The AD-BXD mouse population is a powerful emerging model for studying AD resilience. AD-BXD mice query two different levels of genetic information: genometypes and genotypes. The genetically diverse BXD genometypes are a mosaic of the approximately 6 million segregating single nucleotide polymorphisms between C57BL/6J and DBA/2J mice. The transgenic genotype of the 5 times familial Alzheimer’s disease (5xFAD) transgene, which includes human APP carrying three pathogentic variants and human PSEN1 carrying two pathogenic, can be contrasted with non-transgenic control animals (Ntg). Reproducible BXD genometypes allow repeated measurement of the same mosaic genomes, a strategy that boosts the mappable heritability of genetic loci (cite ). This property facilitates QTL mapping of the relatively lower effect size variants that modify susceptibility to Alzheimer’s-like cognitive phenotypes in 5xFAD animals. Further, the same cognitive phenotype can be measured in both 5xFAD and Ntg mice within the same genometype. The ability to contrast a genometype’s performance with different AD genotypes facilitates the measurement of novel and interesting derived phenotypes based upon the property of trait correlation (cite ). Because of these properties, our lab has successfully leveraged AD-BXD mice to identify genetic modifiers of AD-related phenotypes in recent years. We quantified resilience using a novel regression-based metric. We utilized this measure to map resilience to a locus, then leveraged proteomics data to identify a putative molecular mechanism for the genetic resilience factor. We found potential novel targets for AD by querying elements coregulated in trans to the putative molecular mechanism. Finally, we implicated differential expression of networked synaptic proteins as the likeliest downstream consequences of differences in resilience.

Samples are tissue from the prefrontal cortex of mouse brain from BXD (C57BL/6J and DBA/2J) 5xFAD (5 times familial Alzheimer’s disease) transgenic animals that express human APP carrying three pathogenic variants and human PSEN1 carrying two pathogenic variants and non-transgenic control animals. Tissue is both male and female mice and young (6 months) and old (14 months) mice. Several different strains of the BXD mice are represented.