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-β (Aβ). However, the causal link between Aβ 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 Aβ 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 Aβ 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 Aβ-centric approach, without excluding a role for Aβ, is required to come to an accurate understanding of AD dementia and, ultimately, an effective treatment.