Three Dimensions of the Amyloid Hypothesis: Time Space and Wingmen

摘要

The Amyloid Hypothesis, which has been the predominant framework for research in Alzheimer’s Disease (AD) over the past two decades, has also been the source of considerable controversy within the field. The Amyloid Hypothesis postulates that amyloid-beta peptide (Aβ) is the causative agent in AD, and is strongly supported by data from rare autosomal dominant forms of AD. However, the evidence that Aβ causes age-associated sporadic AD is more complex and less clear, prompting criticism of the hypothesis. Herein, we provide an overview of the major arguments for and against the Amyloid Hypothesis, and review key data supporting or refuting these arguments. We conclude that Aβ likely is the key initiator of a complex pathogenic cascade which causes AD, thus supporting the Amyloid Hypothesis in general. However, we argue that Aβ acts primarily as a trigger of other downstream processes, in particular tau aggregation, which mediate neurodegeneration. Thus, Aβ appears to be necessary but not sufficient to causes AD, and its major pathogenic effects may occur very early in the disease process. We discuss implications for therapeutic development and future research.