How a ‘cognitive footprint’ may put the heat on policy on dementia

It was some considerable interest that I read a contribution in dementia policy, co-authored by one of my previous bosses, Prof Martin Rossor. The other co-author was Prof Martin Knapp. The short piece is called “Can we model a cognitive footprint of interventions and policies to help to meet the global challenge of dementia?”, and is on the Lancet platform here.

I commend the full article to you in fact, but this paragraph will give you a good introduction to the heart of the argument proposed by the two Martins.

“In reframing and extending the debate in this way, it might be helpful to borrow a concept from another major global challenge of modern times: global warming. Can we develop a so-called cognitive footprint that, as with a carbon footprint, can be either negative (impair cognition) or positive (enhance cognition)? A cognitive footprint could then be used to assess and model potential cognitive effects of medical and public health interventions through to social and wider public policies. It could be identified across many public policy areas, including health, social care, education, criminal justice, transport, sport, employment, and doubtless others. The importance of this footprint stems from links between cognitive skills and educational attainment, employment status, earnings, performance in instrumental activities of daily living, and (at national level) to income distribution and economic growth.1 Thus a range of activities will have an effect on cognition throughout the life course that could be associated with footprints as illustrated below.”

First of all, I think we do need to reframe the discussion of dementia at both a domestic and international level. I think use of certain language in the dementia discourse can alter the dynamics of the debate. In my thesis entitled “Living better with dementia: good practice and innovation for the future”, I discuss how abuse of language has helped to advance stigma, discrimination and poor empowerment of people with dementia in one of the early chapters.

I’d like to think the general public’s fundamental knowledge of the dementias has been improved by public ‘awareness campaigns’ in a number of jurisdictions – but there’s no formal way of telling. Sir Gus O’Donnell famously claimed ‘If you treasure it, measure it’, and I think attempts to measure the health related quality of life have attempted to legitimise wellbeing as an outcome not only in clinical trials but in events of clinical commissioning.

Overall I think a ‘cognitive footprint’, if adopted as an innovation in articulating the impact of dementia, might be a very welcome one. I think the understanding of health related quality of life and wellbeing still remains very poor, despite the slogans of ‘living well with dementia’ or ‘living better with dementia’. I think it could act as a very good surrogate measure of how inclusive a society, city or country is of people living with dementia. It also embodies something which I strongly urge people to think; that there is a big non-fatalistic component of dementia. As Richard Taylor PhD, who sadly recently passed away, who had been living with both dementia and cancer, said famously at one of the Alzheimer’s Disease International conferences, “We’re all going to die of something. Having a diagnosis being told to me takes me no closer to the actual day on which I die. I want to think about how to live with dementia, rather than how I am guess how I am going to die from dementia.”

That there are well recognised environmental factors which affect cognition is very important. Infections can indeed produce cognitive impairments, and the article appropriately brings this up in the context of neurocystercosis. I as it happened saw a patient with neurocystercosis in a district general hospital who presented with unexplained epilepsy. And the article is right to identify the ‘bidirectional’ aspect of education and dementia. At one end, we have the ‘lose it or use it’ way of thinking, but at the other end we are well aware that there have been very intelligent people with dementia, for example Baroness Thatcher and Iris Murdoch. Whilst the effects of modifiable risk factors for dementia should not be overstated in policy, the idea that modifiable risk factors can be targeted in work environments or otherwise is important. I also happen to believe we need to forge together the streams of ‘dementia friendly communities’ (a very poor articulation of a worthy concept) and the social determinants of health. I’d also like the term to reflective of the diversity in dementia; for example it might be useful to identify the ‘cognitive footprints’ for young onset dementia. One of my ‘wishes’ is for there to be accurate information about the prevalence of young onset dementia (dementia before the age of 65), country by country.

The two Martins, to give them credit, do appear to be practising what they preach. For example, instead of talking purely in negative terms such as the use of words such as ‘cost’ and ‘burden’, the two Martins talk of ‘cognitive capital’. I think the value of people living with dementia, all 47 million of them, is not to be underestimated. But likewise there are ‘impacts’ of dementia at a country by country level. That is why I think we cannot only see dementia through a developed world prism; and that the Alzheimer’s Disease International are completely justified in pursuing their workstreams in looking at dementia in low and middle income countries as well. A ‘cognitive footprint’ would help not only in communicating the regional impact of dementia in terms of prevalence say, but also would be useful in communicating how successfully local policies are being implemented.

