“Amyloid busting drugs” – true weapons of mass destruction, or blatant puffery?

I must admit I haven’t got anything to gain from the ‘amyloid hypothesis of Alzheimer’s disease’.

I am not a paid researcher to do with dementia, nor am I paid to promote research campaigns. I do not work for any dementia charities.

In fact, you are entitled to think I am pretty useless. But I am not in fact. I care passionately about dementia research, having done my own work in discovering an innovative way to diagnose the behavioural variant of frontotemporal dementia at Cambridge between 1997-2000. In fact, a key supervisor of my Ph.D. was Prof John Hodges who won a lifetime achievement award at this year’s Alzheimer’s Association conference held in Washington. I consider Hodges a friend as well as colleague. I have been open with him about my personal and professional background. Indeed, John, still knowing all the facts, did me the honour of writing the main Foreword to my first book, “Living well with dementia: the importance of the person and the environment.”



So what is the ‘amyloid hypothesis of Alzheimer’s disease‘?  This is, in a nutshell, a build up of an abnormal protein in the brain, as plaques. This build up is like mini brillo pads clogging up the brain, causing the brain to shrink, and buggering up its overall function.

That was my best at being a paid scientific communicator.

But this hypothesis is not without its problems. One key problem is the seminal finding of Price and colleagues (2009) that up to 40% of people without dementia can reach ‘neuropathological criteria’ for Alzheimer’s disease.

And there are in fact perfectly sensible explanations why the amyloid plaques which build up are not the cause of the problems in themselves.



These are summarised well in Morris, Clark and Vissel (2014).  It might be that it is type of amyloid plaque which is important to decline; some plaques are non-toxic; amyloid plaques are not actually the cause of Alzheimer’s disease (but soluble beta amyloid might be); and so on.

The amyloid treatments, or else “anti-Aβ treatments’, may have in fact interesting reasons why the “drugs don’t work”.

Back to Morris, Clark and Vissel (2014).

“So far, anti-Aβ treatments have broadly failed to meet their primary clinical endpoints and some major phase 3 trials were halted early. None of the tested treatments have produced a discernible functional recovery, or altered the course of disease. In fact alarmingly some, specifically inhibitors of γ-secretase, lead to an increased decline in cognition.

Another prominent suggested reason for clinical failures of anti-Aβ drugs in particular are that the agents used initially were not properly validated and were flawed. A recent study has shown the monoclonal anti-Aβ antibodies, solanezumab and crenezumab, fail to target human Aβ as effectively as they target over-expressed human Aβ in mouse models. The possibility was also countenanced that only amyloid plaques, potentially functionally inert, rather than soluble Aβ oligomers were targeted in early trials. Furthermore monotherapies may not be capable of effectively reducing Aβ plaque load. A double pronged approach to reduce Aβ by both active immunisation and inhibition of β-secretase has effectively cleared plaques in mice. However, as reviewed recently, therapeutic approaches targeting plaque and approaches targeting soluble Aβ have both now been tested in humans, with equally negative outcomes.”


One idea which had become in vogue was that it was the artist known as ‘fibrillar β-amyloid (Aβ)’  which was the culprit in Alzheimer’s disease. Look at what Stonnington and colleagues reviewed in 2014.

Fibrillar β-amyloid (Aβ) imaging, most notably with [11C]-benzothiazole radiotracer Pittsburgh compound B (PiB) PET and more recently with the fluorine-18-labeled tracers such as Florbetapir, has emerged as a potential biomarker for preclinical AD. Evidence suggests that increases in fibrillar Aβ deposition precede neuronal injury, and fibrillar amyloid deposition is a potential predictor of later symptomatic cognitive decline. We now have evidence that preclinical cognitive decline correlates with an increased measure of fibrillar Aβ deposition and that this effect is independent of APOE status.



So we have a bit of a problem on our hands. International scientists, and ‘interested parties’, convening in Washington, for the Alzheimer’s Association International Conference 2015, even if battled were on the whole extremely optimistic. I am not going to call it a trade fair. It is meant to be, a rather, serious discussion of the results, as well as methodological concerns, of rather expensive experiments in the “rolls-royce” end of dementia.

It’s well known that the relationship between the media and reporting of dementia has been in the past a tricky one. Take, for example, this response from the Association of Medical Research Charities, Cancer Research UK and the Wellcome Trust to the ‘Leveson inquiry: Culture, practice and ethics of the press’, dated January 2012.

Hype and false hope: The flipside of the health scare is the overcooked breakthrough. Many newspapers (though not all of them) are apt to exaggerate interesting but preliminary advances in biomedical science, proclaiming them as groundbreaking achievements that will transform individuals’ health when in fact they are reporting nothing more than promising results from experiments on mice, or cells grown in culture. 

