"Cognition in a Dish" to Develop New Alzheimer’s Therapies

To recapitulate neuronal network dysfunction in Alzheimer’s disease, which can be used for novel drug screening and validation.

No current treatment for Alzheimer’s disease can stop or reverse the progression of cognitive decline and dementia. We have built a model of Alzheimer’s disease in human brain organoids that shows all classical disease hallmarks, including amyloid plaques, tau tangles, and neuronal death. Now, we will use this model to study the decline of neuronal network coordination as a stand-in for cognition during the progression of Alzheimer’s, attempt to block neuronal network degradation by improving cellular energy metabolism, and explore when anti-amyloid therapies might be most beneficial.

This is the first model to show how Alzheimer’s amyloid peptide (Aß42) drives the main features of Alzheimer’s disease, including Amyloid deposition, Tau tangle pathology, and Neurodegeneration. To avoid the confounding effects of APP overexpression, we contrast toxic Aß42 with benign Aß40. Many models also use continuous Aß generation, which can interfere with neuronal differentiation and mask phenotypes. Our model begins generating Aß only after the brain organoids are fully formed. As such, the model better represents how AD begins in patients, and it is uniquely suited to study previously inaccessible, human-specific aspects of the disease.

Since cognitive decline is the most impactful symptom of AD, our model will enable direct studies of how amyloid and tau accumulation contribute to neural circuit dysfunction in a longitudinal manner. We expect these new, exciting human models to accelerate developing novel Alzheimer’s disease drugs that can reverse cognitive decline in Alzheimer’s disease patients. We will also test drugs to restore mitochondrial health for the first time in a functional human model.