Translational potential of JAX humanized‐APOE mice: Building the foundation for translational validity by applying human clinical trial principles

Abstract

AbstractBackgroundThe 4th isoform of apolipoprotein E is the most prevalent genetic risk factor for Alzheimerʼs Disease (AD) and transgenic APOE animal models are widely used. However, APOE4’s penetrance is only ∼50‐60% and many studies do not use sufficient sample sizes to account for this.MethodTo address knowledge gaps regarding APOE penetrance and advance translatability of JAX humanized APOE (hAPOE) mouse models, we utilized a translational animal data management system recapitulating core aspects of human clinical trials: unique mouse IDs linked to all tissue samples and analytic outcomes. Transgenic C57BL/6J mice carrying hAPOE alleles (hAPOEe3/3, hAPOEe3/4 or hAPOEe4/4) were bred and longitudinally tracked for identification and analysis of susceptible and resilient subpopulations through population‐level studies on monthly weights (N = 1129 mice, N = 13262 weights), clinical observations (N = 2754 mice), and survival rates (N = 559 mice not utilized in studies).ResultColony‐wide analyses showed few differences, potentially leading to incorrect conclusions of minimal allelic effects. In this study, sub‐populations of hAPOEe4/4 mice exhibit divergent weight trajectories beginning at 15mo. Moreover, hAPOEe4/4 females displayed aberrations in fur barbering trajectories. The clinical observation of dermatitis was also noted more often in hAPOEe4/4 mice compared to hAPOEe3/3. Accordingly, hAPOEe4/4 animals, especially females, exhibit reduced survival rates, potentially due to divergent trajectories of susceptibility and resilience.ConclusionThe present study identified distinct subpopulations of hAPOE mice exhibiting clear susceptible vs. resilient phenotypes within longitudinal data. Therefore, results from cross‐sectional studies of hAPOE mice with small, average cohorts will be highly variable. Future studies selecting cohorts based on clinical observations such as weight and phenotypic indicator trajectory will advance translatability to human APOE4‐AD.Acknowledgements: Research supported by T32AG061897, R01AG057931, RF1AG059093, and Center for Innovation in Brain Science (CIBS) to RDB.