Recent clinical trials have shown new drugs to fight Alzheimer’s disease, called anti-amyloids, did not significantly help patients. Other potential treatments have also failed, including those targeting the build up of Tau protein, dysfunction of the neural circuits and interconnections between brain regions, and the ordinary cellular processes involved in brain function, such as movement of nutrients within the brain and removal of waste.
It’s time to question the model of dementia research and funding that’s being energetically pursued around the world. Elevated expectations, promoted by a variety of players, have led to widespread public misunderstanding about the true state of evidence on risk reduction, early detection and diagnosis, and effectiveness of drugs.
Clinical trials haven’t produced real results for people living with Alzheimer’s disease and other dementias. And these negative results have also diminished the credibility of the leading theory of how Alzheimer’s disease works: that it is the result of a buildup of amyloid plaques in the brain.
There are currently no drugs that effectively reverse the disease, only some that slow its progression. Even how dementia develops is still poorly understood – as is the nervous system and brain in general.
We do know that about 80 percent of dementia is in people older than 75 years old. Studies suggest nearly one third of dementia is related to factors we can do something about: increases in education level and physical activity, and reductions in midlife high blood pressure, obesity, diabetes, smoking, hearing loss, social isolation and later life depression.
Yet research about these factors receives far less research attention than drug development.
Pharmaceutical companies are partially to blame. Overstating treatment and clinical benefits contributes to media hype beyond what is justified by original data. Among results reported as positive, it is often actually the case that insignificant differences have been observed between patients who did and did not receive the drug during the trial.
For example, in May 2017, the biotech company Neurotrope reported positive results for their new Alzheimer’s drug, bryostatin. Yet an inappropriate statistical approach was used, in which Neotrope reported results for only about half their enrolled patients. Excluding those using the highest doses of bryostatin allowed Neurotrope to report only desirable results, turning a negative Alzheimer’s study into a positive one.
Drug makers also market unapproved and off-label use of anti-psychotic drugs for dementia, resulting in several pharmaceutical companies being fined billions. Examples include Eli Lily, which was fined $1.5 billion in 2009 for Olanzapine; Pfizer, which was fined $2.3 billion for Ziprasidone in 2010; and Johnson & Johnson, which was fined $2.2 billion for Risperidone in 2013.
A class action lawsuit for false advertising was taken against Accera for promoting its nutritional supplement Axona “…for clinical dietary management of metabolic processes associated with mild to moderate Alzheimer’s disease” on the basis of one trial demonstrating reduced symptoms at 45, but not 90 days. In addition, there are no distinctive nutritional requirements for individuals with mild to moderate Alzheimer’s disease.
Advocates such as researchers, advocacy organizations and patient lobbyists are also partly to blame for the hype. These groups have used extreme language to describe the scale of the issue, such as, “the Alzheimer tsunami” or “the enemy at our gates.” Their efforts may have paid off. The 2013 London G8 Legacy meeting marked a critical turning point for global dementia research with its commitment to increase funding, and new research initiatives, including the Canadian Consortium on Neurodegeneration. Brain Canada also offers promises of progress to Canadians now awaiting the assent of Bill C-233 (the Federal Dementia Strategy).
At the G8 2013 Legacy meeting a pledge was made that by 2025 there would be therapies that slow or halt dementia progression or a cure for dementia. While this can attract commercial interest and investment, it does nothing to promote the science of improvements in care patients receive from family physicians, care homes and assisted living.
Exaggerated claims of ‘soon to be discovered’ cures, and ignoring uncertainty surrounding biomarker tests for Alzheimer’s and other dementias does little to help health care providers deliver better care to persons living with dementia.
Experts and advocates need to review their messages and engage the public in balanced dialogue about new discoveries and their likely importance, and to lower unrealistic expectations.
It is the duty of researchers, funding agencies, academics, drug companies and advocacy organizations alike to discuss the return on investment of dementia research in terms of short, medium and long term outcomes, taking care to ensure that continued funding of research does not come at the expense of societal responsibility.
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On June 19, 2017, the Alzheimer Society of Canada and the Canadian Consortium on Neurodegeneration in Aging with 34 partner organizations released the results of the James Lind Alliance (http://www.jla.nihr.ac.uk/) project on dementia research priorities in Canada. Approximately 1,200 Canadians living with dementia and their caregivers identified unanswered dementia research questions. A representative group of persons living with dementia and their carers ranked these questions and identified the top ten dementia research priorities. The top ten list for Canada is available at http://alzheimersocietyblog.ca/top-10-research-priorities/..
