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However, how\n APOE<\/jats:italic>\n \u03b54 interacts with age and sex to affect cellular and network function in vulnerable regions such as the anterior olfactory nucleus (AON) remains unclear.\n <\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n \n In vivo recordings in awake transgenic mice were used to assess how\n APOE<\/jats:italic>\n \u03b54, age, and sex interact to influence single\u2010cell excitability and network activity.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n \n APOE<\/jats:italic>\n \u03b54 reduces excitability in the AON; adult females show higher excitability than males, a difference that is lost with age. Excitability and network activity vary by genotype and sex, while aging consistently increases network power, underscoring their complex interplay in an AD\u2010vulnerable circuit.\n <\/jats:p>\n <\/jats:sec>\n \n DISCUSSION<\/jats:title>\n \n APOE<\/jats:italic>\n \u03b54, age, and sex interact to shape excitability and network dynamics in the anterior olfactory nucleus, a region affected early in AD. These actions may underlie early olfactory dysfunction and offer electrophysiological markers for early detection and genotype\u2010, age\u2010, and sex\u2010specific interventions.\n <\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n This is the first study on the interactive impact of three Alzheimer's disease risk factors on anterior olfactory nucleus neural functions.<\/jats:p>\n <\/jats:list-item>\n \n Apolipoprotein E \u03b54 reduces neuronal excitability regardless of age and sex.<\/jats:p>\n <\/jats:list-item>\n \n Females show higher excitability than males in the adult group but not in aged group.<\/jats:p>\n <\/jats:list-item>\n \n Age increases excitability in a genotype\u2010dependent manner.<\/jats:p>\n <\/jats:list-item>\n \n Network oscillations vary by genotype and sex but are consistently enhanced by age.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n 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