Acetylcholinesterase Inhibitor Donepezil Effects on Plasma β-Hydroxybutyrate Levels in the Treatment of Alzheimer's Disease

Background: Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by a multi-factorial etiology that is not completely understood. Donepezil is a first-line acetylcholinesterase inhibitor used for the treatment of AD that has been found, in addition to its potent acetylcholinesterase inhibitory effect, to act through other non-cholinergic mechanisms such as affecting mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma coactivator (PGC 1 alpha). Mitochondrial biogenesis and PGC-1 alpha, at least in part, are associated with hepatic fatty acid oxidation and ketogenesis. Whether donepezil regulates ketogenesis in AD treatment remains unclear. Ketogenesis is important in the progression of AD and is a critical consideration during the therapeutic strategy selection for AD. Thus, our goals were to determine the differences in ketone bodies in patients with AD who were taking donepezil treatment and those who were not, to elucidate the potential effect of AD and donepezil therapy on ketone body metabolic parameters, and to discover the effect of donepezil therapy on ketogenesis in patients with AD. Methods: Cross-sectional analysis was performed on plasma collected from 145 individuals, namely, elderly adults as healthy controls (n=30), newly diagnosed patients with AD (n=30), patients with AD who responded to donepezil therapy (n=48) and patients with AD who did not respond to donepezil therapy (n=37). Gas chromatography-mass spectrometry was performed to quantify the lipids in the plasma. The level of beta-hydroxybutyrate, a metabolite, was determined by liquid chromatographytandem mass spectrometry, and to gain further insight into the effect of donepezil on ketogenesis, the effects of donepezil were investigated in a mouse model. Results: The level of beta-hydroxybutyrate decreased in AD patients, and donepezil elevated the plasma level of beta-hydroxybutyrate. Donepezil increased the plasma and liver levels of beta-hydroxybutyrate in mice as well as the hepatic expression of PGC-1 alpha and the mitochondrial expression of HMG-CoA synthetase 2 (HMGCS2) in response to fasting, causing a subsequent increase in ketogenesis. Conclusions: Our study revealed that impaired ketogenesis is a metabolic feature of AD. Donepezil had effects on ketogenesis in mice and reversed the decrease in the level of beta-hydroxybutyrate found in patients with AD.