Ketotherapeutics to Rescue Brain Energy Deficits

Abstract

Abstract Brain glucose uptake has long been recognized to be reduced in Alzheimer’s disease (AD) but was mainly assumed to be a consequence of reduced neuronal activity. More recently, several studies challenged this concept by showing that brain glucose hypometabolism was also present in individuals at high risk for AD before the presence of any cognitive symptoms. Thus, it is of great interest to know whether cognitive decline can be prevented or delayed if the glucose metabolism defect is at least partly corrected or bypassed. The ketones β-hydroxybutyrate and acetoacetate are the brain’s main alternative fuel to glucose, and their uptake in mild cognitive impairment (MCI) and mild to moderate AD is similar to that seen in healthy age-matched controls. Based on these findings, it is conceivable that ketones could be used to help rescue brain fuel supply during aging. Evidence from published clinical trials showed that increasing ketone availability to the brain via nutritional ketosis can have a beneficial effect on brain energy metabolism and cognitive outcomes in both MCI and mild to moderate AD. Nutritional ketosis can be safely achieved by a high-fat ketogenic diet or ketogenic supplements, such as medium-chain triglycerides containing the eight- and ten-carbon fatty acids, octanoate and decanoate. Given the acute dependence of the brain on its energy supply and the ineffectiveness of current therapeutic strategies aimed at AD, it seems reasonable that consideration be given to correcting the underlying problem of deteriorating brain glucose uptake observed with aging.