In the lead up to World Alzheimer’s Day (21 September), we’ve brought together a panel of experts from our partnered institutions to discuss what the future of dementia research might hold. In this written discussion, our panelists discuss a multitude of topics ranging from amyloid versus tau, risk genes, emerging therapeutic approaches, early detection, challenges with funding, the use of digital technology and much more.
Our fantastic panelists include Carol Routledge (Director of Research at Alzheimer’s Research UK, Cambridge, UK), Bart de Strooper (Director at the UK Dementia Research Institute [UK DRI], University College London, UK) and James Pickett (Head of Research at Alzheimer’s Society, London, UK). Take a look at the full discussion below!
Many genetic factors have been identified as contributors to the risk of developing Alzheimer’s disease (AD). What challenges are there in translating genetic data into potential therapeutics?
Carol Routledge: In 2012, researchers from Alzheimer’s Research UK helped make a major genetic breakthrough. The scientists discovered a change in the DNA code of a gene termed TREM2 – people with this change in their gene have a threefold higher risk of Alzheimer’s.
This is just one of the important advances that scientists have made in identifying genetic factors that contribute to the risk of developing dementia. However, diseases like Alzheimer’s are highly complex and several risk genes are likely to act together. This makes developing a therapeutic approach that targets a single gene problematic and one that targets several risk genes difficult to design.
Bart de Strooper: A major challenge for the UK DRI is to understand how our genes mechanistically change the way that the brain copes with neurodegeneration-causing factors like amyloid peptides, neuronal tangles or any other abnormally folded protein. As an example, in AD, we know there are tens of thousands of single nucleotide polymorphisms – small changes in the human genome – that point towards genes which alter your chance of developing the condition. This is also probably true for other neurodegenerative disorders.
“…I think the neurodegenerative field is quite good at turning basic science into clinical practice, but this takes too long. We should aim to work in parallel…”
The main challenge here is modelling these single nucleotide polymorphisms. Although the cell biology and chemistry are very complicated, we are able to do that nowadays. We can take induced pluripotent stem cells and expose them to disease-relevant challenges (e.g., the amyloid peptide) and observe the subsequent cellular reaction – good or bad. Performing this across thousands of cells, we can analyze the ‘big data’ generated to see what is common in both the pathological and healthy reaction. I think it is an immense challenge but one that the UK DRI can tackle with our skills and expertise. Ultimately, it’s something that will give us new drug targets.
Additionally, I think the neurodegenerative field is quite good at turning basic science into clinical practice, but this takes too long. We should aim to work in parallel, for example developing basic insights, faster testing in patient materials (induced pluripotent stem cells, biomarkers, brain samples and clinical phenotypes) and correlating genetic scores, clinical phenotypes and cell biology phenotypes. Performing this in parallel, instead of consecutively, would help enormously.
How can we overcome these challenges?
Carol Routledge: We need to see a more integrated approach to translate our advances in finding new genetic risk factors into a deeper understanding of the disease. This involves improving our knowledge of the biological processes that genes control, exploring potential drug targets affected by genetic changes and allowing this to inform our drug discovery efforts.
To do this, we need to connect disciplines and support collaboration amongst scientists, particularly those from other scientific fields to bring new expertise into dementia research. An integrative method is being championed by the UK DRI – part-funded by Alzheimer’s Research UK, but we must not rest on our laurels, there is more work to do.
What therapeutic approaches are emerging in the field of dementia?
Bart de Strooper: Firstly, anti-inflammatory therapies. We know that inflammation is an important component, especially in AD. What I’m also very excited about are approaches to remove abnormally folded proteins – many people in the UK DRI are investigating the role of cells in this process. Obviously, there is some correlation between the build-up of these abnormally folded proteins and the disease progression, so it appears to be a smart target.
We should also not forget the symptomatic therapies because this is what will bring most benefit to the patient in the short term. I believe there is some hesitation from industry, but a great need exists from the clinical perspective. Symptomatic and causal therapies may also be interlinked, for example, we know that if your brain is hyperexcited because of these abnormal proteins, it also in turn increases their accumulation. If you could intervene with a symptomatic treatment to lower hyperexcitement at the beginning of the disease, you may help both the symptoms immediately and slow down the disease progression in the long term.
“We have recently funded a clinical trial using a cannabis-based medicine to treat the symptoms of agitation.”
Carol Routledge: Our mission at Alzheimer’s Research UK is to bring about the first life-changing dementia treatment. While many of the treatments currently in late-stage clinical trials are disease-modifying drugs, we must continue to approach the problem from all angles.