 Such reporting can have several negative consequences. First, it raises expectations for advances in medical science, many of which will fall by the wayside over the long journey from laboratory bench to patient bedside. This can feed a public perception that science is always promising and never delivering. 

Secondly, and more worryingly, it can often raise false hope among patients. This is particularly true and damaging where it concerns treatments for incurable diseases that are not proven, yet which are portrayed as “miracle cures”. This can lead patients to spend life savings on treatments that are most unlikely to work, or on occasion to eschew the most effective known therapies in favour of alternatives that are untested or disproved.

So we were faced with a difficult situation earlier this week with solanezumab (Lilly).



Key paragraphs from the press release this week are given thus.

Showing that an investigational treatment has slowed the progression of a degenerative brain disease like Alzheimer’s is extremely challenging. Researchers have proposed overcoming this problem with a type of study called a “delayed-start” trial. In delayed-start studies, patients are randomly assigned to start active treatment at the beginning of the study or are placed in a “delayed-start” group that receives a placebo treatment for a period of time before being given the active experimental therapy. Researchers then compare the two groups at a later, pre-defined point in time to assess their response to the treatment.


If the treatment can actually slow disease progression, both groups will benefit, but the group that started active treatment later in the study will have progressed further in the disease before they got the drug – while they were on placebo. As a result, the late starters will not be able to “catch up” to the group whose disease progression was slowed for the full duration of the study.


Treatment differences at 28 weeks in EXP-EXT between the early start and delayed start groups for cognition (ADAS-Cog14) and function (ADCS-iADL) were similar to differences at the end of the placebo-controlled period, within a pre-defined margin. In other words, the delayed starters did not “catch up.

And why 28 weeks?

The answer is actually blindingly obvious – this should be the correct length of time for the drug to have some effect, and our understanding of this is totally dependent on our knowledge of how this drug is metabolised.

Let’s assume that this figure is correct. But even this is not clear-cut.

Turn for a moment to a paper from Liu-Sefert and colleagues this year,

In a delayed-start design, the placebo-controlled period should be sufficiently long to allow a disease-modifying drug to show an effect and the delayed-start period should be long enough to observe a symptomatic effect. Most clinical studies testing potential disease-modifying treatments have used 18 months for the placebo-controlled period, as in the EXPEDITION studies. Given that the half-life of solanezumab is approximately 28 days, a duration of 28 weeks (approximately 6 months) was chosen for the delayed-start period for the primary efficacy analyses of EXPEDITION-EXT to ensure that the duration of the period was over 5 half-lives and was thus adequate for delayed-start patients to achieve pharmacokinetic equilibrium. The literature also suggests that most symptomatic drugs reach peak effect in less than 6 months. EXPEDITION-EXT is still ongoing and future analyses will demonstrate whether the effect persists beyond 28 weeks.”



Do you remember the fibrillar amyloid which might have an effect?

Well, read for a moment a description of solanezumab thus.

Solanezumab is a humanized monoclonal IgG1 antibody directed against the mid-domain of the Aβ peptide. It recognizes soluble monomeric, not fibrillar, Aβ. The therapeutic rationale is that it may exert benefit by sequestering Aβ, shifting equilibria between different species of Aβ, and removing small soluble species of Aβ that are directly toxic to synaptic function. In preclinical research, a single injection of m266, the mouse version of solanezumab, reversed memory deficits in APP-transgenic mouse models while leaving amyloid plaques in place, raising the prospect of targeting the soluble pool of Aβ.


So it doesn’t recognise fibrillar Aβ, but it can reverse memory deficits?

The take-home message there, previously reported only last year, was not good from the phase 3 clinical trial, from Doody and colleagues (Doody et al., 2014):

Two randomized, double-blind, placebo-controlled, phase 3 studies of solanezumab treatment were performed in patients with mild-to-moderate Alzheimer’s disease. … Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability.


Undergraduate students and higher are told that the fundamental problem in Alzheimer’s disease is in the hippocampus, or at least the parahippocampal areas, as this is the heart of learning and memory systems. And yet in the original study the following observation was made (Doody et al., 2014):

However, the current studies failed to show treatment effects on hippocampal or total brain volumes or on amyloid accumulation with the use of 18 F-florbetapir–PET. These results are consistent with the observation that solanezumab does not target fibrillar amyloid. Our PET findings were not conclusive because of the small sample, but sufficient numbers of solanezumab-treated and untreated patients underwent serial MRI to make the failure to detect a slowing of brain atrophy a meaningful finding.

