Solanezumab and the amyloid hypothesis for Alzheimer’s diseaseBMJ 2016; 355 doi: https://doi.org/10.1136/bmj.i6771 (Published 29 December 2016) Cite this as: BMJ 2016;355:i6771
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Prof le Couteur and colleagues provide an authoritative and persuasive comment on the failings of clinical trials for Alzheimer’s disease (1) which extends their critique of research into dementia and provision of care for people with this disability (2). They argue that we must ‘look elsewhere’ for solution to the problem of dementia. We agree, but where should we look?
It now seems that there are multiple pathological processes at work over long periods of time, interacting through feedback and feedforward loops with multiple protective factors to create (or not) the symptoms and behaviour patterns we call dementia. This way of thinking about dementia has one immediate consequence; the hope for a single cure seems unrealistic because so many paths lead towards dementia syndrome. Whilst ‘promissory medicine’ offers the hope that one last heave or one more large cheque will allow substantial clinical gains to be made, approaching dementia as a disability tasks us to reduce the gap between environmental demand and personal (or family) abilities (3). The disability model of dementia turns the fuzziness of the syndrome into an asset, by including dementia as part of a combination of impairments in cognitive, emotional (depression) and physical (frailty) functioning, all amenable to some change (4). Prevention is more valuable than treatment for most real-world situations (5), and we have no reason to think that dementia is an exception (6). Our attention should shift, therefore, towards promoting healthy ageing and increasing cognitive reserve through long term, low-level activities in everyday life (Whitehouse’s ‘echopsychosocial’ approach (3)), even though the work will not be highly profitable and is unlikely to attract a Nobel Prize.
(1) Le Couteur D, D.G, Hunter, S. Brayne C. Solanezumab and the amyloid hypothesis for Alzheimer’s disease,BMJ 2016; 355 doi: http://dx.doi.org/10.1136/bmj.i6771 (Published 29 December 2016)
(2) LeCouteur, D.G., Doust, J., Creasey, H. and Brayne, C. (2013) Political drive to screen for pre-dementia: not evidence based and ignores the harms of diagnosis, British Medical Journal, 347: f5125
(3) Whitehouse, P.J. (2014) The end of Alzheimer's disease--from biochemical pharmacology to ecopsychosociology: a personal perspective. Biochem Pharmacol.;88 (4): 677-81. doi: 10.1016/j.bcp.2013.11.017
(4) Chapko, D., Staff, RT., McNeil, C.J., Whalley, LJ., Black, C. and Murray, A.D. (2016) Late-life deficits in cognitive, physical and emotional functions, childhood intelligence and occupational profile: a life-course examination of the Aberdeen 1936 Birth Cohort (ABC1936). Age & Ageing.45(4):486-493.
(5) Rheinberger,C., Herrera-Araujob, D. and Hammittd, JK. (2016) The value of disease prevention vs treatment Journal of Health Economics, August 2016, http://www.sciencedirect.com/science/article/pii/S0167629616301527
(6) Manthorpe J & Iliffe S (2015) The Dialectics of Dementia, London, King’s College London, http://www.kcl.ac.uk/sspp/policy-institute/publications/the-dialectics-o...
Competing interests: Jill Manthorpe is a Member of the Alzheimer’s Society, a Member of its Care, services and public health research funding board, is editorial advisor Journal of Dementia Care, and is Director of Social Care Workforce Research Unit, King’s College London. She is writing in a personal capacity.. Steve Iliffe was Associate director of DeNDRoN 2006-15, and is a member of the Alzheimer’s Society and member of the editorial board of the Journal of Dementia Care. He is Chair of the Alzheimer’s Society Care, services and public health research funding board (2017) and is Emeritus Professor at University College London. He is writing in a personal capacity
This well written Editorial encourages reflection . It considers what has evolved to be our prevailing approach based on a 1907 case study on a 55 year old woman.
