Contributions of sex and genotype to exploratory behavior differences in an aged humanized mouse model of late-onset Alzheimer's disease.

Age, genetics, and chromosomal sex have been identified as critical risk factors for late-onset Alzheimer's disease (LOAD). The predominant genetic risk factor for LOAD is the apolipoprotein E allele (), and the prevalence of LOAD is higher in females. However, the translational validity of mouse models for AD-related cognitive impairment remains to be fully determined. The present study investigated the role of both sex and genotype on learning and memory in aged, humanized knock-in mice. Aged (23.27 mo ± 1.21 mo; 39 male/37 female) , , and mice performed a novel object recognition (NOR) assay. Task-related metrics were analyzed using two-way sex by genotype ANOVAs. Sex differences were more prominent relative to genotype. Prior to NOR, female mice exhibited thigmotaxic center zone avoidance during the open field task relative to males, regardless of genotype. Within object familiarization and NOR tasks, females had greater object interaction and locomotion. Interestingly, only females on average recognized the novel object. These results suggest that , although strongly related to LOAD pathogenesis, does not drive cognitive decline in the absence of other risk factors even in very aged mice. Chromosomal sex is a key driver of behavioral phenotypes and thus is a critical variable for translatability of interventions designed to preserve learning and memory in animal models of LOAD. Last, there was a very high degree of variability in behavioral performance across genotypes. A cluster analysis of the behavioral data revealed a low-activity and a high-activity cluster. carriers were overrepresented in the low-activity cluster, while male:female distributions did not differ. Collectively, the behavioral data indicate that chromosomal sex has the greatest impact on behavioral phenotype, and carrier status may confer greater risk for cognitive decline in some animals.