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Summary: Female sex and Apolipoprotein (APOE) ε4 genotype are top risk factors for late-onset Alzheimer's disease. This research investigates how these two risk factors might interact to influence biomarkers of brain health at middle age using a rat model. Compared to healthy controls, male rats with hAPOEε4 genotype showed reduced neural stem cell-like cells and new adult-born brain cells and increased microglia (marker of inflammation in the brain) at middle age. In contrast, female rats with hAPOEε4 genotype showed increased new adult-born neurons, but no changes in the other cell types, suggesting a possible compensatory response to the effects of hAPOEε4 at this time point. These results highlight the importance of examining sex-specific pathways in AD, as they may uncover unique protective mechanisms and inform development of tailored treatment strategies. Background: Alzheimer's disease (AD) disproportionately and uniquely affects females, and these sex differences are further exacerbated by the presence of Apolipoprotein (APOE) ε4 alleles, the top genetic risk factor for late-onset AD. To expand our understanding about how late-onset AD risk might differentially influence males and females, this study explores how APOEε4 affects hippocampal neurogenesis and microglia, key neuroplastic markers involved in AD pathogenesis, differently by sex in middle-aged rats. Methods: A rat model expressing the humanized (h) APOEε4 allele was characterized to examine markers of adult neurogenesis (neural progenitor cells and new-born neurons) and immune cells (microglia) in the dentate gyrus of the hippocampus in 13 month-old male and female rats. Results: We observed basal sex differences in neurogenesis at middle age, as wildtype male rats had greater densities of neural progenitor cells and new-born neurons in the dentate gyrus than wildtype female rats. Male hAPOEε4 rats exhibited fewer neural progenitor cells, fewer new-born neurons, and more microglia than male wildtype rats. On the other hand, female hAPOEε4 rats exhibited more new-born neurons than female wildtype rats. Interestingly, females had more microglia than males regardless of genotype. Correlations were conducted to further elucidate any sex differences in the relationships between these biomarkers. Notably, there was a significant positive correlation between neural progenitor cells and new-born neurons, and a significant negative correlation between new-born neurons and microglia, but only in male rats. Conclusion: In contrast to the clear pattern of effects of the hAPOEε4 risk factor on hippocampal neurogenesis in males, females had unaltered levels of neural progenitor cells and increased density of new-born neurons. Furthermore, relationships between neurogenesis and microglia were significantly correlated within males, and not females. This suggests that females may be presenting a compensatory response to the hAPOEε4 genotype at middle age. Collectively, these results exemplify the importance of thoroughly examining influences of sex on AD endophenotypes, as it may reveal sex-specific pathways and protective mechanisms relevant to AD. Highlights: In male middle-aged rats, hAPOEε4 genotype decreased adult neurogenesis on the level of both neural progenitor cells and new-born neurons and increased the density of microglia in the dentate gyrus. In female middle-aged rats, hAPOEε4 genotype increased neurogenesis on the level of new-born neurons and did not significantly affect density of neural progenitor cells. In male rats only, there was a significant positive correlation between neural progenitor cells and new-born neurons and a significant negative correlation between new-born neurons and microglia. This research shows differential effects of hAPOEe4 genotype on hippocampal neurogenesis and microglia between males and females, underscoring the importance for future research to consider sex-specific influences on biomarkers and processes associated with AD. [ABSTRACT FROM AUTHOR]