Isogenic cortical organoids enable precision targeting of APP variant-specific pathways in Alzheimer’s disease
Grass T, Cosacak IM, Ordureau A et al. bioRxiv, 2026.
Alzheimer’s disease is one of the most prevalent neurodegenerative diseases and the leading cause of dementia, the 7th leading cause of death globally. Currently, there is a lack of suitable and relevant disease models, leading to difficulties in both understanding and treating the disease.
Whilst Alzheimer’s disease primarily affects older adults, early onset familial disease has been shown to be caused by pathogenic mutations in the amyloid precursor protein (APP) gene, these mutations may allow the creation of disease models and therefore a method of testing and developing treatments.
This week’s #Fridayread from the lab of Dr. Natalia Rodriguez-Muela describes the generation of an isogenic panel of hiPSC-derived cortical organoids carrying familial Alzheimer’s disease-associated APP variants or the protective A673T variant. Through the panel of 3D models they identified distinct pathogenic pathways specific to each variant.
Proteomic analysis of the organoids allowed them to determine variant-specific defects which related to proteins dysregulated in post-mortem diseased brains, demonstrating the reliability of their in vitro model. Through this they were able to employ targeted interventions and restore neuronal survival in a variant-specific manner.
This study used Qkine BDNF (Qk050) and GDNF (Qk051) at 20 ng/ml in the differentiation of hiPSCs into cortical spheres.
