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  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  and as larger aggregates  in synaptic plasticity and this physiological feature has been interpreted as a measure for Aβ neurotoxicity . 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). 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 . 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.
An ancient Indian subcontinent parable tells a story in which a group of blind men each touch a different part of an elephant. They cannot agree on the nature of the elephant because none of them observed the elephant as a whole.
Posted by Lawrence Broxmeyer, MD on 3 November 2017
Alois Alzheimer might have mentioned plaques and tangles in a single short paper on pre-senile dementia in 1907, but it was the co-discover of Alzheimer’s disease (AD), Oskar Fischer, who in that same year far more extensively reported neuritic plaque in 12 cases of senile dementia, a condition which he and many others refused to differentiate from Alzheimer’s “pre-senile” dementia.
Last comment on 19 November 2017 by Lawrence Broxmeyer, MD
Posted by Amy Clements-Cortes, PhD on 25 August 2017
Music is a wonderful, non-pharmacological intervention to be considered for persons with Alzheimer’s disease (AD). In order to provide appropriate and beneficial music interventions for persons with AD, it is important to understand the range of music experiences that may offer effective complementary management of symptoms associated with AD.
Posted by Judith Miklossy, MD, PhD, DSc on 27 February 2017
The World Health Organization  has declared dementia as public health priority. Alzheimer’s disease (AD) is the most frequent cause of dementia. The challenges to governments to respond to the growing number of people with dementia are substantial. Tremendous efforts have been made in research during the last four decades highlighting important aspects of the pathogenesis of AD, but if the cause of AD is not defined, and treatments to prevent the disease are not provided, the world will face an unprecedented health-care problem by the middle of the century.
Last comment on 23 May 2017 by Lawrence Broxmeyer, MD
Posted by Jack de la Torre, MD, PhD on 10 February 2017
There is increasing concern not only in Alzheimer’s disease (AD) research, but all of modern investigations, that false findings may be the majority or even the vast majority of published research claims .
Last comment on 15 April 2017 by Markku Kurkinen, PhD
Alzheimer’s disease (AD) is the most common cause of dementia and remains incurable. Its prevalence is rising, current afflicting 5 million Americans with projections to affect millions more as the population ages .
Posted by Sergio Salmerón, MD PhD on 2 December 2016
Among patients diagnosed with Alzheimer's disease (AD), the percentage in the severe stage ranges from 28%  to 33%  to a maximum of 50% . In institutionalized patients, prevalence is higher, with an estimated 75% of patients with severe AD .
Last comment on 2 December 2016 by Maheen Adamson, PhD
Posted by Martha Clare Morris, Sc.D. on 9 September 2016
There is no doubt that nutrition is involved in brain health and the development of neurodegenerative diseases. This is an important area of research in the dementia field that has suffered from the absence of trained experts in nutrition and nutritional epidemiology.
Last comment on 30 September 2016 by Thomas B. Shea, PhD
Posted by Ruth Itzhaki, MSc PhD MA on 19 August 2016
Most of us harbour in our body several types of herpes virus—perhaps as many as five—and we provide them with a safe and secluded haven for life, as there are no methods for eliminating or expelling them.
Last comment on 19 August 2016 by Brian Balin, PhD
Posted by Giulio Pasinetti, MD, PhD on 5 August 2016
The ability to maintain normal psychological and physical functioning and avoid serious mental illness when exposed to stress and trauma, a phenomenon known as resilience, is a topic that has been investigated over the past several years with increasing attention [1,2].
Last comment on 5 August 2016 by Heather Snyder, Ph.D.
Posted by Pierre Krolak-Salmon, MD PhD on 29 April 2016
As disease-modifying drugs are crucially missing from the pipeline of treatments available for people with Alzheimer’s disease (AD) or related disorders, physicians, scientists, and public health experts are promoting the concept of early diagnosis.
Last comment on 29 April 2016 by Philip Scheltens, Prof.dr
Alzheimer’s disease (AD) transgenic mice have been used as a standard model for AD drug discovery and basic mechanistic studies. These mouse models overexpress amyloid β precursor protein (APP) or APP/presenilin (PS) with single or multiple familial AD (FAD) mutations, which lead to excess accumulation of amyloid β (Aβ), a well-known driver for AD pathogenesis.
Last comment on 8 April 2016 by Christopher Navara
The microtubule-associated protein tau is mainly expressed within neurons where it performs its physiological function of microtubule stability. However, extracellular tau is found in models of tau overexpression in which neuronal degeneration and cell death is prominent.
Last comment on 8 January 2016 by Alejandra Alonso, PhD
Posted by Jack de la Torre, MD, PhD on 30 October 2015
The field of Alzheimer research has reached an impasse after more than 100,000 clinical and scientific papers published in the last 40 years, because there is yet no hope, no effective treatment, and no knowledge of what causes this dementia.
Last comment on 24 November 2015 by Gustavo Román, MD, DrHC
For most people, older adulthood is associated with some decline in memory and in some aspects of cognitive function. These are age-related changes  that are widely expected, understood, and accepted by the general public.
Last comment on 16 October 2015 by Amy Jenkins, MSc MSc PhD
Posted by Allyson Rosen, PhD, ABPP-CN on 13 August 2015
Over the past few years there has been tremendous progress in diagnosis and therapeutic trials on Alzheimer’s disease (AD) and related dementias. Overall, the cost/benefit relationship is shifting with success.
Last comment on 21 October 2016 by Allyson Rosen, PhD, ABPP-CN
Depression in Alzheimer’s disease (AD) has a substantial impact on disability, disease progression, and caregiver burden. Furthermore, depressive symptoms in normal aging, as well as in mild cognitive impairment (MCI), are associated with cognitive and functional decline.
Two hundred issues and nearly twenty years have positioned JAD at the center of printed and electronic peer-reviewed publications in Alzheimer's disease, as a venue that reflects the breadth of research in the field worldwide.
Last comment on 28 March 2017 by Lawrence Broxmeyer, MD