As the rates of diet-induced obesity continue to rise, with recent estimates indicating that 71.6% of American adults are overweight or obese (Paraiso et al., 2021), increased efforts are warranted to assess the effects of XN on HFD-induced cognitive impairments in middle-aged and aged mice and whether these effects are apoE isoform- and sex-dependent and associated with alterations in specific hippocampal pathways and/or primarily driven by peripheral effects of XN using similar or different pathways as those affected by XN in brain. This evidence concerns the gene APOE and obesity disorder.