The researchers aim to fill the void of approved treatments for mild cognitive impairment, showing the potential of brain energy rescue strategies in this patient population.
A ketogenic medium chain triglyceride (kMCT) drink improved executive function, episodic memory, and language by increasing blood ketone levels and brain energy status in a recent study, the findings of which reinforce the potential of brain energy rescue as a strategy to reduce cognitive decline in mild cognitive impairment (MCI) and Alzheimer Disease (AD).
Stephen Cunnane, PhD, Research Center on Aging, Universite de Sherbrooke, and colleagues found that when compared to placebo, the kMCT group scored higher on free and cued recall (P = .047), verbal fluency (P = .024), Boston Naming Test (P = .033), and the Trail-Making Test (P = .017) after a 6-month randomized, controlled trial.1
Cunnane and colleagues noted that this exploration into the effects of ketones on brain energy rescue as a possible strategy to reduce cognitive decline was undertaken because “slowing progression toward AD during the MCI phase by 1 or more years could result in meaningful improvements for the patient and substantial savings for society.”
This study followed up the Brain Energy, Functional Imaging, and Cognition (BENEFIC [NCT02551419]) study that showed a kMCT drink improved brain energy status and aimed to assess the effect of kMCT on cognitive outcomes.2 Of the 122 patients with evidence of MCI enrolled in the present study, 39 patients (mean age, 71.4 years) completed the mKCT dosing and 44 (mean age, 72.9 years) completed the placebo dosing, which was formulated to be equivalent in fat-calories and organoleptically indistinguishable from the kMCT drink. Both groups ingested 15-g doses twice daily, typically with breakfast and dinner.
The first free recall test, conducted with the Rappel Libre/Rappel Indicé (RL/RI‐16), improved significantly in the kMCT group (partial ƞ2 = 0.046), and no significant changes were observed on the Brief Visual Memory Test‐Revised (BVMT‐R) for either group. The Verbal Fluency (VF) scores were significantly higher post‐intervention in the kMCT group in (+1.9 words) compared to the placebo group (–1.0 words; P = .005), with a moderate effect size (partial ƞ2 = 0.098).
The kMCT group also had markedly fewer errors on all conditions of the Trail‐Making (P = .020; partial ƞ2 = 0.067) and Stroop tests (P = .042; partial ƞ2 = 0.053). Boston Naming Test (BNT) scores also improved post‐intervention in the kMCT group (+1.1 total correct responses), compared to the placebo group (–0.2 total correct responses; P = .018; partial ƞ2 = 0.069).
These differences between treatment groups remained significant after normalization, and no change in raw or normalized attention or processing speed scores in either group was observed. Although MCI causes hypometabolism of glucose, BENEFIC previously found that brain ketone uptake remained normal in both MCI and AD, and demonstrated a link between mild ketosis, brain energy rescue by ketones, and improved cognitive outcomes. No drugs are currently approved for amelioration of MCI and those used in AD do not delay cognitive impairment in MCI. The results achieved by Cunnane and colleagues offer up the possibility of improving cognitive outcomes in MCI with ketogenic supplements.
Cunnane and colleagues stated that “this formulation of a kMCT drink improved 4 cognitive outcomes in MCI by increasing blood ketone levels and presumably improving brain energy supply because blood ketone levels and brain ketone metabolism are directly related.”
No serious adverse events (AEs) occurred in either group, but gastrointestinal-related AEs resulted in 18 participants from the mKCT group and 7 participants from the placebo group discontinuing the study. In the kMCT group, 74% reported at least 1 AE compared to 40% of the placebo group. Around one-third of these AEs resolved after 1 month, and the authors note that “it is safe and feasible for an MCI population to consume a 15 g kMCT supplement twice daily for 6 months,” although an improved formulation or alternative ketone supplement may be developed to decrease these AEs. Protocol compliance was 89% (±9).
The candidates selected for this trial had normal glycemia and it is unknown how the response to kMCT may be affected for older people with pre-diabetes or similar metabolic disorders, common with the high glycemic Western diet. Despite concerns over saturated fat, weight gain, or other changes in cardiovascular health, cardiometabolic measures were unchanged or remained normal after 6 months.
Although not directly assessed in this study, past research has shown a decrease in AD biomarkers in MCI after time on ketogenic diets, possibly delaying the rate of MCI progression to AD. The authors also measured APOEε4 without being able to assess its effect on cognition, and plasma amyloid-beta without finding significant differences between the placebo and kMCT group.
Following the addition of their results to the literature on ketogenic diets and MCI, Cunnane and colleagues concluded that “assessment of whether a ketogenic intervention can delay progression of MCI to AD is now warranted.”