Many people don’t realize that dementia symptoms can include anxiety, aggression and depression and are particularly devastating for those affected by the condition. Promising developments to treat people’s symptoms are important and could be life-changing for individuals.
We have recently funded a clinical trial using a cannabis-based medicine to treat the symptoms of agitation. This trial is getting underway and will tell scientists whether they should go on to perform a much larger clinical trial of the drug in people with the disease.
While some current drugs, such as antipsychotics, do exist to treat some of the behavioral symptoms of dementia, they have significant side effects. We are also teaming up with drug discovery experts and pharmaceutical companies to identify new targets for the psychiatric symptoms of dementia that could improve how these symptoms are treated.
We’re working hard to follow new leads for disease-modifying drugs through initiatives like the Dementia Discovery Fund, Dementia Consortium and the Alzheimer’s Research UK Drug Discovery Alliance, and continue to champion a multi-faceted approach to drug discovery.
What technological advances could be used to better understand vulnerability and resilience in neurons?
Carol Routledge: Everything we do, say or think is the result of electrical signals that pass through nerve cells in the brain. These nerve cells form vast networks that break down in diseases like Alzheimer’s, causing symptoms such as memory loss and confusion. We are investing in research to uncover more about this relationship, relating these changes to patterns of electrical activity in the brain in diseases like Alzheimer’s.
Ways to measure the electrical activity of the brain have already seen significant advancement. We can now measure the electrical activity of the brain using small head devices, hearing aids and even so-called ‘sleep rings’. Add to that the advances in analytics used to look at patterns of activity and we now have ways of understanding the brain in much more depth than we have before.
Researchers also want to discover whether slightest changes in the brain structure can improve early detection of disease. Brain changes can now be measured using cutting-edge imaging technology with MRI and PET brain scans, all advancing significantly in recent years.
In your opinion, what advances from other areas of neurological diseases could be applied to the dementia field to bring us closer to a disease-modifying treatment?
James Pickett: In recent years we’ve seen astonishing results in gene therapy trials to treat incurable debilitating neurological illnesses including spinal muscular atrophy and Huntington’s disease (HD).
“Dementia researchers are watching as these results unfold. They are learning from these breakthroughs, bringing us closer than ever before to seeing a gene therapy for dementia.”
University College London (UCL; UK) researcher, Sarah Tabrizi, has demonstrated in a Phase II trial that gene therapy can reduce levels of the toxic Huntington protein that causes HD. The next step will be to test this therapy on a larger group of people with HD to see if the treatment can prevent the disease from progressing.
Dementia researchers are watching as these results unfold. They are learning from these breakthroughs, bringing us closer than ever before to seeing a gene therapy for dementia.
The UK DRI has recently announced the commitment of £2 million for a new gene therapy platform and researchers such as Adrian Isaacs (UCL) are already using similar approaches to target a faulty gene that causes frontotemporal dementia.
Carol Routledge: Advances made in other neurodegenerative diseases have primarily focused on the genetic causes responsible. The recent promising Huntington’s trial did exactly that. If we can replicate treatments similar to this for the rare familial forms of AD, which have a strong genetic component, then we might see some success. But as the majority of dementia cases aren’t caused by a single genetic risk factor, this approach is unlikely to work for many of those affected by dementia.
We can also look towards developments outside our field to find inspiration – cancer for example. Here we’ve seen significant advances in detecting and then treating cancer earlier before the disease really takes hold. This is something we need to replicate in dementia to have the best chance of developing effective treatments.
If earlier detection and diagnosis of dementia can be achieved, how might the landscape for clinical trials change to mirror this?
Carol Routledge: If we detect neurodegenerative diseases 10–15 years earlier than we currently do, this could revolutionize how we conduct dementia research.
Not only would it will allow us to better understand early disease, which in turn helps the identification of new drug targets, but it would provide additional markers to assess in clinical trials.
To facilitate this, we will need to see a new approach for conducting and implementing pivotal clinical trials. This means not only investing in research but also into work engaging with regulators and the relevant bodies.
James Pickett: Early and accurate diagnosis could change the face of dementia research and clinical trials. Currently, PET scans used to enroll people into clinical trials cost £3000 per scan.
If we can use a simple, accurate blood test alongside genetic information and family history we can dramatically reduce the cost of trials. We hope this will result in a far greater number of trials underway that are enrolling individuals at the very earliest stages of their dementia journey when treatments might be more effective.
