“In vivo validation of late-onset Alzheimer’s disease genetic risk factors.”
Michael Sasner, et al. – The Jackson Laboratory.
Background: The most common mouse models of AD involve genetic variants that are only present in early-onset familial AD, such as mutations of APP and PSEN1. Variants to risk genes associated with late-onset AD (LOAD), which makes up the majority of cases, remain underexplored.
This Study: Sasner and colleagues generated 10 novel mouse lines to study mutations to risk genes identified in GWAS studies, such as ABCA7 and SORL1, and others with predicted links such as CLASP2.
- These lines were crossed onto a background expressing humanized APOE4 and TREM2 R47H, two strong genetic risk factors for LOAD, and studied at 4 and 12 months of age.
- Each line had a gene expression profile that captured a distinct subset of changes observed in LOAD, many of which were not present in the common 5xFAD transgenic model.
- These differences extended to their correlation with different AD molecular subtypes identified in 3 cohorts (ROSMAP, Mayo, Mount Sinai Brain Bank), suggesting that certain lines could serve as animal models for these subtypes.
Bottom Line: These new mouse models allow for studying the distinct molecular events associated with different AD risk genes.
Open Question: In the Discussion, the authors point out that their 12-month time point corresponds to around ages 38-47 in humans, motivating additional ongoing studies extending to 24 months. Given that many previous mouse models exhibit pathology much earlier than 12 months, could findings from these new models at later time points hold greater translational potential?
