Efforts to develop drugs for the treatment of Alzheimer’s disease dementia (AD dementia) have failed for a variety of reasons: it might be that the biological target for the drugs is simply incorrect, or that phase 3 studies (the studies where the effectiveness of a treatment is studied in large groups of people) are undertaken before proof of efficacy was demonstrated in earlier studies, or the drug has not been tested in the right patient population. Another problem is the lack of understanding of the value of the different measures used to judge the success of a particular treatment i.e. are the criteria for deciding a drug is working actually the right ones?
Another common cause of repeated failures in AD dementia drugs trials is that the treatments are given too late in the disease process. EPAD wanted to establish whether there was a way to identify the people who with few or no symptoms of AD but who were at risk, and then follow them over a long period to see if and how they progressed to dementia symptoms. The current way of defining a person’s likelihood of developing AD dementia tends to focus on the stage of AD close to dementia onset, when the likelihood of having a significant effect on the disease is very small. If these cases could be picked up early, it would not only lead to better prevention (and preparation strategies) for patients, it would also help make sure that drug studies recruit people that are in a stage of the disease where there is a much higher chance of the treatment working, thereby reducing the chance of trial failure.
The project revolved around three core elements: first, the EPAD register, which was a database of half a million people from across the entire dementia risk spectrum. The register was used as the recruiting pool for the second element of EPAD, the longitudinal cohort study (LCS), which lasted three years and included nearly two thousand people with mild early cognitive impairment. Finally, the project prepared for a proof-of-concept (PoC) trial, which due to a lack of drug candidates during the project could not be carried out. Nevertheless, a research platform was designed by EPAD that would allow researchers to carry out adaptive, multi-arm clinical studies that would help make early and more accurate decisions in the study of drugs or drug combinations.
Register of recruits
EPAD created the first single, pan-European register of people at risk for developing dementia, resulting in a database of over half a million people. The register was made up of people who had signed up for other European cohort studies, meaning they had already been pre-screened. This allowed EPAD to make sure they were getting the most appropriate candidates for their study. The project partners developed a participant selection software tool called PREPAD, which allowed them to select participants from The register. The EPAD register, and the PREPAD selection software, are a novel and secure participant discovery platform.
The Longitudinal Cohort Study (LCS)
From this register, participants were invited to join an EPAD cohort, the LCS. Those who accepted underwent standardised tests and were followed over several years. Recruitment occurred across 31 centres from 10 different European countries, making the resulting dataset unique in its diversity. A wide range of cognitive, clinical, neuroimaging and biomarker data for 1,828 eligible participants were collected. Data from 1,567 participants were collected 6 months later, 1,188 at one-year follow-up, 383 at two years, and 89 participants at the three-year follow-up visit. As the project progressed, the datasets were made freely available to the Alzheimer’s disease research community worldwide.
The LCS provided a well-phenotyped population from across the risk spectrum. It allowed the EPAD researchers to develop accurate models of the entire course of Alzheimer’s disease (AD) progression prior to the onset of dementia. The researchers applied state-of-the-art modelling and stratification methods to the data from the cohort, using class-specific mixed effects models (statistical models that contain both fixed effects and random effects) and clustering. This modelling produced the four different disease trajectories, stratifying participants into homogeneous subgroups according to their cognitive functioning evolution and biomarker profile.
The LCS also produced a trial-ready cohort for potential recruitment into a trial that would test the efficacy of different interventions for the prevention of AD dementia.
EPAD was unable to initiate a proof of concept trial, but they developed a trial-ready proof-of-concept platform that was capable of running phase 2 clinical trials with research participants with preclinical and prodromal Alzheimer’s disease, with biomarker evidence of Alzheimer’s disease pathology. The platform was open for expressions of interest from pharmaceutical and biotechnology organisations, academic researchers, and funders who had suitable interventions ready for testing.
The platform was designed to efficiently deliver early, accurate results. EPAD studied new drugs in a well-designed phase 2 PoC trial with clinical endpoints, using the power of adaptive design and Bayesian statistics. The EPAD trial platform infrastructure is fully operational.
