by Milene Brownlow, PhD
It is estimated that 5.7 million Americans live with Alzheimer’s disease (AD).1 For decades, research efforts have targeted neuropathological features of the disease (amyloid plaques, tau dysregulation and tangle formation) with little success so far. Impaired brain glucose metabolism is an early hallmark of the disease.2 For instance, cerebral metabolic rate of glucose (CMRglu) utilization was found to be 13% lower in AD compared to healthy, young subjects.3 Conversely, brain ketone metabolism remains unchanged in mild cognitive impairment and AD compared to cognitively healthy older controls.3
Researchers from the University of Sherbrooke (Sherbrooke, Canada), Department of Medicine, investigated whether brain ketone uptake increased in patients with AD in response to dietary supplementation with medium-chain triglycerides (MCTs),4 as previously observed in young adults.5 In a crossover study, 15 patients with mild-to-moderate AD (73.5 ± 7.1 years old) consumed 30 g/day of either caprylic (C8) or a mixture of caprylic (55%) and capric (C10, 35%) acids for one month each, separated by a washout period of 4 weeks.4
Using positron emission tomography imaging, the authors reported that brain ketone uptake in AD patients doubled on both types of MCTs, similarly to previous findings in young adult controls.6 At the doses given in the present study, both MCT interventions increased the CMR of the whole brain (CMRket + CMRglu).4 The lack of difference between interventions was unexpected considering that an acute study with young adults reported 20% higher plasma ketones after C8 administration compared to C8C10.7 The authors speculate that the difference in ketogenic effect of C8 may disappear during chronic supplementation or such a difference simply may not occur in AD.
Moreover, blood glucose and CMRglu remained unchanged.4 This contrasts with previous findings in young adults on a ketogenic diet; in those subjects, brain fuel uptake was already normal, and in the presence of ketones, brain fuel supply exceeded demand resulting in compensatory decrease in glucose uptake.6,8 In AD brains, increased ketone availability partly fills the energy gap imposed by the 13% lower glucose uptake.3
This study demonstrated that, by providing 30g/day of MCTs (regardless if C8 or C8C10 mixture), the brain energy deficit in AD brains was partially compensated for, decreasing from 13% to 10%.4 Additionally, metabolic markers of cardiovascular health were normal at the end of the study, suggesting that the mild ketosis induced over a 1-month period is safe and tolerable in elderly patients.4
Why is this Clinically Relevant?
- Glucose hypometabolism in brain areas relevant to cognitive function is a well-established early feature of AD and can be present decades before clinical symptoms manifest in those at increased risk of AD2
- A potential therapeutic approach in AD is to provide an energy substrate that bypasses the deficit in brain glucose utilization9
- The relationship between blood ketones and brain ketone uptake after MCT supplementation (regardless if C8 or C8C10) suggests that partial metabolic rescue of the brain by a ketogenic MCT intervention is possible in mild-to-moderate AD4
- Further studies should evaluate the potential of ketone-based brain energy rescue on cognitive outcomes (i.e., memory, executive function, language and processing speed)
- https://www.alz.org/alzheimers-dementia/facts-figures. Accessed June 27, 2018.
- Mosconi L, Pupi A, De Leon MJ. Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann N Y Acad Sci. 2008;1147:190-195.
- Croteau E, Castellano CA, Fortier M, et al. A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer’s disease. Exp Gerontol. 2018;107:18-26.
- Croteau E, Castellano CA, Richard MA et al. Ketogenic medium chain triglycerides increase brain energy metabolism in Alzheimer’s disease. J Alz Dis. 2018;64:551-561.
- Courchesne-Loyer A, Fortier M, Tremblay-Mercier K, et al. Stimulation of mild, sustained ketonemia by medium-chain triacylglycerols in healthy humans: Estimated potential contribution to brain energy metabolism. Nutrition. 2013;29:635-640.
- Courchesne-Loyer A, Croteau E, Castellano CA, et al. Inverse relationship between brain glucose and ketone metabolism in adults during short-term moderate dietary ketosis: A dual tracer quantitative positron emission tomography study. J Cereb Blood Flow Metab. 2016;37:2485-2493.
- Vandenberghe C, St-Pierre V, Pierotti T, et al. Tricaprylin alone increases plasma ketone response more than coconut oil or other medium-chain triglycerides: an acute crossover study in healthy adults. Curr Dev Nutr. 2017;1:1-5.
- Hasselbalch SG, Madsen PL, Hageman LP, et al. Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia. Am J Physiol. 1996;270:E746-E751.
- Cunnane SC, Courchesne-Loyer A, Vandenberghe C, et al. Can ketones help rescue brain fuel supply in later life? Implications for cognitive health during aging and the treatment of Alzheimer’s disease. Front Mol Neurosci. 2016;9:53.