Role of Amyloid-β and Tau Proteins in Alzheimer's Disease: Confuting the Amyloid Cascade

The "Amyloid Cascade Hypothesis" has dominated the Alzheimer's disease (AD) field in the last 25 years. It posits that the increase of amyloid-beta (A beta) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing A beta levels have so far failed, and tau-based clinical trials have not yet produced positive findings. This begs the question of whether the hypothesis is correct. Here we have examined literature on the role of A beta and tau in synaptic dysfunction, memory loss, and seeding and spreading of AD, highlighting important parallelisms between the two proteins in all of these phenomena. We discuss novel findings showing binding of both A beta and tau oligomers to amyloid-beta protein precursor (A beta PP), and the requirement for the presence of this protein for both A beta and tau to enter neurons and induce abnormal synaptic function and memory. Most importantly, we propose a novel view of AD pathogenesis in which extracellular oligomers of A beta and tau act in parallel and upstream of A beta PP. Such a view will call for a reconsideration of therapeutic approaches directed against A beta and tau, paving the way to an increased interest toward A beta PP, both for understanding the pathogenesis of the disease and elaborating new therapeutic strategies.