Isogenic cortical organoids enable precision targeting of APP variant-specific pathways in Alzheimer's disease.

Alzheimer's disease (AD) lacks disease-modifying therapies, in part due to the limitations of existing disease models, which have struggled to capture the early pathogenic events leading to neuronal degeneration. Unfortunately, recent therapies targeting hallmarks of AD have proven inefficient in humans, and it is thus necessary to identify alternative targets. Here, by generating an isogenic panel of hiPSC-derived cortical organoids carrying familial AD-associated APP variants or the protective A673T variant, we identified distinct, actionable pathogenic pathways specific to each variant. Proteomic analyses revealed variant-specific molecular disruptions: A673V organoids show impairments in proteostasis and cholesterol metabolism, whereas KM670/671NL organoids exhibit mitochondrial bioenergetic defects. These signatures overlapped with dysregulated proteins in post-mortem AD brains, demonstrating the reliability of our in vitro model. Importantly, targeted interventions restored neuronal survival in a variant-specific manner: overexpression of the master regulator of lysosomal biogenesis, TFEB, rescued A673V neurons, while ferroptosis inhibition selectively protected KM670/671NL neurons. Overall, our results indicate that differential treatments can be tailored based on distinct genetic backgrounds, supporting the development of precision medicine approaches in AD.