Temporal Dynamics of High-Frequency Oscillations in Alzheimer’s Disease: A Longitudinal Study in hAPP-J20 Mice

Abstract Alzheimer’s disease (AD) is characterized by progressive cognitive decline and increased seizure susceptibility; yet both the mechanistic and temporal links between AD and epileptogenesis remain poorly defined. In this study, we conducted a longitudinal analysis of epileptogenesis in relation to AD pathology using hAPP-J20 transgenic mice aged 9 to 27 weeks, encompassing the AD conversion phase. Wireless electroencephalography (EEG) was employed to monitor hippocampal high-frequency oscillations (HFOs), including ripples (80−200 Hz) and fast ripples (250−600 Hz), in conjunction with histological, behavioral, and neurophysiological assessments to characterize underlying neural circuit alterations. We identified three distinct epileptogenic stages in transgenic mice: (1) 9−15 weeks: emerging memory deficits, increased excitatory/inhibitory (E/I) neuron ratio, mossy fiber sprouting, and peak seizure-related mortality, alongside the initial emergence of pathological HFOs; (2) 15−21 weeks: a pronounced escalation of pathological HFO activity and persistent network hyperexcitability preceding detectable amyloid plaque deposition, indicating rapid epileptogenic progression; (3) 21−27 weeks: stabilization of HFO activity despite continued progression of amyloid accumulation, suggesting a plateau in epileptogenic remodeling amid advancing Alzheimer’s pathology. These findings indicate that neuronal hyperexcitability precedes amyloid plaque deposition and likely contributes to disease progression, highlighting a critical early window for therapeutic intervention in AD. Moreover, pathological HFOs hold promise as electrophysiological biomarkers of early circuit dysfunction and represent a promising target for modifying the course of AD. Figure abstract This study examines the temporal dynamics of epileptogenic activity and amyloid pathology in hAPP-J20 transgenic mice, a model of Alzheimer’s disease (AD). Top: Illustration of pre-plaque and post-plaque stages in hAPP-J20 mice, depicting neural network alterations, amyloid plaque deposition, and electrophysiological changes. The top panel shows the transition from a pre-plaque to a post-plaque state, where early hippocampal activity is stable and amyloid plaques are absent. As pathology advances, the network exhibits progressive hyperexcitability, characterized by increased pathological HFOs (ripple-IEDs, fast ripples), neuronal loss, NPY sprouting, and amyloid plaque formation. Bottom: The progression of key biomarkers and disease hallmarks, comparing hAPP-J20 transgenic (Tg) mice with non-transgenic (nTg) controls. The bottom panel quantifies biomarker progression over time, revealing that CaMK2+/PV (C/P) imbalance emerges first, followed by a peak in pathological HFOs incident rate (patho-ripple, fast ripple rate), and finally, amyloid beta plaque (Aβ plaque). These findings establish a temporal relationship between early network hyperactivity and amyloid accumulation, underscoring the importance of targeting neural hyperexcitability as a therapeutic strategy to mitigate AD progression.