Basic Science and Pathogenesis.

Background: The strongest genetic risk factors for AD include the e4 allele of APOE and the R47H point mutation in the TREM2 receptor. TREM2 is required for the induction of a disease-associated microglia (DAM) signature and microglial neurodegenerative phenotype (MGnD) in response to disease pathology, signatures which both include APOE upregulation. There is currently limited information regarding how the TREM2-APOE pathway ultimately contributes to AD risk, and downstream mechanisms of this pathway are unknown. The combination of AD risk factors R47H and APOE4 may help highlight the mechanisms worsening disease and contributing to increased risk in humans.

Method: There are noteworthy sex differences in AD incidence and pathology, such that a greater proportion of AD patients are women, and APOE4-associated risk is stronger in women. We accordingly focused our studies on female mice to examine the effects of combining three substantial risk factors: R47H, APOE4, and female sex. We chose to use the P301S tauopathy model for this study because tau pathology more closely aligns with cognitive decline than Ab pathology in human patients RESULT: Our study has found that the combination of APOE4 and R47H risk factors induces neurodegeneration in female tauopathy mice without significantly impacting hippocampal tau load. A previous study similarly found that R47H does not affect hippocampal tau load in the P301S model, suggesting that R47H risk is driven by disease-enhancing microglial responses to tau, rather than by tau itself. Indeed, we find that APOE4-R47H exacerbates microgliosis, amplifies microglial cGAS-STING signaling and downstream IFN response pathways in a cell-autonomous manner, and increases cGAS- and BAX-dependent microglial senescence. Our study links the strongest AD risk factors, R47H, APOE4, and female sex, with microglial cGAS-STING activation and associated senescence in a tauopathy model, highlighting these pathways as important therapeutic targets in the treatment of AD.

Conclusion: Taken together, cGAS-STING and senescence pathways are known drivers of neurodegeneration, and our study further links upregulation of these pathways to the strongest AD risk factors. This evidence points to cGAS-STING and senescence as vital pathological mechanisms in AD and important targets for future therapeutics.