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

Alzheimer’s disease (AD) is defined by cognitive decline in conjunction with accumulation of aggregated amyloid β (Aβ) and tau, yet existing models of AD fail to provide a simple connection between Aβ 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 Aβ also binds to microtubules with affinity comparable that of tau itself. We hypothesize that displacement of tau by Aβ leads to microtubule dysfunction and facilitates tau phosphorylation and aggregation. Importantly, in this model, aggregation of Aβ is not the primary cause of toxicity, which allows many of the apparent contradictions between Aβ pathology and cognition to be rationalized. This new model highlights the importance of both tau and Aβ and enables novel therapeutic and intervention strategies to be considered.