Abstract
Anxiety is a prominent and debilitating symptom in Alzheimer's disease (AD) patients. Carriers of APOE4, the greatest genetic risk factor for late-onset AD, may experience increased anxiety relative to carriers of other APOE genotypes. However, whether APOE4 genotype interacts with other AD risk factors to promote anxiety-like behaviors is less clear. Here, we used open field exploration to assess anxiety-like behavior in an EFAD mouse model of AD that expresses five familial AD mutations (5xFAD) and human APOE3 or APOE4. We first examined whether APOE4 genotype exacerbates anxiety-like exploratory behavior in the open field relative to APOE3 genotype in a sex-specific manner among six-month-old male and female E3FAD (APOE3(+/+)/5xFAD(+/-)) and E4FAD mice (APOE4(+/+)/5xFAD(+/-)). Next, we determined whether circulating ovarian hormone loss influences exploratory behavior in the open field among female E3FAD and E4FADs. APOE4 genotype was associated with decreased time in the center of the open field, particularly among female EFADs. Furthermore, ovariectomy (OVX) decreased time in the center of the open field among female E3FADs to levels similar to intact and OVXed E4FAD females. Our results suggest that APOE4 genotype increased anxiety-like behavior in the open field, and that ovarian hormones may protect against an anxiety-like phenotype in female E3FAD, but not E4FAD mice.