My major concern is the same as that for any metric. It can be gamed. This would be an unfortunate unintended consequence of what I think potentially is a great idea. I once went to a presentation by a corporate law firm about how city firms could help traders of ‘carbon credits’. Carbon credits were introduced in the climate change world by corporates, and some might say helpfully as a rent seeking device. A “carbon credit” is a “generic term for any tradable certificate or permit representing the right to emit one tonne of carbon dioxide or the mass of another greenhouse gas with a carbon dioxide equivalent equivalent to one tonne of carbon dioxide. It would be incredibly sad if big corporates saw the ‘cognitive footprint’ as a fast way to generate easy bucks instead of focusing on what is a delightful way of encapsulating the public health policy issues surrounding dementia?

Where does ‘rights based advocacy’ leave John’s Campaign?

John Campaign

As explained in a very recent article in the Guardian, “John’s Campaign was launched in the Observer in November 2014 after the death of Dr John Gerrard. The aim of the campaign is to give the carers of those living with dementia the right to stay with them in hospital.”

Carers do not have constitutional rights in the current NHS Constitution, although there is a recent consultation exercise which has been completed this year.

According to the British Institute for Human Rights “A pocket guide for carers”, “In a survey of carers conducted by n-compass: 45% of respondents felt that human rights are very important or important to their caring role; less than 30% felt confident that they knew what their rights were; only 15% felt confident in advocating for the rights of those they care for. Source: Carers’ human rights consultation (September 2011)” (BIHR, 2012).

The current Government is in the process of repealing the Human Rights Act (1999) in accordance to their recent electoral mandate, but most academics in law feel that it would be very difficult for the UK to wish to escape the jurisdiction of the European Convention of Human Rights. This has not only been discussed at length in the academic journals, but also finally in the mainstream newspapers.

The BIHR document lists important human rights for carers, which indeed comprise the “essential toolbox” of a rights-based approach for carers: these are the right to respect for private and family life, home and correspondence (Article 8), freedom from inhuman and degrading treatment (Article 3), the right to be free from discrimination (this is protected by both the Human Rights Act (Article 14) and Equality Act 2010), and in extreme circumstances, your right to life (Article 2).

Looking at the issue of a right for carers of those living with dementia the right to stay with them in hospital, it is essential to note that people with dementia have human rights of their own. Lady Hale in her judgment in P (by his litigation friend the Official Solicitor) (Appellant) v Cheshire West and Chester Council and another (Respondents)  and P and Q (by their litigation friend, the Official Solicitor) (Appellants) v Surrey County Council (Respondent) at [2014] UKSC 19 made it perfectly clear that these rights are indeed universal and inalienable as you would expect them to be (they are also protected by the Universal Declaration of Human Rights).

But I feel it is essential to look at the Convention itself.


You could equally argue that the law should uphold respect for a person’s private life, home and correspondence. It has been, for example, estimated that there were about 670,000 unpaid primary family carers for people living with dementia in the UK. These carers will therefore have their own perspective of ‘private and family life’.

But there are pockets of law from the European Court of Human Rights which throw light on the direction of travel of interpretation of article 8.

Take for example application no. 14462/03 by Valentina Pentiacova and Others against Moldova in 2005. The case essentially concerned the availability of haemodialysis for chronic renal failure. Their case was allowed although there was an obligation to ‘exhaust domestic remedies’ as per article 35(1).

Domestic courts can interpret the European legislation within a margin of appreciation’. However, it is striking that the judgment makes reference to the wellbeing of people with disabilities. Dementia is a disability under the guidance to the Equality Act (2010), and it has been argued that dementia is a disability under the UN Convention of Rights for People with Disabilities.

This section of the judgment points to the Judges’ concern about the law, if not being upheld  acting to the detriment of people with disabilities. One suspects that lawyers defending John’s Campaign in the European Court of Human Rights might be sensibly be advised to advise the Court on whether carers not accompanying a person with dementia acts to the detriment of the wellbeing of that person with dementia.

The section runs as follows:

“The Court has previously held that private life includes a person’s physical and psychological integrity (Niemietz v. Germany, judgment of 16 December 1992, Series A no. 251-B, § 29). While the Convention does not guarantee as such a right to free medical care, in a number of cases the Court has held that Article 8 is relevant to complaints about public funding to facilitate the mobility and quality of life of disabled applicants (see, Zehnalová and Zehnal, cited above, and Sentges v. the Netherlands (dec.) no. 27677/02, 8 July 2003). The Court is therefore prepared to assume for the purposes of this application that Article 8 is applicable to the applicants’ complaints about insufficient funding of their treatment.”

Another interesting case judgment involves the second section decision on the admissibility of application no. 27677/02 by Nikky Sentges against the Netherlands. The applicant had been diagnosed with Duchenne Muscular Dystrophy (DMD), a disease characterised by progressive muscle degeneration, loss of the ability to walk and often the loss of lung or cardiac functions.