While it is not the first of such longitudinal studies, the EPAD study groups were unique in their geographical breadth. This diversity of populations is important because it gives us data that researchers can apply to a wider swathe of the human population than those confined to a specific location.
Both the datasets and samples generated by EPAD are now available for other researchers to use in their own dementia studies. The EPAD datasets have been added to the AD Workbench, an open, global, free and user-friendly data-sharing platform initiated by the Alzheimer’s Disease Data Initiative (ADDI).
Scientists can also apply to access the biological samples collected during EPAD; requests are assessed by a panel of international experts in dementia.
Achievements & News
The guidance influenced the work of IMI project EPAD, which used biomarker tests to collect data on the early stages...
IMI project EPAD has made genomic data from its study of the earliest stages of Alzheimer’s disease available to the...
The EPAD project has used computational models, working on geographically-diverse, high-quality datasets, to help identify subgroups in cognitive function evolution.### Writing in Frontiers in Big Data, the team describes its work on teasing out the different trajectories of people at risk of developing dementia.
The modelling suggests four distinct trajectories, from class zero, characterised by individuals having the highest levels of cognitive functioning with no signs of impairment at the beginning of the study and no decline throughout the course of the study, to class three, which describes individuals who showed the most obvious signs of early cognitive and/or functional impairment in the beginning of the study and continued to show impairment upon follow-up.
The ultimate aim of this work is to establish whether cognitive tests and biomarkers can be used to figure out who is likely to develop dementia, because early intervention offers the best chance of better outcomes.
Find out more
- Read the article in full
IMI’s EPAD project is recruiting people across Europe aged 50 and over to participate in a long-term study that will help to improve our understanding of the very earliest stages of Alzheimer’s dementia – before people have any symptoms. Participants undergo multiple assessments including regular health checks, standardised tests and brain scans over several years.
Now, the project is making data from the first visit of the first 500 participants available to the scientific community. ###The data has been de-identified to protect participants’ privacy, and quality controlled. Access is provided via secure online tools; researchers who want to use it have to apply via the EPAD website.
According to project coordinator Craig Ritchie of the University of Edinburgh, the research participants are enthusiastic about the move to make their data available to researchers. ‘Research participants love and expect it - they want as much knowledge to be gained as possible from their contribution,’ he says. So far, EPAD has recruited almost 2,000 people through 28 study sites in 8 European countries. As the project progresses, further data will be made available to the wider research community.
IMI dementia project EPAD has launched the EPAD Academy with the goal of efficiently leveraging the project’s resources ‘to foster and develop academic research capacity and output in AD [Alzheimer’s disease] across Europe for maximum global impact’. According to the project, among other things the academy will be a space where the next generation of AD researchers and thought leaders can advance their careers. ###This is the focus of the first action of the academy, namely the creation of the register of EPAD fellows;. These early career pre-doc and post-doc researchers will be eligible for academy activities such as stays in other centres, webinars, online forums for brainstorming, competitions around specific challenges, and support for funding applications, among other things. So far, 23 EPAD Fellows have been confirmed from academia, industry and patient organisations in the consortium. In the longer term, the academy will also help in the creation of procedures that will make it easier for research teams both within and outside EPAD to access the project’s data, samples and participants with a view to deepening our understanding of AD onset and progression. Finally, the academy aims to support EPAD’s academic output in terms of scientific publications, participation in conferences and the development of guidelines and studies, and to maximise their visibility and impact. For more information on the academy, contact firstname.lastname@example.org.
Despite considerable efforts and investments over the past decades, there is still no disease-modifying treatment for Alzheimer’s disease. This is probably due in part to the fact that efforts to develop treatments have traditionally focused on those who already have very advanced disease.### However, scientists now know that the earliest signs of Alzheimer’s disease start to appear in people’s brains years and even decades before the first symptoms of dementia appear. The ambitious goal of the EPAD project is to revolutionise the way we carry out clinical trials for treatments designed to prevent Alzheimer’s dementia. ‘What that means is taking people who show evidence of Alzheimer’s disease, but don’t yet have dementia, and trying to prevent that from happening,’ explains project coordinators Craig Ritchie of the University of Edinburgh in an interview with the IMI Programme Office. Together with fellow coordinator Serge Van der Geyten of Janssen Pharmaceutica, he explained what the project has achieved so far and why the project team is like a family.
