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Lee, Bonnie

University of British Columbia

Alzheimer’s disease (AD) disproportionately affects females, and these sex differences are further exacerbated by the presence of apolipoprotein E (APOE) ε4 alleles, the top genetic risk factor for late-onset sporadic AD. To further understand these sex differences, it is pertinent to investigate the contributions of sex-specific factors. In particular, parity (pregnancy and parenthood) has lasting effects on brain health and AD risk in females. This thesis investigates how sex and previous parity in females modulate the effects of APOEε4 genotype on biomarkers of brain health at middle age in a rat model. Chapter 2 characterized sex differences in the effects of humanized (h)APOEε4 genotype on hippocampal neuroplasticity and microglia. In males, hAPOEε4 genotype reduced both neural progenitor cell density and neurogenesis, which was correlated with increased microglia density. In contrast, in females, hAPOEε4 genotype did not alter neural progenitor cell density, yet increased neurogenesis, indicating sex-specific effects of hAPOEε4 on hippocampal neuroplasticity. Chapter 3 explored the impacts of previous primiparity (one reproductive experience) and hAPOEε4 genotype and found that primiparity enhanced hippocampal neurogenesis in wildtype rats but impaired it in hAPOEε4 rats. Primiparous hAPOEε4 rats also displayed increased use of a non-spatial cognitive strategy and reduced activation of new neurons in response to memory retrieval. Chapter 4 examined brain-wide functional connectivity in response to spatial working memory and showed that primiparous hAPOEε4 rats exhibited disrupted neural integration and reduced activation in regions implicated in memory and AD pathogenesis, including the dorsal striatum, nucleus accumbens, frontal cortex, and retrosplenial cortex, whereas primiparous wildtype rats exhibited cohesive and efficient neural networks. Moreover, hierarchy of region influence within the neural network and regions in which activation predicted cognitive performance differed by primiparity and hAPOEε4 genotype. Collectively, the findings from this thesis highlight sex-specific pathways in how hAPOEε4 impacts hippocampal neuroplasticity at middle age and consistently demonstrate paradoxical effects of parity on brain health depending on hAPOEε4 genotype. This work provides critical insights into the mechanisms driving sex differences in AD and emphasizes the need to consider within-sex factors, such as parity, in understanding the aging brain.

Text

2025-04-04

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/90587

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/