We need to see clinical trials for new treatments keep up with the pace of the improvements we have seen in diagnostic methods.
How might digital technologies assist with clinical trial recruitment and retention if earlier detection/diagnosis becomes possible?
“Researchers are starting to demonstrate that digital measures such as gait, can correlate with clinical stages of diseases like Alzheimer’s.”
Carol Routledge: Digital technologies are now being used to continuously collect health data including speech patterns, gait and motor activity, texting patterns and more. Researchers are starting to demonstrate that digital measures such as gait, can correlate with clinical stages of diseases like Alzheimer’s.
Marrying technologies that pick up subtle changes in someone’s health could help recruit people with disease earlier than we currently do. Using these technologies to recruit and then test drugs in people without obvious signs of dementia could significantly increase the likelihood of success for novel therapeutics.
James Pickett: Alzheimer’s Society have partnered with the University of Oxford (UK) to test the power of smartphone technology in engaging and retaining large cohorts of people. In a year we have recruited over 16,500 people to play smartphone games each day for a month with surprisingly good retention. As a result, the research team have huge quantities of in-depth data that we simply could not collect in the clinic.
There is work to be done in refining and understand the best way to use this type of technology but we see success already in using technology to improve recruitment through Join Dementia Research, an online platform that has now recruited 20,000 people into research studies.
Is the amyloid versus tau debate driving the most valuable research, or should we be championing a multi-faceted approach?
Bart de Strooper: To be honest, I think we are beyond that debate. I hope so in fact. Firstly, those people that championed the amyloid hypothesis, including myself, had to temper claims with the unsuccessful trials that have followed. Additionally, the tau field started to appreciate the problems that the amyloid approaches had encountered (e.g., side effects, difficulty with antibody penetrance into the brain and unclear mechanisms behind neuronal death). Each side now understands that both proteins are important in disease, which is supported by the genetic evidence.
“Alzheimer’s disease is not amyloid, or tau, or dementia even – it is a complex disorder that starts as a subclinical issue and progresses to full decay of the brain.”
What’s interesting is that we are starting to uncover the role of many other players in disease, for example, neuroinflammation and accumulating evidence for a vascular component, which is overwhelming. The latter has long been neglected because of the amyloid/tau focus but approximately 50% of people with dementia have vascular problems. I hope, particularly in the UK DRI, that we take a more holistic approach going forward.
Alzheimer’s disease is not amyloid, or tau, or dementia even – it is a complex disorder that starts as a subclinical issue and progresses to full decay of the brain. The challenge for us is to understand that as broadly, and in as much depth, as we can. I think this also implies that the outdated dichotomy of amyloid and tau isn’t helpful because it is clear we will need several drugs in combination and to treat at different stages of the disease. On one hand, this complexity can make us very pessimistic, but we are now much more realistic, and it is an exciting time for research.
James Pickett: The genetic evidence for the amyloid hypothesis is compelling; mutations in the amyloid pathway clearly cause familial AD and even for sporadic late-onset disease the links between risk genes and amyloid pathways are present. Whilst amyloid-based therapies have failed to date, it would still be premature to risk throwing the ‘baby out with the bath water’ and deliberating excluding amyloid in our future research.
“…I think there is much more to be learnt about the role of vascular changes in all forms of dementia, not only in vascular dementia.”
Research is moving from understanding the biochemistry protein-driven elements of the disease to understanding at a cellular and brain systems level what’s going on. For example, I think there is much more to be learnt about the role of vascular changes in all forms of dementia, not only in vascular dementia.
There hasn’t been a new treatment for dementia in over 15 years so it’s vital we explore every avenue that could make a difference to the lives of people affected by dementia.
Carol Routledge: At Alzheimer’s Research UK we are championing a multi-faceted approach. Not only should we investigate anti-amyloid and anti-tau drugs further, particularly earlier in disease progression, but we should also research novel disease-modifying drug targets.
Alzheimer’s Research UK’s drug discovery programs are set up to do just this. The Dementia Consortium, which pulls together pharmaceutical and academic researchers, is looking at novel drug targets including those involved the brain’s immune system.
The first project to receive funds from the Dementia Consortium targeted the brain’s immune system with an aim to halt nerve cell damage in Alzheimer’s and Parkinson’s. Blocking a protein called CSF1R was found to reduce the immune response and slow the death of nerve cells. The project completed all its aims and Alzheimer’s Research UK has committed an additional £150,000 to support clinical trials targeting the CSF1R protein.
