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

Abstract

AbstractFemale sex and Apolipoprotein E (APOE) ε4 genotype are top non-modifiable risk factors for Alzheimer’s 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 APOEε4 genotype by examining behavioural and neural biomarkers of brain health in middle-aged female rats. Our findings show that primiparous (parous one time) hAPOEε4 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 hAPOEε4 genotype synergistically modulate neuroinflammatory markers in the ventral hippocampus. Collectively, these findings demonstrate that previous parity in hAPOEε4 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.HighlightshAPOEε4 rats made more errors and used a non-spatial cognitive strategyPrimiparous hAPOEε4 rats increased use of a non-spatial cognitive strategyParity increased neurogenesis in wildtype rats, but decreased it in hAPOEε4 ratsPrimiparous hAPOEε4 rats had less active new neurons in response to memory retrievalParity and hAPOEε4 affect the neuroimmune milieu in a region-specific manner