Young APOE4 knockin (E4-KI) mice exhibit hippocampal region-specific network hyperexcitability that serves as a precursor to cognitive deficits associated with Alzheimer’s disease (AD). This hyperexcitability is linked to distinct subpopulations of smaller, hyperexcitable neurons and can be mitigated by the selective removal of neuronal APOE4. As these mice age, they develop further granule cell hyperexcitability and an imbalance in excitation and inhibition within the dentate gyrus, highlighting the progressive nature of APOE4’s impact on neuronal function. Single-nucleus RNA sequencing has identified age-dependent transcriptional changes, revealing Nell2 as a potential mediator of early neuronal hyperexcitability, which, when targeted via CRISPR interference, can restore normal excitability levels.

The findings underscore the critical role of APOE4 in early AD pathogenesis, emphasizing that hyperexcitability may precede observable cognitive decline. The study demonstrates that elevated interictal spikes (IIS) in young E4-KI mice correlate significantly with later learning impairments, suggesting that early network dysfunction is a reliable predictor of future cognitive decline. This aligns with existing literature indicating that hyperexcitability contributes to cognitive deficits in both human and animal models of AD, reinforcing the notion that network-level dysfunction is a key target for therapeutic intervention.

These results shift the focus of AD research towards understanding the early neuronal mechanisms driven by APOE4 and their implications for cognitive health. Given that hyperexcitability serves as an early biomarker for cognitive decline, this research could inform the development of preventative strategies and therapeutic targets aimed at mitigating the effects of APOE4 before the onset of full-blown AD. This approach may accelerate drug development timelines and enhance the efficacy of interventions designed to preserve cognitive function in at-risk populations.

Source: nature.com