Effects of ketone bodies in Alzheimer’s disease in relation to neural hypometabolism, β-amyloid toxicity, and astrocyte function
Brain hypometabolism precedes clinical signs ofAlzheimer’s disease: Frackowiak et al. (1981) found a decline in cerebral bloodflow and mean cerebral oxygen utilization, i.e., hypometabolism, which is correlated with the severity of dementia. Global oxygen extraction ratio was not increased, providing evidence against chronic ischemia. Shortly afterward deLeon et al. (1983) found that aged patients with senile dementia showed consistent diminutions in regional glucose use compared to elderly normal persons, also with significant correlation between hypometabolism and decreased cognitive functioning. Thirteen additional studies (till 2009) all showed glucose hypometabolism (Cunnane et al. 2011), and since then glucose hypometabolism has repeatedly been confirmed in Alzheimer’s patients. In contrast, metabolism of ketone bodies is unaltered, at least in early stages of thedisease (Castellano et al. 2015).
Alzheimer’s disease as well as some forms of epilepsy can be treated more or less effectively with ketogenic diet. In epilepsy, it appears advantageous to administer the highest possible fraction of the patients’ calorie need in the form of ketone bodies, which may reduce glucose metabolism sufficiently to impair glutamate production in neurons. Much lower doses of ketone bodies can have therapeutic effect inAlzheimer’s disease by different mechanisms. Enabling ketone bodies to supply a fraction of needed ATP may partly compensate for the deficiency in glucose metabolism in Alzheimer’s patients. An alternative mechanism of action could be to prevent or reduce gliotransmitter release ofglutamate. Stimulation from subcortical nuclei can induce gliotransmitter release besides decreasing inflammation and enhancing metabolism.
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