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.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1918-8) contains supplementary material, which is available to authorized users.

C99 selectively accumulates in vulnerable neurons in Alzheimer's disease

“…Accumulation of Aβ is a cardinal feature of AD, but its role in causing injury in AD remains unclear. Thus, the distribution of Aβ deposits in AD brains has a poor correlation with dementia severity, loss of neural function, and cognitive impairment . Therefore, it is possible that APP metabolites other than Aβ make a significant contribution to AD pathophysiology.…”

Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity

“…The need to understand in better detail the PK/PD properties of lead candidates may be a key aspect of this disconnect (Morgan et al., ; McGonigle & Ruggeri, ; Kleiman & Ehlers, ). Other issues reflect the potential for compound tolerance (Bespalov et al., ) and the actual relevance of the animal model to the human disease which, in AD, currently relates to the amyloid hypothesis (Morris et al., ; Mullane & Williams, , ).…”

“…As a result, considerable resources have been expended over the past forty years in searching for therapeutics to treat AD, all of which have failed—sometimes repeatedly—in late‐stage clinical trials (Khachaturian, ; Martin, ; Morris, Clark, & Vissel, ; Mullane & Williams, ; Panza et al., ). Among the reasons for these failures are: (i)The politicization of AD, which has tended to confuse the guidelines for the diagnosis and treatment of a disease that is increasingly viewed as multifactorial and non‐linear in both causality and progression (De Strooper & Karran, ; Medina, Khachaturian, Rossor, Avila, & Cedazo‐Minguez, ).…”

“…While EOAD “exhibits all of the behavioral and pathological hallmarks of sporadic AD” (Barrett & McGonigle, ), preclinical models based on the genetics of EOAD do not fully recapitulate the full spectrum of human LOAD in terms of genetics (Newman et al., ) or in terms of the onset, progression and duration, of the LOAD disease phenotype which is often non‐physiological (Drummond & Wisniewski, ; Puzzo, Lee, Palmeri, Calabrese, & Arancio, ; Sabbagh, Kinney, & Cummings, ; Webster et al., ). Some transgenic models can present a very aggressive disease phenotype compared to the human form of the disease (Mazi et al., ; Sasaguri et al., ), the possible result of post‐translational modifications of Aβ in the transgenic models being different from those in the human (Morris et al., ), while others fail to demonstrate aspects of neuronal loss and dysfunction, including synaptic and axonal function (Drummond & Wisniewski, ; Onos, Sukoff Rizzo, Howell, & Sasner, ). As in the case of many other transgenic models, this can lead to both false positives and false negatives, in the present instance putative amyloid clearing therapeutics that are either more effective in the models than they are in the clinic (Drummond & Wisniewski, ) or inactive, in which instance clinical data is unlikely to be generated.…”

“…As a result, considerable resources have been expended over the past forty years in searching for therapeutics to treat AD, all of which have failed-sometimes repeatedly-in late-stage clinical trials (Khachaturian, 2018;Martin, 2018;Morris, Clark, & Vissel, 2018;Mullane & Williams, 2018a;Panza et al, 2019). Among the reasons for these failures are:…”