Simon Lovestone of IMI’s dementia projects EMIF and EPAD has been awarded a knighthood in the Queen’s birthday honours ‘for services to neuroscience research’. Professor Lovestone is the coordinator of IMI’s EMIF project, which is developing a common information framework of patient-level data that will link up and facilitate access to diverse medical and research data sources, opening up new avenues of research for scientists.### He also leads the work package on scientific challenges in IMI’s EPAD project, which is revolutionising the way we carry out clinical trials for treatments designed to prevent dementia. Professor Lovestone described himself as ‘thrilled and delighted’ by the honour. ‘The past 25 years working in dementia research has been, and continues to be, the most fulfilling and rewarding experience and it has been the greatest of pleasures to work with superb scientists and students in my group and through collaboration; I am humbled by the excellence of their work and their dedication,’ he said. ‘We are making progress towards therapies and tests for Alzheimer's disease and this award only spurs me on to redouble our efforts and defeat this disease that causes so much unhappiness to so many people. I remain convinced that we will succeed; and such success cannot come soon enough.'
Miia Kivipelto, a scientist in IMI’s Alzheimer’s disease project EPAD, has received a MetLife Foundation Award for Medical Research in Alzheimer’s Disease at the Alzheimer’s Association International Conference (AAIC) in Toronto, Canada. Dr Kivipelto was one of two scientists to win a ‘Major Award’, the other going to Guojun Bu of the Mayo Clinic in the US.### ‘MetLife Foundation is proud to present the Major Awards to Dr Bu and Dr Kivipelto for their exceptional scientific research contributions, which help bring us closer to finding a cure for Alzheimer’s disease and related dementias,’ said MetLife Foundation President and Chief Executive Officer Dennis White. ‘Their outstanding contributions, recognised around the world, have helped us better understand this devastating illness, and both awardees have laid the groundwork leading to effective treatments.’ Now in their 30th year, the MetLife Foundation awards are administered by the American Federation for Aging Research. Awardees are selected by an expert advisory committee. The Major Award comes with a USD 100 000 (approx. EUR 88 300) institutional grant and a personal prize of USD 25 000 (approx. EUR 22 100). Dr Kivipelto works at Karolinska Institutet in Sweden and at the University of Eastern Finland. In EPAD, she co-leads the team responsible for setting up the EPAD cohort of 6 000 people who will undergo a range of tests that will help scientists identify early warning signs of dementia before symptoms appear.
IMI Alzheimer’s project EPAD has recruited its first volunteer in a major study that aims to add to our understanding of the earliest stages of dementia, before symptoms appear, and open up new avenues to prevent it. Julie Duffus from Scotland was inspired to take part in the project by her parents, both of whom had dementia.### ‘My mum and dad both had Alzheimer’s disease so I’ve seen first-hand the devastating effects it has on patients’ lives and those around them,’ she said. ‘I hope that my contribution will in some way help scientists to find better ways of diagnosing the disease and potentially, one day, to prevent it.’ The project aims to recruit a total of 6 000 people from across Europe to take part in the project. Participants will have regular health checks including blood tests and brain scans. Researchers will also track their thinking skills over time using tests of mental agility. The team hopes to develop tests to identify early signs of Alzheimer’s disease that may indicate when a person is at risk of dementia before symptoms appear. They will then invite these people to take part in clinical trials aimed at testing interventions that could delay, or even prevent, the onset of dementia.
Read EPAD’s press release.
IMI Alzheimer’s disease project EPAD launched a new website on World Alzheimer’s Day, 21 September 2015. The website aims to inform different audiences, including the scientific community, companies, people with dementia, families and carers, Alzheimer associations and the general public, about the project’s existence, its progress and its achievements.### ’EPAD wants to contribute to raising awareness on Alzheimer’s disease and more specifically on the importance of the prevention of Alzheimer’s dementia,’ asserts Alzheimer Europe Executive Director Jean Georges.