The top ten priorities from this innovative project are what the Healthy Debates “Dementia research is oversold” article emphasized. The article encourages the need to “promote the science of improvements in care patients receive from family physicians, care homes and assisted living…to help health care providers deliver better care to persons living with dementia.”
Canadian researchers should focus on these ‘validated’ ten dementia research questions as a priority so that resources allocated to their research activities will “not come at the expense of societal responsibility”.
The authors are to be commended for a thoughtful article. The article focuses on flaws in drug research as illustrated by specific dementia research examples- exaggerated claims, obscured shortcomings in findings, etc. Another reason for shifting focus away from cure is the fact that by the time people exhibit discernible symptoms of dementia, they have experienced significant and irreversible brain cell death. Cure is not a reasonable goal, until we can treat people who are asymptomatic. Accordingly, dementia research will be more effective to the extent that resources are shifted in favour of research regarding the following priorities:
1) bio markers and other predictors of high risk of dementia;
2) prevention and risk mitigation – it is clear that physical activity, diet, social connections and intellectual exercise all have preventive properties. We need research to help us get more granular about this knowledge (e.g. specific type, duration and intensity of exercise).
3) care improvement – rehabilitation strategies; improvement of care processes that support dignity; triggers and management of psychiatric symptoms, including responsive behaviours; end-of-life care.
I agree with the authors that resources need to be redirected to research goals that have a reasonable chance of improving the lives of people with dementia.
Holy cow!
I have read with interest the comments of Warrick et al., yet I am confused about what is the message being transmitted. As a physician, one is trained from the first day of medical school that the most important thing to be done for patients is to encourage them to control vascular risk factors such as “high blood pressure, obesity, diabetes, and smoking”. Does anybody think otherwise? The fact that only 1/4 elderly individuals with high blood pressure have it properly controlled is both a challenge (how can we do it better) and a disappointment (even 50 years of strongly encouraged treatment, and a wealth of effective medications, have not abolished hypertension). As for the other risk factors, it is evident that poverty, lack of education, social isolation, poor nutrition, may predispose to dementia (although their exact role and extent remain debated). But this article implies (but is too clever to outrightly suggest) two elements that are highly questionable: 1. Knowing risk factors is the end of the story. Simply abolish these risk factors, and this disease (and a lot of others) will disappear. 2. We will never have a medical therapy that stops or prevents or reverses Alzheimer Disease or mixed dementia anyway. One would have to respond to these implied statements in the following way. For #1 – “We know SOME of the risk factors, but what is it that we do NOT know? What exactly IS it in the exposome, in epigenetics, in the environment that causes dementia? And if we really mount interventions to prevent or reverse or negate these factors (assuming that we can pin them down sufficiently), what degree of prevention will ensure? Theoretically Dr. Brayne suggests 1/3 of cases could be prevented, but that is based on theoretical models. Surely the impetus should be to mobilize the research community to carry out the research necessary to prove there is actually this degree of benefit. But are the authors calling for the community to actually carry out these expensive trials? I am not at all sure. For #2 – Since we do not know the cause of Alzheimer Disease (or Lewy Body Dementia, or Frontotemporal dementia, or most of the Mixed dementias with elements of neurodegenerative disease), isn’t it premature to throw in the towel? I don’t know how far away we are from real pharmacological cures, and neither do these authors. Why is one valid statement (“anti-amyloid therapies have not produced results”) equated with another -(“there will never be medical cures”)?
In fact, the neurodegenerative diseases are a huge medical challenge, and one that is not going to go away. Yes, hype and overselling of any therapies for illness is always bad. Medicine has always been rife with premature declarations of therapeutic victory. But I don’t see this as much evident in the dementia field (where the main declarations have been of failed anti-amyloid trials lately!), as much as I see the valid concern of patients, families, and policymakers that more can be done, more effort is needed, and that more funding might result in more rapid progress against the diseases. We do not know what causes these diseases, so (unsurprisingly), we do not know yet how to cure them. Lets mobilize to fight the dementias with the energy, people and funding that might make a difference.
Howard’s remarks about the work to be done on prevention are bang on. I share his concern that the disappointing results in drug trials should not be seen as a reason to throw in the towel. Given the rapidly increasing impact of dementia on the lives of Canadian families we need to increase funds for dementia research and redirect these resources for prevention (as Dr. Chertkow suggests) and improving the capacity of families, long-term care and home care workers to help people with dementia live dignified lives.