Alzheimer’s Disease Tau Consortium: Toxic Consequences of Early Tau Seeding

This project aims to understand the very earliest steps of tau dysfunction in Alzheimer’s disease, before visible tangles form, to identify which forms of tau are most harmful to neurons. While tau tangles are a defining feature of Alzheimer’s, recent work from Drs. Hyman and Bennett shows that many neurons begin to fail and die before tangles appear. This suggests that early, misfolded forms of tau may be the true drivers of neuronal dysfunction and disease progression.

To address this, the team is pursuing two complementary aims. First, they are using advanced imaging techniques to watch, in living mice, how tau seeds taken from human Alzheimer’s brain tissue enter neurons and trigger the earliest misfolding events. These tools allow the same neurons to be followed over time, revealing how tau pathology begins and evolves. Second, they are testing whether these early tau aggregates directly disrupt neuronal function by introducing tau seeds and monitoring how neuronal activity changes, making it possible to separate the effects of early misfolded tau from those of later tangle formation.

By the end of the first year, the team made strong progress despite temporary disruptions to animal studies. They successfully purified and validated tau seeds from human Alzheimer’s brains and developed new viral tools that allow tau misfolding to be visualized in the living brain. These tools have been tested and are now being used to track early tau aggregation. During the pause in animal work, the team advanced parallel studies using human 3D neuron cultures, launched collaborations using human iPSC-derived models, and created new systems to simultaneously measure tau aggregation and neuronal activity. They also prepared brain and vascular samples for detailed protein analyses and shared key reagents with CureAlz collaborators.

In the coming year, the team will resume in vivo imaging, complete longitudinal analyses, and directly test how early tau aggregates affect neuronal function. Together, this work will clarify which forms of tau are most toxic and help guide strategies aimed at preventing neuronal damage at the earliest stages of Alzheimer’s disease.