Exploring the parity paradox: Differential effects on neuroplasticity and neuroinflammation by APOEe4 genotype at middle-age

Female sex and Apolipoprotein E (APOE) {varepsilon}4 genotype are top non-modifiable risk factors for Alzheimers disease (AD). Although female-unique experiences like parity (pregnancy and motherhood) have positive effects on neuroplasticity at middle age, previous pregnancy may also contribute to AD risk. To explore these seemingly paradoxical long-term effects of parity, we investigated the impact of parity with APOE{varepsilon}4 genotype by examining behavioural and neural biomarkers of brain health in middle-aged female rats. Our findings show that primiparous (parous one time) hAPOE{varepsilon}4 rats display increased use of a non-spatial cognitive strategy and exhibit decreased number and recruitment of new-born neurons in the ventral dentate gyrus of the hippocampus in response to spatial working memory retrieval. Furthermore, primiparity and hAPOE{varepsilon}4 genotype synergistically modulate neuroinflammatory markers in the ventral hippocampus. Collectively, these findings demonstrate that previous parity in hAPOE{varepsilon}4 rats confers an added risk to present with reduced activity and engagement of the hippocampus as well as elevated pro-inflammatory signaling, and underscores the importance of considering female-specific factors and genotype in health research. O_LSTHighlightsC_LSTO_LIhAPOE{varepsilon}4 rats made more errors and used a non-spatial cognitive strategy C_LIO_LIPrimiparous hAPOE{varepsilon}4 rats increased use of a non-spatial cognitive strategy C_LIO_LIParity increased neurogenesis in wildtype rats, but decreased it in hAPOE{varepsilon}4 rats C_LIO_LIPrimiparous hAPOE{varepsilon}4 rats had less active new neurons in response to memory retrieval C_LIO_LIParity and hAPOE{varepsilon}4 affect the neuroimmune milieu in a region-specific manner C_LI