Alzheimer’s Research UK’s Drug Discovery Alliance is also working on developing drugs against many different aspects of disease. The Oxford Drug Discovery Institute (UK) is also targeting brain inflammation while the ALBORDA Drug Discovery Institute in Cambridge (UK) focuses on drugs that boost the cell’s waste-disposal system.
What are the biggest pitfalls in funding and what effect is this having on the outlook for dementia research and treatment? How could these challenges be overcome?
James Pickett: Since the G8 commitment to find a disease-modifying therapy in 2025, the UK and particularly the USA have significantly increased funding for dementia research.
“I’d like to see a greater appreciation and funding for psychosocial research and the impact this can have on people with the disease.”
The majority of funding is still focused on understanding the underlying biology of the disease. We need to continue to broaden the research agenda; studying and developing drugs for the non-cognitive symptoms of dementia such as agitation and sleep disturbance. Tackling these challenges will significantly improve the quality of life of people living with dementia as well as their loved ones.
As well as continuing to support work to tackle the underlying causes of dementia and the best path to prevention it’s vital we support people living with the condition today. I’d like to see a greater appreciation and funding for psychosocial research and the impact this can have on people with the disease.
Research will beat dementia but that simply can’t happen without more funding. It’s vital the government continue to grow investment in dementia research so we can change the lives of the 850,000 living with the condition in the UK today.
Carol Routledge: We know that research breakthroughs are made possible by sustained funding. Looking at cancer, in the UK alone, 50 years of committed and increasing investment from 1970 have led to a doubling in the cancer survival rate in this country. We hope to replicate this success for dementia.
But right now, a major gap exists between research funding for serious diseases. In 2016/2017, cancer research received £269 million in UK government funding compared with £83.1 million for dementia in the same year.
“We must see the UK step up to join this global effort and commit to invest 1% towards research to bring an end to the fear, harm and heartbreak of dementia.”
Globally, we’re seeing governments commit to increase budgets for dementia research – the USA now spends the equivalent of 1.5% of the annual cost of dementia on research, Denmark spends 2.4% and Canada has pledged to spend 1%. In the UK this figure stands at just 0.3%.
We must see the UK step up to join this global effort and commit to invest 1% towards research to bring an end to the fear, harm and heartbreak of dementia. We’re doing our part to close the funding gap too and have committed to spend a landmark £250 million in dementia research over the next 5 years thanks to our incredible supporters.
Bart de Strooper: Funding is a broad issue; we have funding from the government, philanthropic sources and our industry partners. It is also all connected; if the government increases funding to an area, industry is also interested and vice versa. If industry states something is hopeless, the other funding bodies close their wallets too. We experience this in waves within the neurodegeneration field.
We have a long way to go; since the 1970s, the research budgets for cancer have been 15- to 20-fold higher than for dementia, despite there currently being more dementia patients than those with cancer. 40 years later we now have a huge knowledge gap between the two disorders, and if we want to fill that gap, we will need an acceleration in research funding and efforts over the next few years. It also largely explains why we have effective drugs for cancer and not dementia – there is 15- to 20-times more money available.
However, people do realize the burden of neurodegenerative diseases is a huge global problem. There is an overall increase in funding focus, and even if we have problems with economy, I believe this trend will continue.
How could academia and industry work together to help bring potential therapies to the clinic sooner?
Carol Routledge: Although some of the headlines might suggest that large pharmaceutical companies are pulling out of research, it’s true to say they’re actually beginning to invest in a different way. Several key drug discovery and pharmaceutical companies have invested into Alzheimer’s Research UK’s Dementia Consortium and its sister initiative the Psychiatric Consortium. These programs provide a cost- and risk-sharing approach for partners investigating potential new drug targets.
This relatively new external-facing approach from pharmaceutical companies is gaining traction and projects are now underway. The Alzheimer’s Research UK Drug Discovery Alliance is also helping maintain a healthy pipeline of drugs. Recently a new start-up company called AstronauTx was spun out of work from the UCL Drug Discovery Institute, and will invest a further £6.5 million to help realize the potential of their new drug targets.
“The work we do as academics is very exploratory and it’s very difficult to know where it will go. Therefore, courage and trust are important.”
Bart de Strooper: There are some intriguing collaborations already occurring and industry is very interested in the efforts from academia. Furthermore, academia is beginning to understand that collaboration with industry doesn’t always mean you have to give up all your freedom etc. I think it is extremely important to formulate agreements between the two partners, so we are transparent about the goals of the two sides. At the end of the day, industry needs to earn money and we should respect that model as academics.
