On the origin of Alzheimer's disease. Trials and tribulations of the amyloid hypothesis

The amyloid cascade hypothesis, which implicates the amyloid A beta peptide as the pathological initiator of both familial and sporadic, late onset Alzheimer's disease (AD), continues to guide the majority of research. We believe that current evidence does not support the amyloid cascade hypothesis for late onset AD. Instead, we propose that A beta is a key regulator of brain homeostasis. During AD, while A beta accumulation may occur in the long term in parallel with disease progression, it does not contribute to primary pathogenesis. This view predicts that amyloid-centric therapies will continue to fail, and that progress in developing successful alternative therapies for AD will be slow until closer attention is paid to understanding the physiological function of A beta and its precursor protein. (C) 2013 Elsevier B.V. All rights reserved.