Small-molecule ketone esters treat brain network abnormalities in an Alzheimer's disease mouse model

Altered brain network activity and the resulting hypersynchrony are important for the pathogenesis of cognitive decline in Alzheimer's disease (AD) mouse models. Treatments that reduce epileptiform discharges (EDs) or network hyperactivity improve cognition in AD models and humans. We first show that ketogenic diet, but not fasting, rapidly and persistently reduced EDs in the hAPPJ20 Alzheimer's mouse model over timescales of hours to months. Then, to identify the specific mechanism of the pleiotropic ketogenic diet, we developed small molecule ketone esters to deliver ketone bodies pharmacologically. Two ketone esters recapitulate ED suppression without other dietary manipulation, over time scales of minutes to one week. This small molecule rescue was associated with reduced low-frequency oscillatory activity similar to the recently reported mechanism of an NMDA receptor modulator molecule in this model. Long-term KD resulted in cognitive improvement and in a sex-stratified analysis also improved survival in the more severely affected hAPPJ20 males. Agents that deliver ketone bodies via small molecules or act on downstream targets may hold therapeutic promise in AD through the mechanism of improved network function and reduced epileptiform activity. ### Competing Interest Statement J.C.N., E.V., and S.U. are co-inventors on a patent application which includes the ketone esters described here. J.C.N. and E.V. are co-founders and hold stock in BHB Therapeutics, Ltd. and Selah Therapeutics Ltd., which develop ketone esters for consumer and therapeutic use. J.J.P. holds a minority financial interest in Cure Network Dolby Acceleration Partners (CNDAP) LLC.