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 (PGC1α).
Mitochondrial biogenesis and PGC-1α, 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 β-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 β-hydroxybutyrate decreased in AD patients, and donepezil elevated the plasma
level of β-hydroxybutyrate. Donepezil increased the plasma and liver levels of β-hydroxybutyrate in
mice as well as the hepatic expression of PGC-1α 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 β-hydroxybutyrate found in patients