Neuronal apoE4 induces early hyperexcitability in select populations of hippocampal neurons by altering Nell2 expression

The impact of apolipoprotein E4 (apoE4), the strongest genetic risk factor for Alzheimer’s disease (AD), on neuronal function remains unclear. We investigated this by examining excitatory neurons in the hippocampus of young and aged human apoE4 knock-in (apoE4-KI) and apoE3-KI mice using electrophysiology and single-nucleus RNA-sequencing (snRNA-seq). In young apoE4-KI mice, we identified region-specific subpopulations of excitatory neurons with hyperexcitability underlain by reduced cell size, which were eliminated by selective removal of neuronal apoE4. Aged apoE4-KI mice showed an increased fraction of hyperexcitable granule cells, a pronounced inhibitory deficit, and E/I imbalance in the dentate gyrus, contributing to network dysfunction. snRNA-seq analysis revealed neuron type-specific and age-dependent transcriptomic changes, identifying Nell2 overexpression in apoE4-KI mice. Reducing Nell2 expression in specific neuronal types of apoE4-KI mice with CRISPRi rescued their morphological and excitability phenotypes, supporting Nell2 overexpression as a cause for apoE4-induced neuronal dysfunction. Our findings highlight the early transcriptomic and morpho-electric alterations behind the apoE4-induced neuronal dysfunction in AD. ### Competing Interest Statement YH is a cofounder and scientific advisory board member of GABAeron, Inc. Other authors declare no competing interests.