The amyloid hypothesis has been leading in the field of Alzheimer's disease (AD) research since its formulation. Due to the failure of many clinical trials targeting amyloid beta (Aβ), the causative factor proposed by the amyloid hypothesis, criticism of this hypothesis is increasing and arguments against it are consequently emerging. These arguments include the aforementioned failure of clinical trials, high amounts of Aβ plaques found in healthy individuals, the strong association of age with AD, inconsistencies in the timeline of the amyloid hypothesis, and significant differences between sporadic and familial AD. This review proposes a preclinical period for AD, in which Aβ deposition has already started but symptoms are quiescent. The symptoms would then appear when a threshold level of Aβ is reached. This review also supports the hypothesis that Aβ is induced by stressors, and is thus not the only causative agent underlying AD pathology. A (re)evaluation of the amyloid hypothesis in the light of other theories is necessary in order to determine to what extent the hypothesis can remain viable by itself, and may pave the way for a more complete understanding of AD pathology and a subsequent relief of the burden of the disease on patients and society.
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