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

Abstract

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.

Fig. 1

A chronological sequence of questions, assumptions and findings leading to the current Aβ-centric ‘consensus’ Alzheimer’s disease neuropathological diagnostic guidelines. Major observations, findings and assumptions have been distilled into the current ‘consensus’ diagnostic guidelines for AD. In brief, these guidelines are derived from the hypothesis that the relative levels of amyloid plaques and NFTs in specific brain regions differentiates AD dementia from normal cognitive aging. Combined with the amyloid hypothesis they predict Aβ and  tau pathology to be a specific marker of AD at symptomatic and possibly preclinical and prodromal stages, with Aβ considered causative of tau pathology (and other AD-associated pathologies). NFTs neurofibrillary tangles, Aβ  amyloid-β

Fig. 2

The missing pieces of the puzzle in the chronological sequence of questions, assumptions and findings that lead to the current Aβ-centric ‘consensus’ Alzheimer’s disease diagnostic guidelines. Many problems with the evidence used to support the current consensus diagnostic guidelines and the amyloid hypothesis still exist. 1. Aβ pathology does not correlate well spatially to areas undergoing atrophy. 2. Other pathologies correlate better (synapses, NFTs) but have not been as extensively studied. 3. Early-onset AD and late-onset AD might be different diseases based on evidence suggesting they can be distinguished in various ways. 4. AD may not be one single homogenous disorder. 5. Aβ pathology exists in cognitively normal individuals. 6. Aβ pathology is lacking in some with AD dementia. 7. Aβ pathology is not unique to AD dementia. 8. It is not conclusive that Aβ pathology is, temporally, the first ‘biomarker’ of AD. 9. Deleterious mutations in many genes can be linked to Aβ, but not all of them necessarily mechanistically contribute to disease through an effect on Aβ metabolism. 10. Protective environmental and genetic factors are not necessarily mechanistically protective through some effect on Aβ. 11. Much of the genetics of familial AD remains unresolved. 12. Senescence, autophagy, genetic, microbial, lifestyle choices/environmental and cardiovascular/traumatic injury risk factors are potential upstream ‘causes’ of AD, but their mechanism contribution to pathogenesis is not necessarily through Aβ. 13. Apart from genetics, most evidence supporting the amyloid hypothesis comes from preclinical research (toxicity studies, expression of human AD mutations in mice), much of which has dubious relevance to the human condition [179]. 14. Many valid alternate hypotheses of AD aetiology exist. 15. Many other possible factors independent of Aβ that could provide clues to causality exist. 16. Other methods for defining disease in preclinical, prodromal and symptomatic stages that do not require a priori stratification on the basis of Aβ measurement may exist, and remain untested. NFTs neurofibrillary tangles, Aβ amyloid-β