The applicant complained that his request to be provided with a robotic arm was denied. He submitted that the right to respect for his private life, as guaranteed by Article 8 of the Convention, entailed a positive obligation for the State to provide him with, or pay for, this medical device.

But here the discussion included what the ‘positive obligations’ of the State might be, and the exact scope of Article 8.

“However, Article 8 does not apply to situations concerning interpersonal relations of such broad and indeterminate scope that there can be no conceivable link between the measures the State is urged to take and an individual’s private life (see Botta, cited above, § 35). The Court has also held that Article 8 cannot be considered applicable each time an individual’s everyday life is disrupted, but only in the exceptional cases where the State’s failure to adopt measures interferes with that individual’s right to personal development and his or her right to establish and maintain relations with other human beings and the outside world. “

Here it might be that the European Court of Human Rights views that the admission of a person with dementia into care does not constitute an exceptional disruption of private and family life, and so would therefore not apply. However, against this, there is a huge literature in the medical press on how an acute admission of a person with dementia is incredibly disruptive to the ‘caring relationship’.

A third interesting judgment is a fourth section decision as to the admissibility of the application no. 56550/00 by Antoni Mólka against Poland.

The applicant was living with a ‘severe dysfunction of the limbs and is confined to a wheelchair’.

And here the judgment is very telling.

“The Court notes that in a number of cases it has held that Article 8 is relevant to complaints about public funding to facilitate the mobility and quality of life of disabled applicants (see Marzari v. Italy (dec.), no. 36448/9, 4 May 1999; Maggiolini v. Italy, (dec.), no. 35800/97, 13 January 2000; Sentges v. the Netherlands (dec.), no. 27677/02, 8 July 2003; and Pentiacova and Others v. Moldova (dec.), no. 14462/03, ECHR 2005-…). More generally, the Court observes that the effective enjoyment of many of the Convention rights by disabled persons may require the adoption of various positive measures by the competent State authorities. In this respect, the Court refers to various texts adopted by the Council of Europe which stress the importance of full participation of people with disabilities in society, in particular in political and public life (see “Relevant domestic and international law” above).”

Here, lawyers defending John’s Campaign would do well to emphasise that measures such as the company of a carer for a person with dementia in an acute admission would facilitate the wellbeing of that person with dementia. This is a very powerful case to make, as shared care plans involving the carer are designed precisely to optimise the health and wellbeing of the person with dementia (see the RCN/Carers Trust “Triangle of Care”).

All three judgments are not directly about the material facts in John’s Campaign. I am not in fact aware of the exact same case in any jurisdiction covered by the jurisdiction, which would lead me to think this would make an interesting ‘test case’ of public policy. Despite the fact domestic jurisdictions are free to operate a principle of subsidiarity in law, I think a legal case for the substantive issues in John’s Campaign can be made out, especially if such arguments emphasised the person wellbeing of the person with dementia and carer, and the economic wellbeing of the country.

This is definitely, as such, ‘unfinished business’.


A quick word about Richard Taylor Ph.D.

I am mindful that others will wish to say a few words about Richard Taylor Ph.D., so I’ll try to keep my contribution brief.

A short while ago, I had come to know that Richard did not have long to live. That’s why Kate starting her section of our event in Camden was all the more poignant to her – and to me. Kate was in tears at the end of it. Beth handed her a tissue.

Even this morning Kate told me that Richard was her hero.

Kate Swaffer is certainly not one to use language casually.

When I came to learn of Richard’s passing away a few days ago, I still was shocked, but not surprised. I did not ‘expect’ Richard’s imminent death. Even Richard had posted a few days ago on how he was looking forward to moving into his hospice.

I occasionally would find that Richard had shared my book ‘Living better with dementia’.

Kate sent me a copy of her manuscript “What the hell happened to my brain?” in early January (2015). Kate was really looking forward to Richard’s Foreword for the book. The book is amazing, by the way.

I should like to say that I have never met Richard. But he touched many of our lives. As a Co-founder of the Dementia Alliance International, he took on one of the greatest injustices of the policy world.

That the people who represent dementia the best are not Big Charity, CEOs, academics and researchers, physicians and psychiatrists, psychologists, social work practitioners.. or even carers.

The people who best represent dementia are people living with dementia.

There should never be any more the refrain that ‘we couldn’t find anyone with dementia’ – there are 47 million people living with dementia in the world.

Richard identified how Big Charity used stigma to raise monies. This was a massive breakthrough in our thinking. Richard would turn up at international conferences to explain he was fed up that ‘people with dementia were being used’.

Richard would say, “I want to think how I am to live with dementia, not to die from dementia.”

I would never pretend that I ‘knew’ Richard. There are some people who knew him really well. Mick Carmody, whom I ‘zoomed’ yesterday, was in a state of shock.

But Richard had many brilliant qualities.

