The metastability of γ‐secretases as foundation for AD onset and prevention

Our study supports a unified model of AD pathogenesis, in which mutation-mediated destabilization of γ-secretase leads to its dysfunction and shifts Aβ profiles towards generation of longer peptides. The molecular composition of (mutant) Aβ profiles largely determines AAO in carriers of mutations in the causal genes. This emphasizes the pathogenicity of Aβ profile imbalances, rather than specific peptide elevations. Our findings offer potential for predictive AAO modeling with implications for clinical and genetic research, and support γ-secretase targeting strategies in ADAD therapy and potentially more broadly in AD.