate the weekly mean. Regarding withdrawals, all data up to the point of withdrawal are shown, with regression imputation used to calculate values for the weekly means post-withdrawal. Error bars indicate standard error

Fig. 3

Mean within-individual changes in a cognition (ACE-III), b daily function (ADCS-ADL), and c quality of life (QOL-AD) scores (both the actual scores as well as changes in baseline scores are shown) for all randomized patients (n = 26 for ketogenic diet, n = 26 for usual diet). Regarding withdrawals, all data up to the point of withdrawal are shown, with regression imputation used to calculate values for the week(s) post-withdrawal. Error bars indicate standard error