Publication
Neurons from individual early Alzheimer’s disease patients reflect their clinical vulnerability
Publisher:
Cold Spring Harbor Laboratory
Date:
11-11-2021
DOI:
10.1101/2021.11.09.467891
Abstract: Establishing preclinical models of Alzheimer’s disease that predict clinical outcomes remains a critically important, yet to date not fully realised, goal. Models derived from human cells offer considerable advantages over non-human models, including the potential to reflect some of the inter-in idual differences that are apparent in patients. Here we report an approach using induced pluripotent stem cell-derived cortical neurons from people with early symptomatic Alzheimer’s disease where we sought a match between in idual disease characteristics in cells with analogous characteristics in the people from whom they were derived. We show that the response to amyloid-β burden in life, as measured by cognitive decline and brain activity levels, varies between in iduals and this vulnerability rating correlates with the in idual cellular vulnerability to extrinsic amyloid-β in vitro as measured by synapse loss and function. Our findings indicate that patient induced pluripotent stem cell-derived cortical neurons not only present key aspects of Alzheimer’s disease pathology, but also reflect key aspects of the clinical phenotypes of the same patients. Cellular models that reflect an in idual’s in-life clinical vulnerability thus represent a tractable method of Alzheimer’s disease modelling using clinical data in combination with cellular phenotypes.