The inclusion criteria for the actual trial though is interesting (Doody et al., 2014), and this presumably are the inclusion criteria for the follow up presented at #AAIC2015 this week.

Both trials involved otherwise healthy patients 55 years of age or older who had mild-to-moderate Alzheimer’s disease without depression. Mild-to-moderate Alzheimer’s disease was documented on the basis of a score of 16 to 26 on the Mini–Mental State Examination (MMSE; score range, 0 to 30, with higher scores indicating better cognitive function)  and the criteria of the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association.”

and depression was excluded.

How many clinical raters? If there were more than 1, did they show good agreement? How accurate is a combined score of the MMSE and NINCDS-ADRDA criteria in producing a definitive diagnosis of Alzheimer’s disease? There will be some – and we don’t know how many – who will not have a diagnosis of Alzheimer’s at all in the Alzheimer’s disease randomised patients group.

Vellas and colleagues (2013) had previously warned about a biomarker problem in looking at the methodological issues of solanezumab in doing a ‘lessons learned’ type of report:

Solanezumab, another humanized monoclonal antibody, targets an epitope in the middle of the Ab peptide. The predominant message emerging from results of the two phase 3 trials (EXPEDITION 1 and 2) is that targeting amyloid appears to have a positive effect on cognition in mild AD, although there were no biomarker changes that indicated a treatment effect.”


As it happens, if the Strictly judges make or break Strictly contestants, it is a concern that investors were not that impressed with the AAIC2015 outcomes. An underwhelming performance of solanezumab was described here this week. Apparently, Lilly shares fell 3.3 percent in early trading.

All of this smacks somewhat of puffery.

I asked somebody who has quite a strong family history of dementia, and a Daily Express reader, what she thought of a possible research development in a cure. She answered straight away, “I think it’s brilliant. Who wouldn’t want a cure for dementia?”

And I have a lot of sympathy with this view. But in law, puffery is a promotional statement which presents subjective rather than objective views. The defense of the media, even reputable broadcasters, that in the relative absence of ‘good news’ about dementia, ignoring completely the vast field of living better with dementia that I and many work in, there is a need to grasp onto any titbits of good news.

But hyperbole is ‘exempt’ from the normal standards of relying on a statement to make a decision.

This is established in English law in a seminal case (albeit only from the Court of Appeal), but the same principles currently apply in other jurisdictions, in the late 19th Century (Carlill v Carbolic Smoke Ball Company 1892).

The United States Federal Trade Commission (FTC) defined puffery as a “term frequently used to denote the exaggerations reasonably to be expected of a seller as to the degree of quality of his product, the truth or falsity of which cannot be precisely determined.”

A “puff piece” is an idiom for “a journalistic form of puffery: an article or story of exaggerating praise that often ignores or downplays opposing viewpoints or evidence to the contrary“.

But there are 47 million people in the world who are relying on news of developments in Alzheimer’s disease and the 100 or so other types of dementia. Some of the Alzheimer’s disease research community have now successfully dug themselves into a hole.


I would strongly urge them to stop digging.




Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R; Alzheimer’s Disease Cooperative Study Steering Committee; Solanezumab Study Group.Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014 Jan 23;370(4):311-21.

Liu-Seifert H, Andersen SW, Lipkovich I, Holdridge KC, Siemers E (2015) A Novel Approach to Delayed-Start Analyses for Demonstrating Disease- Modifying Effects in Alzheimer’s Disease. PLoS ONE 10(3): e0119632. doi:10.1371/journal.pone.0119632

Morris GP, Clark IA, Vissel B. Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease.  Acta Neuropathol Commun. 2014 Sep 18;2:135. doi: 10.1186/s40478-014-0135-5.

Price JL, McKeel DW Jr, Buckles VD, Roe CM, Xiong C, Grundman M, Hansen LA, Petersen RC, Parisi JE, Dickson DW, Smith CD, Davis DG, Schmitt FA, Markesbery WR, Kaye J, Kurlan R, Hulette C, Kurland BF, Higdon R, Kukull W, Morris JC (2009) Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging 30:1026–1036.

Stonnington CM, Chen K, Lee W, Locke DE, Dueck AC, Liu X, Roontiva A, Fleisher AS, Caselli RJ, Reiman EM. Fibrillar amyloid correlates of preclinical cognitive decline. Alzheimers Dement. 2014 Jan;10(1):e1-8. doi: 10.1016/j.jalz.2013.01.009. Epub 2013 Apr 11.

