Editors' Blog

What is Aβ?

The search to find therapeutic targets in Alzheimer's disease (AD) has been dominated for over 25 years by research into the roles in the initiation and progression of dementia of the amyloid beta protein (Aβ) [1, 2], derived from the β-pathway of amyloid beta protein (AβPP) cleavage.

Last comment on 7 March 2018 by Sally Hunter

I thank Peter Whitehouse and Danny George sincerely for their very generous comment. The wider issues they raise are important and reflect the diversity of perspectives in Alzheimer’s disease (AD) research. Each of the questions they ask could fill many pages with discussion. However, my intention here is to examine a very narrow part of one narrow approach to AD research. Even though the amyloid beta protein (Aβ) has been a focus of intense research for over two decades, the concept of what Aβ is lacks clarity both in theory and in laboratory practice – hence the title of the blog.

As Whitehouse and George suggest, if space had allowed I would indeed have included considerations relating to the physiology of Aβ and further expanded this to include the wider APP proteolytic system – I could have asked the question “What is Aβ and what is it doing?” However, understanding of the physiology of Aβ depends to some extent on what we understand Aβ to be. As others have asked before, is it a neurotoxic culprit, neuroprotective [1] or is it a perfectly normal part of our complex human physiology? As an example, Aβ has been associated previously with long term depression (LTD) as oligomers [2] and as larger aggregates [3] in synaptic plasticity and this physiological feature has been interpreted as a measure for Aβ neurotoxicity [4]. However, if we view Aβ in the wider context of the APP proteolytic system as a coherent whole, there is a case that the actions of Aβ balance with the physiological actions of sAPPα – that of promoting long term potentiation (LTP)[5]. We can then see the APP system as part of the dynamic regulation of synaptic plasticity with Aβ playing an appropriate role. The evidence we currently have for the involvement of Aβ in LTP and LTD can be interpreted to support both views, so how do we tell between them? I suggest that we do not have the evidence with the depth of detail required to answer this question with certainty. Given the current state of AD research and its move towards defining AD in terms of biomedical models, there seems little interest in investigating exactly what we mean by the term Aβ as though this question has already been answered, when in fact it hasn’t.

The reduction of the complexity of (AD) to a few biomedical “markers” of disease, one of which is Aβ, raises many issues relating to the diagnosis of AD at the individual level that are challenging and as yet unresolved. Whitehouse and George quite rightly highlight the difficulties in assigning binary diagnostic cut off points to what are continua of pathological changes. Although AD-related pathologies, including tau-associated neuritic plaques and tangles and Aβ-associated plaques and deposition as cerebral amyloid angiopathy are considered as “diagnostic” in the sense that the presence of these neuropathologies confirm a clinical probabilistic diagnosis of AD, the relationships between dementia status and neuropathology seen in the older population - where most dementia occurs - are complex. The associations between dementia and pathology do not fully support the interpretation of any AD- related pathology as being qualitatively diagnostic - having a positive score for an amyloid- (or tau-) associated biomarker does not correspond to having AD-type dementia with certainty nor has prognostic value of these measures been proven [6]. Diagnostic protocols highlight ambiguities in how AD is defined and understood by different research approaches. AD can be defined in many ways, as a clinical entity, as a neuropathological entity, as a genetic entity for familial forms, as a combined clinicopathological entity and as a clinicopathological entity with biomarkers. However, no single definition is currently agreed by all researchers and not all definitions translate well between research approaches. Issues relating to AD definitions have been previously explored by Whitehouse (https://www.j-alz.com/editors-blog/posts/is-there-alzheimers-disease ).

I hope those with diverse perspectives outside the immediate biomedical models of AD based on Aβ will forgive this narrow consideration, it has to be narrow in order to re-think what we mean by Aβ and how we understand its roles within wider contexts. Our understanding of what Aβ is and what it is doing depends on flexibly integrating contributions from many research perspectives. I suggest that we in the AD research community have a collective responsibility to examine the evidence relating to Aβ accumulated so far in detail including considerations of limitations arising from straightforward issues such as anti-Aβ antibody cross reactivities and the more complex issues surrounding how the definition of AD impacts experimental design in different experimental approaches.


1.            Bishop, G.M. and S.R. Robinson, The amyloid paradox: amyloid-beta-metal complexes can be neurotoxic and neuroprotective. Brain Pathol, 2004. 14(4): p. 448-52.

2.            Wang, H.W., et al., Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res, 2002. 924(2): p. 133-40.

3.            Chiang, H.C., et al., Distinctive roles of different beta-amyloid 42 aggregates in modulation of synaptic functions. FASEB J, 2009. 23(6): p. 1969-77.

4.            Koffie, R.M., B.T. Hyman, and T.L. Spires-Jones, Alzheimer's disease: synapses gone cold. Mol Neurodegener, 2011. 6(1): p. 63.

5.            Ishida, A., et al., Secreted form of beta-amyloid precursor protein shifts the frequency dependency for induction of LTD, and enhances LTP in hippocampal slices. Neuroreport, 1997. 8(9-10): p. 2133-7.

6.            McKhann, G.M., et al., The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement, 2011. 7(3): p. 263-9.




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