Assertive, not aggressive, Richard was highly principled.

People knew Richard’s boundaries, and he knew theirs.

Overall, having lost now a humble, and most talented individual, the living world is much the poorer.

We have lost one of our very best advocates for living with dementia, but I’ve always said that anything can happen to anyone at any time.

It’s for others to rise to the challenge, and make sure that Richard’s hope lives on in the difficult years to come.


Why I love dementia research

First of all, I should not actually ‘love dementia research’ if only because I’ve been doing it discontinuously since my finals in neuroscience at Cambridge in 1995-6. Familiary breeds contempt, and all that.

I think meeting three people in the last year really turbo-boosted my interest in research into dementia. And I think if you compare the contents and style of my two books in dementia, published last year and this year, I feel the second book, as Steve Hilton might put it, is ‘more human’.

The three people are Wendy Mitchell, Chris Roberts and Hilary Doxford – of all these three, I know Chris by far the best, but I find the eagerness of all three to promote dementia research awesome.

Chris Roberts, living with a mixed vascular and Alzheimer’s dementia (not uncommon a combo), managed to do two interviews on the BBC last week, “Victoria Live” and “BBC World”, managing to get a plug in for ‘Join Dementia Research’.

Join Dementia Research’ (@beatdementia) is an initiative anyone can join in to take part in dementia research. It’s sort of like a different sort of dating agency – one where you paired up to the research project most suitable to you. You don’t have to be living with dementia to participate.

When I  tweeted this picture earlier today, I did not actually realise Chris Roberts and Jayne Goodrick were standing on the far right (where they are not politically.) Hilary’s on the far left (not politically either, to my knowledge) and Wendy’s in the eye-catching red jacket (not a political statement either, I think.)


Chris here explains his own experience of dementia, and explains the need for research in his BBC World interview. Any person with dementia becomes an expert in his or her own condition in time and place.

But having thought about it a lot recently, in light of national policy, I’ve concluded that I like research into dementia a lot. I enjoy reading about it all the successes and failures. I like doing my work, even though it does not consume any expensive resources. I’ve so far got a chance to present my findings, which have not cost anything at all, at two international conferences: Alzheimer’s Europe and Alzheimer’s Disease International.

I think I would strongly recommend anyone living with dementia or closest to such a person to think about even doing research for himself or herself, and publishing the research. Once you get involved with the research bug, it’s a great way to meet people, and talk effortlessly with people who share your interests. I’m invariably impressed by medics who’ve had the time, opportunity or resources to pursue research of some sort, not least because they’re furthering the knowledge and reputation of the profession. It also tells me that “they’re not one trick ponies”.

I don’t think of a primary goal of a researcher should be gainful paid employment. The people I’ve found who excel at research are the ones who are genuinely passionate about it. It’s a great privilege I feel to be able to study a topic in detail, and to take on contemporary challenges. As a person, I feel philosophically that nothing goes to waste, so for me even ‘negative findings’ have value.

Whilst I do not share in the hyperbole surrounding the drug trials research presented last week in Washington at the Alzheimer’s Association conference, I think any development which overall increases our understanding, however small or incremental, is to be welcomed. The advantage of well designed trials, even if they do not throw up the ‘clean results’ many would like to see, not least for a ‘return on investment’, is that they provide something people in the future can rely on. Money we spend on research is literally investing in hope. A love of knowledge I suspect would get a widespread democratic mandate, as would a greater understanding of human experience. All of this helps the NHS in our jurisdiction to offer a better care and support environment, with colleagues in social care, in theory and hopefully in practice.

I don’t feel it’s a just but lost cause, like any good Jacobite would, although I’ve been in love with lost causes since I became a supporter of Tottenham Hotspur, or a book called ‘Jude the Obscure’ (St Jude was apparently the Patron Saint of Lost Causes).

Possibly even there’s no such thing as satisfaction. In “The Dawn”, the 19th century philosopher Friedrich Nietzsche claimed that that which is erroneously called ‘pity’ is not selfless but actually self-motivated. Am I motivated by negative emotions such as ‘pride and satisfaction’ in doing research into dementia? Am I ‘taking control of biology’? Possibly.

I published my paper in 1999 with Prof John Hodges and various others for a reason. This was because they were patients turning up in cognitive neurology clinic, query the behavioural variant of frontemporal dementia, whose tests appeared at first blush entirely normal. And yet these tended to be people in their 50s or 60s with quite profound changes in personality which had been noticed by their closest. I provided an explanation for why this paradox exists in this paper which is now cited in the current Oxford Textbook of Medicine. I argued it’s because the part of the brain which is affected, a part of the brain near the front of the head towards the eye, is hard to investigate.

