Ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease: A systematic review and critical appraisal

Background There is increasing interest in therapeutic ketosis as a potential therapy for neurodegenerative disorders–in particular, mild cognitive impairment (MCI), Alzheimer's disease (AD), and Parkinson's disease (PD)–following a proof-of-concept study in Parkinson's disease published in 2005. Methods To provide an objective assessment of emerging clinical evidence and targeted recommendations for future research, we reviewed clinical trials involving ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease reported since 2005. Levels of clinical evidence were systematically reviewed using the American Academy of Neurology criteria for rating therapeutic trials. Results 10 AD, 3 MCI, and 5 PD therapeutic ketogenic trials were identified. Respective grades of clinical evidence were objectively assessed using the American Academy of Neurology criteria for rating therapeutic trials. We found class “B” evidence (probably effective) for cognitive improvement in subjects with mild cognitive impairment and subjects with mild-to-moderate Alzheimer's disease negative for the apolipoprotein ε4 allele (APOε4-). We found class “U” evidence (unproven) for cognitive stabilization in individuals with mild-to-moderate Alzheimer's disease positive for the apolipoprotein ε4 allele (APOε4+). We found class “C” evidence (possibly effective) for improvement of non-motor features and class “U” evidence (unproven) for motor features in individuals with Parkinson's disease. The number of trials in Parkinson's disease is very small with best evidence that acute supplementation holds promise for improving exercise endurance. Conclusions Limitations of the literature to date include the range of ketogenic interventions currently assessed in the literature (i.e., primarily diet or medium-chain triglyceride interventions), with fewer studies using more potent formulations (e.g., exogenous ketone esters). Collectively, the strongest evidence to date exists for cognitive improvement in individuals with mild cognitive impairment and in individuals with mild-to-moderate Alzheimer's disease negative for the apolipoprotein ε4 allele. Larger-scale, pivotal trials are justified in these populations. Further research is required to optimize the utilization of ketogenic interventions in differing clinical contexts and to better characterize the response to therapeutic ketosis in patients who are positive for the apolipoprotein ε4 allele, as modified interventions may be necessary.


Notes:
1. In addition to the criteria above, any causal inference requires that exposure to the risk factor precede the development of the outcome. In addition, there may be need to allow for an induction period. 2. In translating evidence, a requirement of two or more studies implies that such studies should not include the same subjects. 3. Exploratory studies involving multiple comparisons of a variety of exposures and outcomes may be rated lower if it is evident that the study was designed without an a priori hypothesis or focus upon the specific exposure and outcome of interest. 4. Randomized clinical trials (RCTs) are equivalent to prospective cohort studies in which the risk of confounding has been minimized. Evidence from such studies may be considered Class I, provided it satisfies criteria (a), (b), and (d) above. Note, however, that it is preferable to apply the AAN criteria for therapeutic studies when classifying evidence pertaining to the experimental (treatment) variables of an RCT.

Classification of Recommendations
A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)* B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.) C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.) U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.
*In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome > 5 and the lower limit of the confidence interval is > 2).

Classification of Recommendations (causation)
A = Risk factor is a highly probable contributor to the development of disease or outcome.
(Level A rating requires two or more consistent Class I studies all showing an effect size (R.R.) ≥2 with lower confidence limits >1. In addition, either (1) a causal inference is coherent with known biologic mechanisms and related scientific evidence or (2) findings clearly demonstrate that higher doses of exposure increase likelihood of disease or outcome.) B = Risk factor is a probable contributor to the development of disease or outcome. (Level B rating requires at least one Class I study fulfilling other criteria above, OR two or more consistent Class II studies, showing an effect size (R.R. or O.R.) ≥1.5 with lower confidence limits >1.) C = Risk factor is a possible contributor to the development of disease or outcome. (Level C rating requires 1 Class II or 2 or more Class III studies, showing effect estimate(s) with consistent significant departure(s) from null value.) U = A causal relationship between the risk factor and disease or outcome is unproven or unsupported.