KETOGENIC DIET OR BHB IMPROVES EPILEPTIFORM SPIKES, MEMORY, SURVIVAL IN ALZHEIMER’S MODEL

Abstract

Links between epilepsy and Alzheimer’s disease (AD) are seen in both human patients and mouse models. Human patients with AD may commonly have subclinical epileptiform spikes (EP spikes)[1][1], and overt epilepsy is associated with more rapid cognitive decline[2][2]. Mechanistic studies in mouse models of Alzheimer’s disease (AD) have shown that altered network activity and epileptiform spikes stem from dysfunctional inhibitory interneurons[3][3], which are key elements of cortical circuits underlying cognition[4][4]. Treatments that reduce epileptiform spikes improve cognition in these models[5][5],[6][6]. Thus, targeting subclinical epileptiform activity may be a promising new therapeutic approach to AD[7][7]. Ketogenic diet (KD) has long been used to treat forms of epilepsy[8][8], including Dravet syndrome, a childhood epilepsy caused by mutations in a gene that is critical for inhibitory interneuron function in mouse AD models[5][5],[9][9]. However, the concurrent effects of a ketogenic diet on brain electrical activity, cognitive decline, and survival have not been tested, and the translational rationale and feasibility of such an intervention remain uncertain. Here we show that a ketogenic diet reduces epileptiform spikes in the hAPPJ20 mouse model of AD. Similar reduction of EP spikes is observed using a β-hydroxybutyrate (BHB) ester in both AD and Dravet mice. A ketogenic diet improves context-dependent and visuo-spatial learning in hAPPJ20 mice. It also reduces the high seizure-related mortality observed in male mice of this model. Therapies derived from β-hydroxybutyrate may have potential application in ameliorating cognitive dysfunction in AD through reducing subclinical epileptiform activity. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-6 [7]: #ref-7 [8]: #ref-8 [9]: #ref-9