Likewise, industry should understand that, for us, the movement of knowledge, communication and capacity for early-career researchers to publish is essential and inherent to our values. Additionally, we should retain independence and not be required to hide data at request from our industry partners. We should be able to talk and criticize and keep the open academic debate protected. If there is absolute transparency there, we have a very good base from which to work together.
I think the second issue is about risk. The work we do as academics is very exploratory and it’s very difficult to know where it will go. Therefore, courage and trust are important. Industry protect their financial interests but anxiety from universities is increasing too. I think we should be less worried at the academic stage, and more open in sharing knowledge because, ultimately, we are a public effort. The funding is not solely an investment but a subsidy that allows good research to take place. In turn, we lay the foundations for industry to take it forward in a commercial sense.
“…I would like greater opportunity for academics to do more clinical work. There are no clear pathways or funding behind hypothesis testing with drugs that do not have commercial interest.”
Finally, I would like greater opportunity for academics to do more clinical work. There are no clear pathways or funding behind hypothesis testing with drugs that do not have commercial interest. It would be beneficial for both academia and industry. As an example, a Phase II/III trial is carried out but there is no commercial viability as the drug exhibits side effects. Industry abandon the drug and it sits on the shelf. If someone was to interrogate that data further, stratify the patients and identify an opportunity to test the drug again, there is no way to do that. This is something I would like to see addressed by the alliance of funding, academia and industry partners.
Where do you hope to see the field in 5–10 years’ time?
Bart de Strooper: I think we need to start by gaining a greater knowledge of the molecular processes underlying the decline seen in disease (e.g., what is protective and what is harmful, to the cells, vasculature etc.). I think this will occur in next 3–5 years, but I am impatient and want to see it applied sooner in clinical settings. Following the first 5-year period and armed with this knowledge, we as the UK DRI will be fully ready to translate the novel targets identified in these different pathways, working hard to see which are clinically feasible and interacting with industry to translate these insights in a whole category of novel drugs. I want to see significant effort in translating our knowledge base into patient-relevant work.
I would like to move away from a linear strategy and adopt a more parallel model, akin to two triangles or wedges over the 10-year period. In the first years, a lot of basic research will take place to fill the knowledge gap. That will become narrower over the decade, but importantly still exist as it is a fundamental driving force of progress. On the other side, the translational triangle involving industry, opens up and becomes bigger towards that 10-year milestone – much more clinical-/drug target-orientated research. I hope the UK DRI is a central player in the worldwide effort.
The big difference 10 years ago was the majority of effort was focused on basic science and then we hoped industry picked up a few things, which they did. However, that was too slow and linear. The model I envisage is in parallel with a graduated shift in focus towards translation, which I think will accelerate the development of therapies.
“…I hold great hope for the prospect of gene-therapy approaches that are even today changing lives for people with other neurological conditions.”
James Pickett: I hope we will be seeing the impact of the biomedical research underway today and that it brings a wealth of new biology and molecules into clinical trials.
Some drugs will fail as they progress through trials, but I hope there will be a volume of studies, which means every study isn’t scrutinized and held up by the global press. In dementia, when a trial fails it generally will make headlines – partly because they are so few and far between – but unfortunately this reinforces a negative narrative about dementia. We know that things are much more positive than this and there is hope in dementia research.
We will also have learnt more about how to select relevant groups of people for clinical trials based on biomarkers or other phenotypes.
Finally, I hold great hope for the prospect of gene-therapy approaches that are even today changing lives for people with other neurological conditions. Perhaps we will have shown these to be beneficial in small groups of patients that carry mutations for familial disease.
“Alongside investing in research, we must keep the pressure on the government to head up national health campaigns specifically designed to help prevent dementia.”
Carol Routledge: Ultimately, I would like to see a life-changing dementia treatment and help stop dementia stealing our loved ones from us. Detecting diseases earlier will be critical for success and will hopefully revolutionize the field within 5–10 years.
But prevention of a disease is also generally better than trying to cure one and the implementation of population-wide prevention strategies could also significantly help us tackle dementia head on. Alongside investing in research, we must keep the pressure on the government to head up national health campaigns specifically designed to help prevent dementia.
The opinions expressed in this discussion are those of the interviewees and do not necessarily reflect the views of Neuro Central or Future Science Group.