Life Science Paradigm Challenge

Brain cells don't just passively die in Alzheimer's; they 'bulk up' their communication machinery to actively resist toxic proteins.

April 1, 2026

Original Paper

Cholinergic synaptic plasticity shapes resilience and vulnerability to tau

Onuska, K. M.; Shanks, H. R.; Devito, L. A.; Qi, Q.; Crooks, A. M.; German-Castelan, L.; Ngo, G. N.; Haast, R. A.; Andrews, T. S.; Williams, K. M.; Beraldo, F. H.; Qiu, T.; Fajardo-Valdez, A.; Remz, J.; Wearn, A.; Turner, G. R.; Aumont, E.; Thiessen, J. D.; Fox, M. S.; Hicks, J. W.; Bussey, T. J.; Saksida, L. M.; Tremblay-Mercier, J.; Breitner, J. C.; Soucy, J.-P.; Poirier, J.; Bedard, M.-A.; Villeneuve, S.; Prado, V. F.; Prado, M. A.; Spreng, R. N.; Schmitz, T. W.; for the PREVENT-AD Research Group,

bioRxiv · 2025.05.27.656174

The Takeaway

Using multi-tracer brain imaging, researchers found that cholinergic neurons increase their protein levels when they come into contact with tau pathology. This presynaptic response is a form of active 'cognitive resilience' that explains why some people stay sharp longer despite having the hallmarks of the disease.

From the abstract

Synaptic dysfunction is a hallmark of Alzheimer's disease (AD). Yet due to their plasticity, synapses may also adapt to early AD pathology. Here, we demonstrate that cholinergic neurons mount a presynaptic response to tau pathology in the living human brain. Using multi-tracer positron emission tomography in cognitively normal older adults at risk for AD, we observe that cholinergic neurons increase presynaptic vesicular acetylcholine transporter (VAChT) protein levels when colocalized to tau, b

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