The vast majority of my colleagues in research have confirmed this finding, which brings me onto my final point. It is incredibly rewarding when someone you’ve never met before claims to agree with you and have taken your results further. And it’s wonderful when somebody you’ve never met before knows your research and likes it – this happened to me when I met Prof Brendan Boeve from the Mayo at the Alzheimers Association conference last year in Copenhagen.

“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.

Researchers, like politicians, must represent the general public in the dementia discourse

Politicians are democratically elected, but researchers are not.

It might be inferred, sometimes, that researchers get their ‘political mandate’ from politicians. Against this idea is that members of the general public are free to see research monies going into research which is particularly merit-worthy.

It struck me how little intellectual rigour has been applied into thinking about the research challenges of a ‘global dementia research strategy’. The usual narratives, such as sharing of ideas and data sharing, as well as the need for ‘intelligent regulation’, are usual brought to the table and I have no problem with that.

In a way, research is like a market. It could be argued that there is a supply and demand. One can argue that some parts are actively ‘competing’ against others, leading to fragmentation. This fragmentation at worst leads to an unnecessary reduplication, with wasting of resources.

Working together, or collaboration, allows a pooling of resources, not just in financial terms but also in human capital and talent. It can mean that the same research question is not dealt with by numerous labs in the world.

But like markets, it can mean that there is not universal coverage of the entire gamut of research questions. Research into dementia is not simply about research into Alzheimer’s disease. While there is a collective sense of excitement at possible ‘cures’, we should be entitled to stop to think this is for one type of dementia at one particular stage. Research, like markets, can be forced to concentrate on areas of high profitability; but this runs the risk out of outright failure.

I have noticed a real reluctance in the Alzheimer’s Association conference in 2014 to engage with research questions of real “mettle”. For example, people who present with later stages of dementia, or present with ‘mixed’ pictures of dementia, such as Alzheimer’s disease and vascular dementia.

Or even that people with dementia rarely present as pure medical models of dementia. People living with dementia in the majority present with multiple co-morbidities, which makes discussion of their potential future pharmacy more complex than many would admit.

At worst this type of research, focusing on ‘pure’ biological models such as amyloidopathies for Alzheimer’s disease, synucleinopathies for diffuse Lewy body disease, or tauopathies for frontotemporal dementias, encourages a very ‘silo’ mindset, attractive that might be for enhancing shareholder dividend from Big Pharma and subsequent research laboratory funding.

But excluding people actually living with dementia from the conversation is painful. Where were the views of the Dementia Alliance International in #AAIC2015? They’re the group of people living with dementia – and yes, there are about 47 million people currently living with dementia around the world, of which a few million are in the U.S.

Excluding them from identifying the questions needing to be answered runs the risk of a global research policy which is deliberately ageist, or discriminatory towards certain groups of people who live with dementia.

I agree there are many ‘barriers’ to effective research into dementia at a global level, but they’re not simply barriers to biological research.

Take for example this passage from a research paper:

“To date, qualitative researchers have already addressed a series of important issues including: (a) individuals’ perception of their illness; (b) exploration of carers’ experiences; (c) impact of dementia on friends and family (Prorok, Horgan, & Seitz, 2013); among others. However, several gaps in our knowledge remain (e.g. optimal psychosocial interventions for carers, achieving social integration, evaluation of training and education in dementia care) (Moniz-Cook et al., 2011). Careful prioritization of the gaps which warrant further qualitative research is needed (Prorok, Horgan, & Seitz, 2013).”

But other issues definitely exist: such as recognising the cultural and ethnic diversity of people who are entitled to be diagnosed by and given support from services around the world; or the method of obtaining consent.

We cannot, also, keep on viewing the global research strategy through the prism of well funded jurisdictions; much dementia ‘exists’ in lower and middle income countries, so we must make sure that the “outputs” from our current global dementia strategy, whatever the so-called “barriers”, are fit for purpose for them too.

But therein lies the problem. Some researchers are indirectly accountable to shareholders of big companies, who will wish to see a ‘return on investment’.

Without any doubt, in my mind, the discussion of barriers to research in dementia has become too easily conflated to barriers to return on investment in neurochemical research (e.g. all ‘trials’ with harmonised entry requirements, and not seeking out valid qualitative perceptions.) It would be a massive mistake, I feel, if we simply went down this financial route, as the discussion of the value of human capital is different from econometrics you might have heard elsewhere.




Moniz-Cook, E, Vernooij-Dassen, M, Woods, B, Orrell, M & Interdem Network (2011). Psychosocial interventions in dementia care research: The INTERDEM manifesto. Aging & Mental Health, 15, 283-290.

Prorok, J. C., Horgan, S., & Seitz, D. P. (2013). Health care experiences of people with dementia and their caregivers: A meta-ethnographic analysis of qualitative studies. Canadian Medical Association Journal, 185, e669-680. doi:10.1503/cmaj.121795

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.