Vellas B, Carrillo MC, Sampaio C, Brashear HR, Siemers E, Hampel H, Schneider LS, Weiner M, Doody R, Khachaturian Z, Cedarbaum J, Grundman M, Broich K, Giacobini E, Dubois B, Sperling R, Wilcock GK, Fox N, Scheltens P, Touchon J, Hendrix S, Andrieu S, Aisen P; EU/US/CTAD Task Force Members. Designing drug trials for Alzheimer’s disease: what we have learned from the release of the phase III antibody trials: a report from the EU/US/CTAD Task Force. Alzheimers Dement. 2013 Jul;9(4):438-44. doi: 10.1016/j.jalz.2013.03.007.




Puffery discussion acknowledgement to Peter Watt.

A personal thank you to Prof John Hodges from me – and congratulations for his #AAIC2015 lifetime achievement award

I am delighted that Prof John Hodges has been honoured in this year’s #AAIC2015.

John took a major rôle in guiding me over my own Ph.D. thesis at the University of Cambridge on the M.B./Ph.D. programme under Prof Tim Cox.

He is an unique individual in every sense.

John is a very generous man with his kindness and attention. He also has a keen interest in jazz music.

I remember chatting for a long time with John on a rather bumpy boat trip for the World Federation of Neurology in 2010 in Turkey on the Bosphorus. The event was hosted by Prof Facundo Manes, another student who trained under John, now head of department in the Institute of Cognitive Neurology in Argentina.

I went to see Prof Oliver Piquet, this year, in Sydney; who equally knows John well.

His contribution to the clinical work and academic research of frontotemporal dementia has been second to none in the world. He is extremely well respected by other specialists in this field. He, in fact, helped to train many of them.

As a personal friend, too, he has never been judgmental, and has never been equivocal in his support of me. In fact, he has been an instrumental part in me being a medical doctor in the UK jurisdiction.

I am honoured that I have been often quoted in his own academic papers. I am indeed quoted in the Foreword to the hugely popular ‘Cognitive assessment for clinicians‘. He in fact quotes my Brain paper in the chapter on dementia in the current Oxford Textbook of Medicine. Both books are published by the Oxford University Press.

The #AAIC2015 statement reads as follows:

John Hodges, M.D., Professor of Cognitive Neurology at the University of New South Wales, Australia. Dr. Hodges has been a longtime researcher of cognition in the context of neurodegenerative disorders. He has authored more than 450 journal articles and five books relating to cognition and dementia. His current research focuses on frontotemporal dementia.

John’s NeuRA page is here.


John’s Foreword to my first book on dementia is as follows.

Hodges foreword


My second book on dementia is being published tomorrow, “Living better with dementia: good practice and innovation for the future“.

Finally, I admire John’s interest in jazz.

On advising me about an outlook of life, he once told me, “Just remember Shibley,  if he you get hit by a bus, there’ll always be someone to take your place professionally.” Of course John meant this nicely – I think John meant that the vast majority of us aren’t as disposable as we would like to think.

I have never forgotten these words. Indeed, my life’s philosophy is actively guided by them.

World research into dementia, whether cure or care, must be legal and ethical

The eyes of the world, particularly those involved in research into the dementias like me, are currently fixed on Washington DC for the duration of #AAIC2015. This is the Alzheimer’s Association conference.


I suspect one of the big themes to emerge from this important conference will be to discuss innovative ways to get people involved in research in the first place. I think many of us have to work much harder on the message that people not living with dementia are essential for understanding dementia too.

In the old days, and I guess so now (provided ‘allowed for’ by local research ethics committees), people might be financially rewarded for their involvement in research.

With 850,000 people currently living with dementia in the UK, research into dementia is very likely to touch someone that someone knows at the very least.

But I’m sure we can rev up participation in research to an altogether different level. Instead of financial rewards, there is much intrinsic reward to be gained from taking part in research. The ‘points and levels’ are likely to trigger the ‘feel good factors’ of the brain, in the same way that primary rewards such as food are, I feel. I dare say there are neurology papers being peer-reviewed as we speak on the chemical dopamine release in the midbrain of successful participants in gasification.

Of course, I was delighted to see in a tweet Marc Wortmann leading a workshop; but equally importantly, perhaps, the air con appears to be functioning properly (in a subsequent tweet).

But smashing all records was the later news from Marc.

cure and care

Don’t get me wrong. We have our own ‘internal difficulties’ in English policy: for example, the care costs cap delayed until 2020.

But the facts do speak for themselves. There are around 47 million people around the world living with dementia. It’s essential we have leaders from this community speaking up for what is needed from dementia research and service provision. Speaking personally, I am not at all impressed at their representation this year in the published timetable of #AAIC2015.

