Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer's disease

The dominant hypothesis of Alzheimer's disease (AD) aetiology, the neuropathological guidelines for diagnosing AD and the majority of high-profile therapeutic efforts, in both research and in clinical practice, have been built around one possible causal factor, amyloid-beta (A beta). However, the causal link between A beta and AD remains unproven. Here, in the context of a detailed assessment of historical and contemporary studies,we raise critical questions regarding the role of A beta in the definition, diagnosis and aetiology of AD. We illustrate that a holistic view of the available data does not support an unequivocal conclusion that A beta has a central or unique role in AD. Instead, the data suggest alternative views of AD aetiology are potentially valid, at this time. We propose that an unbiased way forward for the field, beyond the current A beta-centric approach, without excluding a role for A beta, is required to come to an accurate understanding of AD dementia and, ultimately, an effective treatment.