Young APOE4 knockin (E4-KI) mice exhibit hippocampal region-specific network hyperexcitability, a phenomenon that predicts later cognitive deficits. This study identifies that the hyperexcitability arises from smaller, hyperexcitable neuronal subpopulations and is reversible through the selective removal of neuronal APOE4. As these mice age, they develop further excitatory dysfunction and an imbalance between excitation and inhibition in the dentate gyrus, highlighting a progressive decline in network function associated with APOE4. Notably, single-nucleus RNA sequencing reveals age-dependent transcriptional changes, pinpointing candidate mediators such as **Nell2, whose knockdown rescues abnormal excitability, linking it to APOE4-driven dysfunction.**

The findings underscore the critical role of **APOE4 in early neuronal network impairment and Alzheimer’s disease (AD) pathogenesis. The study shows that young E4-KI mice display elevated interictal spike (IIS) rates in the CA3 and dentate gyrus regions, which correlate with later cognitive decline. This hyperexcitability is not only present in aging but also manifests in younger mice, suggesting that APOE4’s detrimental effects on cognition begin long before the clinical onset of AD. The identification of Nell2 as a key player in this process opens new avenues for therapeutic intervention, potentially allowing for early treatment strategies that target neuronal excitability.**

The implications of this research are significant for the field of aging and neurodegeneration. By establishing early network hyperexcitability as a predictor of cognitive decline, this study shifts the paradigm towards focusing on **preventative strategies in APOE4 carriers, particularly during the preclinical stages of AD. The ability to modulate hyperexcitability through targeted interventions such as CRISPR-based approaches could accelerate drug development timelines, paving the way for novel therapies aimed at mitigating cognitive decline in at-risk populations.**

Source: nature.com