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

Bonnie H Lee; Melike Cevizci; Stephanie E Lieblich; Muna Ibrahim; Yanhua Wen; Rand S Eid; Yvonne Lamers; Paula Duarte-Guterman; Liisa A M Galea

doi:10.1016/j.bbi.2024.05.019

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

Brain Behav Immun. 2024 May 19:120:54-70. doi: 10.1016/j.bbi.2024.05.019. Online ahead of print.

Authors

Bonnie H Lee¹, Melike Cevizci², Stephanie E Lieblich², Muna Ibrahim², Yanhua Wen², Rand S Eid³, Yvonne Lamers⁴, Paula Duarte-Guterman², Liisa A M Galea⁵

Affiliations

¹ Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
² Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada; Department of Psychology, University of British Columbia, Vancouver, BC, Canada.
³ Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.
⁴ Food Nutrition and Health Program, Faculty of Land and Food Systems, University of British Columbia, Vancouver, BC, Canada.
⁵ Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada; Department of Psychology, University of British Columbia, Vancouver, BC, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, ON, Canada. Electronic address: liisa.galea@camh.ca.

PMID: 38772427
DOI: 10.1016/j.bbi.2024.05.019

Abstract

Female 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 inflammatory 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 underscore the importance of considering female-specific factors and genotype in health research.

Keywords: APOE; Alzheimer’s disease; Female; Frontal cortex; Hippocampus; Kynurenine; Neurogenesis; Pregnancy.