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

SUBMITTER: Morris GP

PROVIDER: S-EPMC6208728 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Morris Gary P GP Clark Ian A IA Vissel Bryce B

Acta neuropathologica 20181022 5

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, dia ...[more]

PMID: 30349969

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Project description:Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson's and Alzheimer's. Over the past 15 years, there has been a paradigm shift in understanding the structural basis for these proteinopathies. Precedent for this shift has come from investigation of soluble A? oligomers (A?Os), toxins now widely regarded as instigating neuron damage leading to Alzheimer's dementia. Toxic A?Os accumulate in AD brain and constitute long-lived alternatives to the disease-defining A? fibrils deposited in amyloid plaques. Key experiments using fibril-free A?O solutions demonstrated that while A? is essential for memory loss, the fibrillar A? in amyloid deposits is not the agent. The AD-like cellular pathologies induced by A?Os suggest their impact provides a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Alternative ideas for triggering mechanisms are being actively investigated. Some research favors insertion of A?Os into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. A?O binding triggers a redistribution of critical synaptic proteins and induces hyperactivity in metabotropic and ionotropic glutamate receptors. This leads to Ca(2+) overload and instigates major facets of AD neuropathology, including tau hyperphosphorylation, insulin resistance, oxidative stress, and synapse loss. Because different species of A?Os have been identified, a remaining question is which oligomer is the major pathogenic culprit. The possibility has been raised that more than one species plays a role. Despite some key unknowns, the clinical relevance of A?Os has been established, and new studies are beginning to point to co-morbidities such as diabetes and hypercholesterolemia as etiological factors. Because pathogenic A?Os appear early in the disease, they offer appealing targets for therapeutics and diagnostics. Promising therapeutic strategies include use of CNS insulin signaling enhancers to protect against the presence of toxins and elimination of the toxins through use of highly specific A?O antibodies. An AD-dependent accumulation of A?Os in CSF suggests their potential use as biomarkers and new A?O probes are opening the door to brain imaging. Overall, current evidence indicates that A? oligomers provide a substantive molecular basis for the cause, treatment and diagnosis of Alzheimer's disease.

Dataset Information

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

Publications

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

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