Reproductive history differentially shapes the neural response of middle-aged hAPOEɛ4 female rats to estradiol therapy after a metabolic challenge.

BACKGROUND: Advancing age, the APOEɛ4 allele, and female sex are the top nonmodifiable risk factors for Alzheimer's disease (AD). Female-specific experiences, such as parity and hormone therapy (HT) affect aging biomarkers such as metabolism and immune signaling, and may affect AD risk. Estradiol (E2), a component of many HTs, affects cognition and brain health in aging females although studies suggest the effects can vary depending on parity, genotype, and metabolic status which may account for some of the inconsistencies in the literature. We hypothesized that prior parity influences brain and metabolic health, including response to E2, depending on APOE genotype. METHODS: Middle-aged female (10 month) wildtype (WT) or humanized (h) APOEɛ4 expressing rats, with different reproductive experience (nulliparous or primiparous) were fed a Western (WD) or standard diet (SD) for 2 months. In the second month, rats were given E2 or vehicle (oil) injections daily. Fear associative learning, plasma metabolic hormones, hippocampal inflammatory cytokine expression, and neuroplasticity (neurogenesis, synaptic protein) were assessed. RESULTS: Females fed a WD gained weight and displayed metabolic dysregulation, regardless of genotype. E2 treatment reduced WD-induced weight gain and reduced metabolic hormones, with stronger effects in WT rats. E2 treatment increased dorsal hippocampal inflammatory cytokine expression selectively in primiparous hAPOEɛ4 females fed a WD. Previous parity increased neurogenesis and reduced certain cytokine expression in the hippocampus of middle-aged WT rats under a SD. Both E2 treatment and previous parity decreased dorsal neurogenesis in hippocampus of hAPOEɛ4 rats. In hAPOEɛ4 females, higher weight was associated with reduced contextual fear memory, an effect driven by primiparous females. In the cued fear conditioning task, hAPOEɛ4 females displayed better cued fear memory than WT, however, WD exposure reduced cued fear memory only in this group. Together, this indicates that diet and weight gain may be more detrimental to associative memory in hAPOEɛ4 females and that E2 treatment has more favourable outcomes in WT rats. CONCLUSIONS: Previous parity alters how females respond to E2 and metabolic stress in midlife. Primiparous hAPOEɛ4 females were especially vulnerable to the effects of WD and E2, exhibiting more inflammation, impaired memory, and reduced weight-loss. These findings highlight the importance of considering parity and genotype when evaluating midlife metabolic and cognitive risk.