The microtubule nexus linking amyloid beta and tau: A simple and unifying theory for the underlying cause of Alzheimer's Disease

Shoff, T. A.; Derbez-Morin, M.; Cai, P.; Julian, R.

doi:10.1101/2025.09.16.676664

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bioRxiv · 10.1101/2025.09.16.676664

The microtubule nexus linking amyloid beta and tau: A simple and unifying theory for the underlying cause of Alzheimer's Disease

Shoff, T. A.·Derbez-Morin, M.·Cai, P.·Julian, R.

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Abstract

Alzheimers disease (AD) is defined by cognitive decline in conjunction with accumulation of aggregated amyloid {beta} (A{beta}) and tau, yet existing models of AD fail to provide a simple connection between A{beta} and tau. However, microtubules provide an intriguing nexus for pathological interactions between the two. Tau binds to microtubules and is critical to maintain their proper function. We demonstrate that A{beta} also binds to microtubules with affinity comparable that of tau itself. We hypothesize that displacement of tau by A{beta} leads to microtubule dysfunction and facilitates tau phosphorylation and aggregation. Importantly, in this model, aggregation of A{beta} is not the primary cause of toxicity, which allows many of the apparent contradictions between A{beta} pathology and cognition to be rationalized. This new model highlights the importance of both tau and A{beta} and enables novel therapeutic and intervention strategies to be considered.

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Shoff, T. A., Derbez-Morin, M., Cai, P., Julian, R.. 2025-09-17. The microtubule nexus linking amyloid beta and tau: A simple and unifying theory for the underlying cause of Alzheimer's Disease. https://doi.org/10.1101/2025.09.16.676664

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