Neurons derived from individual early Alzheimer’s disease patients reflect clinical vulnerability

Modelling sporadic Alzheimer’s disease (sAD) with patient-derived induced pluripotent stem cells (iPSCs) is challenging yet remains an important step in understanding the disease. Here we report a novel approach of sAD modelling with patient iPSC-derived neurons by integrating cellular and clinical phenotypes from individual early symptomatic sAD patients. We establish a correlation between cellular vulnerability to extrinsic amyloid-β in vitro measured by synapse loss with clinical vulnerability to amyloid-β burden in vivo measured by cognitive decline and brain activity levels. Our findings indicate that patient iPSC-derived neurons not only preserve some pathological phenotypes of disease measured in the people they were derived from, but also preserve, from people to cells, the impact of those pathological phenotypes on function. Cellular models that reflect an individual’s in-life clinical vulnerability thus represent a tractable method of sAD modelling using clinical data in combination with cellular phenotypes.