Axons, Synapses, and Myelin: Where Does Alzheimer's Strike First?

This project uses cutting-edge human stem cell technology to build a miniaturized brain model that captures how Alzheimer’s genetic risk factors damage brain connectivity, through axons, synapses, and myelin, and to identify shared mechanisms that could lead to new treatments.

Alzheimer’s disease begins years before symptoms appear, with one of the first signs being a breakdown of the fibers that carry signals between neurons, but we still do not know if this damage occurs first in axons, synapses, or myelin, which together control the brain’s communication system. To determine this, we will grow human brain cells in a new platform that recreates how these structures connect and communicate, allowing us to watch early problems as they emerge. By studying genetic variants, we aim to reveal how Alzheimer’s disease starts and open paths for prevention and treatment.

This project is among the first to integrate human iPSC-derived neurons, glial cells, and oligodendrocytes in a single compartmentalized chip with simultaneous live readouts of axonal transport, synaptic connectivity, and myelination. By introducing Alzheimer’s genetic risk factors into specific cell types, we can ask which compartment, axon, synapse, or myelin, fails first and whether damage spreads from one to another. The molecular signatures we generate will create a direct bridge from human disease mechanism to druggable target, with a platform designed to scale across multiple neurodegenerative diseases.

This project will deliver a validated human platform that captures the earliest steps of Alzheimer’s disease in a way no existing model can. For the research field, it opens a direct path to identifying and testing new drug targets. For the public, it brings us closer to treatments that could stop neurodegeneration before symptoms appear, and a platform that could accelerate drug discovery across multiple brain diseases.