Arguably one of the central “messages” of this Editorial relates to reductionism. The philosopher Mary Midgley has argued that “crude reduction is always an exaggeration” . Leon Eisenberg has stated “the remedy does not lie in abandoning reductionism where it is appropriate but in incorporating it within a larger social framework.” 
The rise of “Alzheimer’s” discourse has been extraordinary in our time. I have previously argued that research criteria have too often been extrapolated prematurely into a general clinical setting and outlined how this has encouraged a cultural change where healthcare professionals talk interchangeably of pathology (“Alzheimer’s disease”) and clinical syndrome (“dementias”). It is no wonder then that the general population is increasingly using the word “Alzheimer’s” instead of “dementia.” I have suggested that this widespread confusion about pathology may have been driven by fear, marketing and misunderstanding of risk .
We have yet to disentangle the complex interactions between “normal” ageing and a range of as yet poorly understood pathological processes. This is particularly the case for the oldest generation. . Suggesting otherwise risks undermining science and scientific progress.
 Le Couteur D, Hunter S, Brayne C. Solanezumab and the amyloid hypothesis for Alzheimer’s disease. 29 Dec 2016 BMJ 2016;355:i6771
 Midgley, M. Heart and Mind, Routledge, 2003.
 Eisenberg, L. Eisenberg, L. Science in Medicine: Too Much or Too Little and Too Limited in Scope? Conference on Biopsychosocial Medicine, May 1987,
 Gordon P. Confusion is everywhere. BMJ 2013;346:f511 Published letter 30 Jan 2013
 Gordon P. “Undiagnosing” dementia. BMJ 2015;350:h290 Published 20 January 2015
Competing interests: Dr Peter J Gordon raised a petition with the Scottish Parliament to consider introducing a Sunshine Act for Scotland: http://www.parliament.scot/GettingInvolved/Petitions/sunshineact
This is unsurprising as across the neurological spectrum two underlying causes repeatedly crop up these being neuronal apoptosis and afferent pain levels. These are seen in seemingly diverse patterns as MS and ADD... Might I suggest a link? In the first 10 days of growth the face, which is arguably the most intensely innervated region, has its growth largely determined. Sub-optimal naso-maxilla growth patterns ensure both a mismatch between jaws and an impaired airway. Bonuck and Freeman showed snoring-breathholding oral breathing babes who did this at 6 months old and persisted at 4 years all went on to have significant behavioural problems. Slater talks of infant cortical pain responses. Gozal's group show 3 yo snorers have high levels of cytokines and prostaglandins - if they snore. Conversely in 1945 Price showed dietary change, mainly sugar produced facial change, as did his veterinary colleague using more processed food.
Tammy Heit in Toronto showed in a small MS group high afferent nociception [HAN] from the TM Joint was associated with loss of myelin as reduction of HAN myelin regrowth. The role of Tau and Amyloids is subject to changes in myelin more than likely and the fastest way to kill off cortical neurons is the cycle of hypoxia and recovery. When deprived of oxygen - even for short periods - there is a potent downstream series of events which can be seen in the comorbidities. Olmos's recent paper outlines these well.
To me the attribution of Amyloids as 'cause' is misleading... it's why they arrive and stay is more telling. There are good indicators for these, and perhaps the history is the predictor. Price in 1945 showed the increase in refined sugar and processed food had profound, if small changes and this has been extended. The epidemiology of AD follows suit. Goryacheva shows some rats adapt and alter NO production to Intermittent hypoxia [IH], Kihara indicates nicotinic receptor activity prevents beta amyloids - HL Chen shows White matter damage in OSA... Note Gozal's group shows this in 3 yo 'snorers'. Breathing is so important that impairment has subtle but severe consequences. How does the HAN/IH cycle alter the neuronal surface might be a profitable approach...
Personally most of the males in my family devolve to AD in due course, so this is both personal and social. Don't stop hunting.
Competing interests: No competing interests