My book “Living better with dementia” is released this Tuesday

I don’t suppose more than a few people on the planet read my Ph.D. thesis which was called ‘Specific cognitive deficits in the frontal lobe dementias’.

Releasing a book is altogether more nerve-wracking in that you become aware of feedback almost instantaneously.

I’m sure people will tweet me to my @dr_shibley account.

I would like to say a few words about the book here.

I’d like to thank all three people who’ve written brilliant forewords for my book: Kate Swaffer (@KateSwaffer), Chris Roberts (@mason4233) and Beth Britton (@BethyB1886).

book cover design

In this book, I call for people living with dementia, and their closest – including friends and family, to be called to the forefront of developing and implementing policy.

I hope I’ve written the book in a style which means anyone from any background can ‘dip into’ the book as they wish. In fact, the book covers some pretty heavyweight topics in cognitive neurology, domestic and international law, medical research and leadership. So I feel it unlikely that any training grade doctor will be familiar with all the topics in depth.

I unreservedly have written this book for people living with dementia and their closest, but I feel the people who might also benefit from reading this book include doctors, nurses, AHPs, commissioners, academic researchers, social care practitioners, the media, the voluntary sector, and other interested members of the general public.

The future is very organic – and we are writing the future as we speak. I have no doubt there will be advances in drug therapy for Alzheimer’s disease in the very near future, but we all have a society to ensure that the 47 million or so people living with dementia have their human rights observed. Identifying ability and disability produces the landscape for rights-based approaches, including reablement and rehabilitation.

It’s not good enough, I feel, for there to be ‘dementia friendly communities’. There needs to be a fundamental re-wiring to ‘mainstream inclusive communities’.

I’d be very surprised if you agree with the book in its entirety. It’s meant to ‘spark’ a debate, that’s all.

The book is not professional advice either – which gives me some licence to bring the future closer.

The details of the book are here.

It’s released in the UK this Tuesday (21st July 2015).



Al PowerSilly pic#yougooseDSC_0008DSC_0009DSC_0013DSC_0014DSC_0017DSC_0018 (1)DSC_0018DSC_0020DSC_0022

Once bitten, twice shy? No – we should remain cheerful about dementia research.

The idiom “Once bitten, twice shy” is well known to all of us: “When something or someone has hurt you once, you tend to avoid that thing or person. ”

There are 47 million people living in the world with dementia.

Alzheimer’s disease is the most common cause of dementia around the world. It inevitably takes up the ‘lion’s share’ of interest, but it’s important to note that there are many other people living with other types of dementia, for example, frontotemporal dementia, we have to meet the needs of as well.

Let me lay my cards on the table.

I think it’s possible to create an environment such that people living with various dementias can be at their best, whether in work or not. I feel the emphasis must be on acknowledging dementia as a disability; and, from this, arises a mature conversation about reablement and rehabilitation.

But likewise I don’t think we should be subsumed with previous failures in neuropharmacology for us to ‘give up’ on medications which might ‘stabilise’ any underlying disease processes in dementia. I don’t think we should subject them to hyperbole either, but when there are glimpses of hope we should not be in the business of extinguishing hope.

I think one of my greatest privileges of all time was a chance to sit next to César Milstein at dinner in Cambridge.

The story of monoclonal antibodies is also well known.

Monoclonal antibodies were pivotal in medically treating a person who’d contracted Ebola.

Monoclonal antibodies are proteins that recognise and fight “aliens”, such as bacteria or viruses. Since the early twentieth century scientists had been keen to produce large amounts of antibodies specific to a particular target for research or clinical purpose, but with no success.

However, in 1975 César Milstein and his colleague Georges Köhler at the MRC Laboratory of Molecular Biology in Cambridge developed a way to produce monoclonal antibodies by fusing myeloma cells — a type of cancerous immune cell — with mouse spleen cells that had been exposed to a target. As well as creating a research tool for investigating the immune system and the pathways of disease, this innovative research also laid the foundations for the production of antibody-based drugs against specific diseases.


But this initial success has inevitably caused others to raise their game.

First identified by Alois Alzheimer in 1906, Alzheimer’s disease is an irreversible, progressive brain disease that slowly destroys memory and cognitive skills (Alzheimer, 1096).

Accumulation of Aβ (“beta-amyloid”)in the brain, manifesting as β-sheet rich plaques, is a hallmark of Alzheimer’s disease. Attacking amyloid plaques in symptomatic patients is sometimes referred to as ‘too little, too late’.  (However, it has also been suggested that plaques may be the body’s way of sequestering the toxic Aβ oligomers.)

