Background

kMCT-ONS is a nutritional drink that raises blood ketone concentrations. The brain uses ketones as an energy source when glucose is limited, and inducing mild ketosis has emerged as a strategy to overcome the decline in glucose uptake that occurs in people with Alzheimer’s disease. In multiple small pilot studies, ketogenic diets such as the Atkins regimen, or ketogenic supplements, improve brain energy status and cognitive function in people with MCI and AD (reviewed in Cunnane et al., 2020).

The active components of kMCT-ONS are medium-chain triglycerides of caprylic acid and capric acid. Metabolism of these fats in the liver produces the ketones acetoacetate and β-hydroxybutyrate, which freely enter the brain. kMCT-ONS is produced by emulsifying a commercially available 60:40 mixture of the two fats derived from palm oil into lactose-free skim milk. kMCT’s composition is similar to the medicinal food Ketasyn or the experimental ketogenic drink Tricaprylin, both of which contain caprylic acid triglyceride as their main active ingredient.

kMCT has been shown to increase plasma ketone levels and brain ketone uptake in healthy adults and in people with AD (Croteau et al., 2018). Brain uptake of ketones does not appear to be diminished in people with AD compared to healthy people  (Castellano et al., 2015).

In preclinical studies and one pilot clinical trial, inducing ketosis was reported to reduce amyloid load, ameliorate Aβ toxicity, and improve AD biomarkers (Kashiwaya et al., 2013; Zilberter et al., 2012; Neth et al., 2020).

A commercially available caprylic acid triglyceride supplement derived from coconut oil was claimed to stabilize or improve cognitive scores in most participants in a cross-over study of 20 people with mild to moderate AD (Juby et al., 2022). Longer treatment of up to 11 months was reportedly associated with better scores on the MMSE and a Cogstate computerized battery in this study.

Findings

In June 2015, investigators at the University of Sherbrooke, Quebec, began the BENEFIC trial to test effects on brain metabolism of a six-month course of kMCT in 52 people with mild cognitive impairment. The active treatment was a twice-daily shake containing 15 g MCT, or a calorie-equivalent placebo of non-ketogenic high oleic sunflower oil. The primary outcome of the trial was brain glucose and ketone uptake, measured by FDG-PET and ¹¹C-acetoacetate-PET, and tolerability. Secondary outcomes included performance on a neurocognitive battery, changes in global brain energy supply, and the relationship between ketone uptake and cognitive outcomes. According to published results, 19 and 20 people completed the treatment and placebo arms, respectively. Most participants reported gastrointestinal side effects, and one-quarter dropped out because of them. The kMCT group had a doubling of plasma ketones and brain ketone uptake compared to placebo; brain glucose uptake did not differ. The study was not powered to detect treatment effects on cognition, but improvements from baseline in the treated group were noted in several domains (Fortier et al., 2019). An increase ketone uptake into white-matter fascicles, and an associated increase in processing speed, was also reported (Roy et al., 2021).

Based on these results, a larger six-month trial enrolled 122 participants with MCI who were randomized to the same kMCT treatment or placebo. The primary outcome was scores on the neurocognitive battery. In this study, the dropout rate was 32 percent, mainly due to GI side effects. In all, 39 and 44 people completed the active and placebo treatments, respectively. Compared to the placebo group, the treated group improved on tests of memory, executive function, and language; their scores correlated with plasma ketone levels. A metabolic substudy found plasma ketones were elevated for one to two hours post-dosing, and this response was unchanged from the beginning to the end of the study. Results are published (Fortier et al., 2021).

In September 2018, University of British Columbia investigators began enrolling 40 people with a diagnosis of mild to moderate AD for an ascending-dose, safety, and pharmacokinetic study of the kMCT drink. Participants are to receive 10 to 50 g MCT or placebo per day for 10 days. Primary outcomes are serious adverse events and plasma ketone concentrations. Other outcomes include FDG-PET, cerebral blood flow, MR spectroscopy to assess brain chemistry, and daily physical activity.

For details on these trials, see clinicaltrials.gov.