It is, however, important to be cheerful. Our friend and colleague, Hilary Doxford, has a seat at the table of the World Dementia Council, where Hilary’s views are definitely actively sought and acted upon. There’s no escaping that it is daunting task and ask for Hilary to represent 47 million of the world’s population.

Kate Swaffer, Co-Chair of the Dementia Alliance International or ‘DAI’, has been instrumental in changing atitudes around the world about dementia. Kate, herself living with a dementia, and also with a personal background of immense value, has been a relentless advocate, and some will rightly say, ‘crusader’ for the rights of people with dementia.

That is, because, we do in fact agree, surprising though that seems. Even in a brave new world where research has been able to provide a way of stabilising the main dementias in futures, there needs to be some sort of strategy, pharmacological or otherwise, to provide an environment to encourage the re-growth of appropriate nerve connections.

The idea that we might be able to identify those people who are at risk of developing dementia, say from their genetic profile, is not in fact an objectionable one. We have to be though realistic about the substantial contribution of the non-modifiable risk factors to the main dementias, particularly dementia of the Alzheimer type.

I don’t deny also there’s a rôle for elaborate Big Data analysis, but more doesn’t necessarily equal better. I was very pleased to see Martin Rossor, somebody I used for work briefly for more than a decade ago (and who was exceptional) and a Professor at UCL, present a ‘big picture’ look at Big Data.

I think Prof Rossor is indeed right when he says ‘Culture eats logic for breakfast’ even though it does sound like a punchy soundbite especially for Twitter – but like any innovation, the success is in the adoption and diffusion. And that is indeed where the ecosystem ‘kicks in’.



The UK clearly lags behind the US in research monies – but most of us here in the UK feels that UK research into dementias punches far above its weight, due to effective leadership and management of funds in part.

But if we are to aim for parity of esteem in service provision, where mental health is not seen as inferior to physical health, we should not see dementia as a second class citizen in research priorities either. Research in dementia lags far behind cancer in pure budgetary terms globally. Also it is convenient that dementia gets seen as a ‘social care issue’ rather than a medical issue for many, denying many citizens of monies which they need.

And let’s do have a frank discussion about diagnosis. I have a feeling we have an agenda here that many people at #AAIC2015 will not openly admit to. GPs in England are not given the resources including training often to make a diagnosis of Alzheimer’s disease confidently, arguably. It might be argued that GPs, who are incredibly hardworking and trained to a sophisticated level, do not feel as confident in diagnosing certain dementias, say primary progressive aphasia or diffuse lewy Body disease, as might be with appropriate backup.

I think it might be possible to have a ‘test’ for pre symptomatic Alzheimer’s disease. But let us be clear about this – how are we going to roll out lumbar punctures for millions of people? Lumbar punctures, if not clinically contraindicated, are invasive tests.

How are we going to get round the false positives or false negatives?

And let us talk about the therapy for the dementias for a moment? I assume we will see from #AAIC2015 some discussion of risk mitigation, not simply for Chinese information firewalls in the flow of Big Data globally. Researchers, and the public demand too, a mature debate about the adverse effects of medications in trial at the moment; and also we need to have those presentations on the ability of those potential orphan drugs in crossing the blood brain barrier.

Orphan drugs for dementia have existed before.

One example is the a copper-binding chemical penicillamine for Wilson’s disease. I myself have spoken to the ‘doctorpreneur’ about this leap forward, Dr Walshe, at the Royal College of Physicians London in its building in St Andrew’s Place.

It won’t have escaped national governments that, even if they succeed in developing new orphan drugs for dementia, it can’t then get ‘blocked’ – in the UK, the NICE regulator could deem it cost ineffective.

“Living better” with dementia, I feel, is a reality, if we also invest in research here. This is not to undermine the brilliant work being done in “early detection”. We need to know about what conservative treatments in incontinence work, why music can seemingly unlock emotions in some people living with dementia, or why some people living with dementia experience a sudden emergence of new artistic talent?

All this research is essential, whether cure or care, or living better, for enhancing people’s quality of life, people living with dementia, as well as those closest to them. There’s no definitive right answer about the type of research which could or should be done.

But the research has to be ethical – it should respect autonomy, a wish to do good (beneficence), a wish not to do harm (non-maleficence), and justice (put in one way only, greatest good for the greatest number of people).

Quite often, I think we get obstructed about a fixation problem into the legality of research, important though that is from the harmonisation of research guidelines. These guidelines are critical, and followed Nuremberg.

The research has to be legal – but public policy demands are important too, as well as data protection, confidentiality and disclosure legalities across jurisdictions.

World research into dementia, whether cure or care, must be legal and ethical. I am proud of the UK’s involvement in world research in dementia.

We do need more money. I would say that wouldn’t I.