The European Lead Factory has also recently given its website make over and has now a new, user-friendly look, that will make it easier for scientists to find out how they can take advantage of the project’s resources.
ParticipantsShow participants on map
- Ac Immune SA, Lausanne, Switzerland
- Amgen, Brussels, Belgium
- Biogen Idec Limited, Maidenhead, Berkshire, United Kingdom
- Boehringer Ingelheim Internationalgmbh, Ingelheim, Germany
- Eli Lilly And Company LTD, Basingstoke, United Kingdom
- F. Hoffmann-La Roche AG, Basel, Switzerland
- H. Lundbeck As, Valby, Denmark
- Janssen Pharmaceutica Nv, Beerse, Belgium
- Merck Sharp & Dohme Corp, Whitehouse Station, New Jersey, United States
- Novartis Pharma AG, Basel, Switzerland
- Pfizer Limited, Sandwich, Kent , United Kingdom
- Sanofi-Aventis Recherche & Developpement, Chilly Mazarin, France
- Takeda Pharmaceuticals International AG, Glattpark-Opfikon (Zurich), Switzerland
- UCB Biopharma, Brussels, Belgium
Universities, research organisations, public bodies, non-profit groups
- Assistance Publique Hopitaux De Paris, Paris, France
- Cardiff University, Cardiff, United Kingdom
- Centre Hospitalier Universitaire De Toulouse, Toulouse Cedex 09, France
- Erasmus Universitair Medisch Centrum Rotterdam, Rotterdam, Netherlands
- Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V., München, Germany
- Fundacio Barcelonabeta Brain Research Center, Barcelona, Spain
- Institut National De La Sante Et De La Recherche Medicale, Paris, France
- Karolinska Institutet, Stockholm, Sweden
- Klinikum Der Universitaet Zu Koeln, Cologne, Germany
- Medical Research Council, Swindon, United Kingdom
- Stichting Radboud Universiteit, Nijmegen, Netherlands
- Stichting Vumc, Amsterdam, Netherlands
- The University Of Edinburgh, Edinburgh, United Kingdom
- Universite De Geneve, Genève 4, Switzerland
- University Of Leicester, Leicester, United Kingdom
- University of Cambridge, Cambridge, United Kingdom
- University of Oxford, Oxford, United Kingdom
Small and medium-sized enterprises (SMEs)
- Aridhia Informatics Limited, Glasgow, United Kingdom
- Berry Consultants Llp, London, United Kingdom
- Ixico Technologies Limited, London, United Kingdom
- Synapse Research Management Partners SL, Barcelona, Spain
- Alzheimer Europe, Luxembourg, Luxembourg
- Region Stockholm, Stockholm, Sweden
Non EFPIA companies
- Araclon Biotech S.L., Zaragoza, Spain
- Quintiles Limited, Reading, United Kingdom
|Name||EU funding in €|
|Alzheimer Europe||321 556|
|Assistance Publique Hopitaux De Paris||681 100|
|Berry Consultants Llp||219 000|
|Cardiff University||141 100|
|Centre Hospitalier Universitaire De Toulouse||2 084 650|
|Erasmus Universitair Medisch Centrum Rotterdam||337 922|
|Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V.||340 475|
|Fundacio Barcelonabeta Brain Research Center||3 258 316|
|Institut National De La Sante Et De La Recherche Medicale||223 600|
|Ixico Technologies Limited||528 355|
|Karolinska Institutet||567 000|
|Klinikum Der Universitaet Zu Koeln||336 014|
|Medical Research Council||134 120|
|Stichting Radboud Universiteit||84 464|
|Stichting Vumc||2 236 543|
|Synapse Research Management Partners SL||1 543 976|
|The University Of Edinburgh||7 631 711|
|Universite De Geneve||1 479 626|
|University of Cambridge||892 859|
|University Of Leicester||479 800|
|University of Oxford||1 894 313|
|Name||Funding in €|
|Region Stockholm||463 500|
|Total Cost||25 880 000|