UC Irvine

Alzheimer's disease (AD) is a complex neurodegenerative disorder with a multifactorial etiology, including genetic factors that play a significant role in disease susceptibility. However, in preclinical studies, the role of an individual's genetic makeup has been largely overlooked. To address this gap, we aimed to investigate the impact of genetic diversity in mouse models of AD on translational potential. In this study, we utilized a well-established AD mouse model and combined it with a complex genetically diverse reference panel to generate a novel AD mouse population. These mice carried identical high-risk human mutations for AD, but differed in the rest of their genome, allowing us to examine the effects of genetic variation on AD-related phenotypes. Our results demonstrated that genetic variation had analogous impact on pathological phenotypes associated with AD mutations. Mice with different genetic backgrounds exhibited consistent degrees of pathological changes, highlighting the importance of genetic diversity in AD research. Furthermore, we validated this complex AD model by demonstrating high degrees of genetic, transcriptomic, and phenotypic overlap with human AD, supporting its translational relevance. The findings of our study have significant implications for AD research. By incorporating genetic diversity into mouse models of AD, we have created an innovative and reproducible resource for studying the mechanisms underlying AD. Our results suggest that preclinical models that incorporate genetic diversity may better reflect the complex nature of human AD, potentially leading to improved translation of findings from mouse models to human disease. In conclusion, our study highlights the importance of considering an individual's genetic makeup in the context of AD research. Incorporating genetic diversity in mouse models of AD can provide a more comprehensive understanding of the disease and improve translational potential, offering new opportunities for investigating AD mechanisms and developing effective therapeutic interventions.