Christos Panagiotis Lisgaras

Objective To test the hypothesis that high‐frequency oscillations (HFOs) between 250 and 500 Hz occur in mouse models of Alzheimer's disease (AD) and thus are not unique to epilepsy. Methods Experiments were conducted in three mouse models of AD: Tg2576 mice that simulate a form of familial AD, presenilin 2 knock‐out (PS2KO) mice, and the Ts65Dn model of Down's syndrome. We recorded HFOs using wideband (0.1–500 Hz, 2 kHz) intra‐hippocampal and cortical surface electroencephalography (EEG) at 1 month until 24 months of age during wakefulness, slow wave sleep (SWS), and rapid eye movement (REM) sleep. In addition, interictal spikes (IISs) and seizures were analyzed for the possible presence of HFOs. Comparisons were made to the intra‐hippocampal kainic acid and pilocarpine models of epilepsy. Results We describe for the first time that hippocampal and cortical HFOs are a new EEG abnormality in AD mouse models. HFOs occurred in all transgenic mice but no controls. They were also detectable as early as 1 month of age and prior to amyloid beta plaque neuropathology. HFOs were most frequent during SWS (vs REM sleep or wakefulness). Notably, HFOs in the AD and epilepsy models were indistinguishable in both spectral frequency and duration. HFOs also occurred during IISs and seizures in the AD models, although with altered spectral properties compared to isolated HFOs. Significance Our data demonstrate that HFOs, an epilepsy biomarker with high translational value, are not unique to epilepsy and thus not disease specific. Our findings also strengthen the idea of hyperexcitability in AD and its significant overlap with epilepsy. HFOs in AD mouse models may serve as an EEG biomarker, which is detectable from the scalp and thus amenable to noninvasive detection in people at risk for AD.