Combining high-risk ADRD mutations across genetically distinct mice

Alzheimers disease and related dementias (ADRD), including Alzheimers disease, frontotemporal dementia, Lewy body dementia, and mixed dementia are characterized by diverse pathologies and etiologies. ADRDs are typically distinguished based on combinations of associated pathologies in the brain such as amyloid, tau, TDP-43 inclusions, alpha-synuclein aggregates, and cerebral amyloid angiopathy, and these pathologies often co-occur even in cases clinically diagnosed as one disease. The heterogeneity of ADRDs presents significant challenges in model development for disease mechanism elucidation, drug discovery, and preclinical testing. Current animal models of ADRD fail to incorporate mixed pathologies and demonstrate low concordance with the diverse genetic, molecular, pathological, and cognitive features of human disease. Further, genetic background is critical for accurately modeling the complex genetic, molecular and cognitive features of late-onset AD in mice, and that incorporation of genetic diversity significantly improves concordance between mouse models and human patients in these parameters. Using CRISPR genome editing, we knocked-in several known human disease-causing mutations into C57BL/6J mice. Through serial breeding, we combined these KI mutations into various 3X, 4X, 5X and 6X knock-in models. We then crossed these models to various genetic backgrounds (C57BL/6J, DBA/2J, FVB/NJ, WSB/EiJ) to achieve a diverse F1 panel of genetically altered mice. Our goal was to maintain physiological expression levels of genes that induce commonly co-occurring pathologies in brain and peripheral tissues, while addressing these critical concerns often overlooked in most mouse models of neurodegenerative diseases (i.e., genetic diversity, late symptom onset, systemic expression of mutations, etc.).