Cell Type-Specific Structural and Functional Signatures of APOE4, Age and Sex in the Mouse Anterior Olfactory Nucleus.

As the strongest genetic risk factor for late-onset Alzheimer's disease (AD), the human APOE ε4 allele alters neuronal physiology before overt pathology. However, how aging and sex modify these effects in the anterior olfactory nucleus (AON), an early AD-affected brain region, remains unclear. Here, we performed whole-cell recordings and post hoc morphological reconstructions of pyramidal cells (PCs) and interneurons (INs) in acute AON slices from adult and aged humanized APOE3 (E3) and APOE4 (E4) knock-in mice of both sexes with identification of context-dependent remodeling across structural, intrinsic, and synaptic domains. In PCs, morphology was broadly susceptible to APOE genotype x age x sex and their interactions. Functionally, aged E4 PCs exhibited a more depolarized resting membrane potential than aged E3 PCs. Additionally, afterhyperpolarization amplitude displayed a marked age x genotype interaction, reversing the direction of the E4 - E3 difference from adulthood to aging. Excitatory synaptic event frequency showed a complex genotype and age and sex interaction, whereas inhibitory synaptic event amplitude was elevated in E4 mice. In contrast, INs displayed far more restricted alterations. Morphological changes were limited to dendritic length, which was modulated by age and sex specifically in E4 mice. Physiologically, genotype effects were confined to action potential amplitude, while aging primarily altered membrane properties and excitatory synaptic inputs. Together, these findings demonstrate that APOE genotype cell-specifically shapes AON neuronal properties through interactions with age and sex, suggesting that APOE4 establishes altered cellular states that influence how this circuit responds to subsequent disease-related stress.