Sex-specific factors and APOEε4 genotype alter functional connectivity at middle age

Cognitive aging is influenced by sex and sex-specific factors. Indeed, research has shown that parity (pregnancy and parenthood) uniquely alters biomarkers of brain health in middle age depending on Alzheimer's disease (AD) risk. This study investigated functional connectivity changes and network dynamics at middle age based on parity and APOEε4 genotype, the top genetic risk factor for late-onset sporadic AD risk. Neural activation was assessed in middle-aged wildtype and hAPOEε4 rats that were either nulliparous (0 litters) or primiparous (1 litter), by quantifying expression of the immediate early gene, zif268, across 19 brain regions implicated in memory and AD. Primiparous hAPOEε4 rats exhibited widespread reductions in neural activation, particularly in the dorsal striatum, nucleus accumbens, frontal cortex, and retrosplenial cortex. Network analyses further revealed that primiparous wildtype rats had the most cohesive and efficient functional connectivity networks. Activation of hippocampal new neurons in conjunction with the dorsal striatum, frontal cortex, and retrosplenial cortex dynamically predicted cognitive performance depending on parity and hAPOEε4 genotype. These findings underscore the importance of considering sex-specific factors in aging and AD research.