I first became interested in amyloid because of its effects all over the body, but its effects in the brain are extremely noteworthy.

Eli Lilly & Co.’s drug solanezumab, and bapineuzumab – a drug developed jointly by Pfizer Inc., Johnson & Johnson and Elan Corp. – had also targeted amyloid plaques.

The prediction that “immunotherapies” targeting soluble Aβ oligomers will elicit clinical benefit is supported by studies of human Aβ autoantibodies, of which only a subset appears to be ‘disease-protective’ (in particular, the subset that preferentially recognizes Aβ oligomers) (see papers by Dodel et al., 2011; Moir et al., 2005).

Thus, immunotherapeutics with high selectivity for soluble Aβ oligomers, which resemble these protective auto-antibodies, might be expected to deliver a clinical advantage compared with the non-selective immunotherapies in clinical development?

One important caveat when considering the activity of Aβ assemblies is the dynamic nature of the aggregation process.

Initial studies clearly demonstrated that aggregation of Aβ was essential for toxicity, but characterisation of the assemblies used was limited and it was assumed that, because amyloid fibrils were detectable, it was fibrils that mediated the observed toxicity.

Yet, this appeared inconsistent with a finding that there might be actually a relatively weak correlation between the severity of dementia and the density of fibrillar amyloid (Terry et al., 1991).

In contrast, robust correlations between the levels of soluble Aβ and the extent of synaptic loss and severity of cognitive impairment have been fairly consistently demonstrated (e.g. Lue et al., 1999; McLean et al., 1999) – the term soluble Aβ refers to all forms of Aβ that remain in aqueous solution following high speed centrifugation of brain extracts.

It has been critical, some argue, to re-ignite the interest in finding a pharmacological means of stabilising dementia of the Alzheimer type, in light of recent clinical failures of several high-profile experimental therapeutics for dementia of the Alzheimer type, and the high risks and costs of such development endeavours.

The work of Dr Dennis Gillings and colleagues at the World Dementia Council has definitely kept a show on a road.

The recent clinical failures also have intensified scrutiny of the ‘amyloid cascade hypothesis’, which spawned many of the recent experimental drugs for dementia of the Alzheimer type, targeting the amyloid-beta (Aβ) peptide.

Nevertheless, the causal linkage between Aβ and dementia of the Alzheimer type appears to remain strong and appears to be supported by numerous different studies spanning the past two decades (e.g. Ferreira and Klein, 2011).

Let me know turn to BiiB037, which is Aducanumab.

I think there is cause to be extremely cheerful about this novel agent, though we need to be cautious: once bitten, twice shy.

Aducanumab is a human IgG1 monoclonal antibody derived from a patient with AD by using reverse translational medicine methodology (the background to this is described here in “World Intellectual Property Organization International Publication Number WO 2008/081008 A1″). The overall rationale was that these donors’ immune systems had successfully resisted Alzheimer’s disease and that the operative antibodies could be turned into therapeutics by a process called “reverse translational medicine”: these agents target ‘neb-epitopes’ in the jargon.

A Phase 1 safety and pharmacokinetics study began with a single-ascending-dose trial of 0.3 mg/kg to 30 mg/kg intravenous BIIB037 in 56 people with “mild to moderate dementia of the Alzheimer type”. Participants were assessed at 10 time points up to two years after dosing.

It seems that, according to the available data, BiiB037 binds soluble Aβ oligomers and fibrillar Aβ with high affinity and binds monomeric Aβ with low affinity.

But the next stage of the drug development process inevitably has to turn to safety and efficacy, and I am positive that Biogen will be open in discussing their data with peers in due course.

Amyloid-related imaging abnormalities (ARIAs) have been reported in clinical trials of monoclonal antibodies in the dementia of the Alzheimer type.

Concerns raised by the US Food and Drug Administration regarding MRI abnormalities observed associated with amyloid-modifying therapy in patients with the dementia of the Alzheimer type prompted the Alzheimer’s Association to convene a work group (Sperling et al., 2011).

The work group coined the phrase ARIA (amyloid-related imaging abnormalities) to describe a spectrum of MRI findings that include sulcal effusion and parenchymal edema (ARIA-E) and haemosiderin deposition (ARIA-H). Specifically, ARIA-H refers to areas of hypointensity on gradient echo MRI that are believed to represent deposits of iron in the form of haemosiderin.

Animal models currently appear to indicate that anti-amyloid β treatment removes vascular amyloid with a corresponding compromise of the integrity of the vascular wall and leakage of blood resulting in microhaemorrhages and haemosiderin deposition (Zago et al., 2013).

The aetiology of ARIA remains unclear but the prevailing data support vascular amyloid as a common pathophysiological mechanism leading to increased vascular permeability. In the phase 2 bapineuzumab trial, dose-related vasogenic oedema (ARIA-E) had been observed (Salloway et al., 2009). Twelve cases of vasogenic oedema were reported, all in treated patients, and all resolved over time. But it seems that ARIA does not seem to be associated with all monoclonal antibodies?

As reported elsewhere, PRIME is an ongoing Phase 1b randomised, double-blind, placebo-controlled, multiple-dose study evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of aducanumab in patients with prodromal or mild AD.

This interim analysis of PRIME reflects data for 166 patients, up to week 54 in the placebo (n=40), 1 mg/kg (n=31), 3 mg/kg (n=33) and 10 mg/kg (n=32) dose arms, and up to week 30 data for the 6 mg/kg (n=30) dose arm.

On March 20 2015, it was reported that:

“CAMBRIDGE, Mass.–(BUSINESS WIRE)–Today Biogen Idec (NASDAQ:BIIB) announced data from a pre-specified interim analysis of PRIME, the Phase 1b study of aducanumab (BIIB037), in which aducanumab demonstrated an acceptable safety profile and positive results on radiologic and clinical measurements in patients with prodromal or mild Alzheimer’s disease (AD). These data are being presented today at the 12th International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders in Nice, France.

Treatment with aducanumab produced a dose- and time-dependent reduction of amyloid plaque in the brain. Amyloid plaque is believed to play a key role in the development of the symptoms of AD. In exploratory analyses, a dose-dependent, statistically significant effect of slowing clinical decline was observed on the Mini Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scales.”

The safety observations are particularly interesting.

“Aducanumab demonstrated an acceptable safety and tolerability profile in this analysis. The most frequently reported treatment-related serious adverse event (SAE) and adverse event (AE) was ARIA (amyloid-related imaging abnormalities). Based on MRI scans, the incidence of ARIA-E (edema) was dose- and apolipoprotein E4-(ApoE4) status-dependent. In general, the onset of ARIA-E was observed early in the course of treatment and was asymptomatic or with mild, transient symptoms. The majority of patients with ARIA-E continued treatment and did so at a lower dose.”

It will be helpful if there is more research into characterising ARIA.

I was struck by one line in the abstract of the paper by Zago and colleagues (2013), in particular:

“These data suggest that vascular leakage events, such as microhemorrhage, may be related to the removal of vascular Aβ. With continued treatment, this initial susceptibility period is followed by restoration of vascular morphology and reduced vulnerability to further vascular leakage events. The data collectively suggested a vascular amyloid clearance model of ARIA, which accounts for the currently known risk factors for the incidence of ARIA in clinical studies.”

All of this makes you wonder whether we are to be cheerful or cautious?

I think both, and I keep reminding myself that we have come an extremely long way.

Reason to be cautious? Yes. Reason to be cheerful? As long as we don’t neglect the 47 million people living in the world with dementia, yes.



Selected readings

Alzheimer A. Über einen eigenartigen schweren Erkrankungsprozeß der Hirnrinde. Neurologisches Zentralblatt. 1906;23:1129–36.

Dodel R, Balakrishnan K, Keyvani K, Deuster O, Neff F, Andrei-Selmer L-C, Röskam S, Stüer C, Al-Abed Y, Noelker C, Balzer-Geldsetzer M, Oertel W, Du Y, Bacher M. Naturally occurring autoantibodies against β-amyloid: investigating their role in transgenic animal and in vitro models of Alzheimer’s disease. J Neurosci. 2011;31:5847–5854.

Ferreira ST, Klein WL. The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol Learn Mem. 2011;96:529–543.

Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol. 1999;155:853–62.

McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol. 1999;46:860–6.

Moir RD, Tseitlin KA, Soscia S, Hyman BT, Irizarry MC, Tanzi RE. Autoantibodies to redox-modified oligomeric Aβ are attenuated in the plasma of Alzheimer’s disease patients. J Biol Chem. 2005;280:17458–17463.

Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E, Lieberburg I, Schenk D, Black R, Grundman M. Bapineuzumab 201 Clinical Trial Investigators. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;5:2061–2070.

Sperling RA, Jack CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P, Carrillo MC, Thies W, Bednar MM, Black RS, Brashear HR, Grundman M, Siemers ER, Feldman HH, Schindler RJ. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;5:367–385.

Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–80.

Zago W, Schroeter S, Guido T, Khan K, Seubert P, Yednock T, Schenk D, Gregg KM, Games D, Bard F, Kinney GG. Vascular alterations in PDAPP mice after anti-Aβ immunotherapy: Implications for amyloid-related imaging abnormalities. Alzheimers Dement. 2013 Oct;9(5 Suppl):S105-15. doi: 10.1016/j.jalz.2012.11.010.

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.