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On 30 September and 1 October, the European Prevention of Alzheimer’s Dementia (EPAD) project held its General Assembly meeting online. Chaired by Craig Ritchie and Serge Van der Geyten, the EPAD project coordinators, the online GA meeting welcomed over 100 delegates, including representatives from the 39 institutions and organisations that make up the EPAD consortium. Leaders of each work package had the opportunity to reflect on the achievements and important lessons learned for future studies. Between some of the talks, a testimonial was given by several epadistas (members of the project, study sites members and research participants making up the EPAD family). Following the Work Package updates, Elisabetta Vaudano IMI Principal Scientific Officer, gave a presentation on IMI and shared some recommendations.

Craig Ritchie started the second day with an update on the EPAD asset portfolio. Next, a series of fireside chats took place. The aim of this session was to discuss a series of key topics that the clinical and clinical research field has been grappling with over the years with much work still to be done. 20 leaders in the field were invited to join the discussion with an emphasis on how we can learn in each topic from the past to help envisage the future direction. Before the wrap-up session, the IMI NEURONET project was presented along with the opportunities for EPAD. Craig Ritchie and Serge Van der Geyten then drew the meeting to a close, thanking all the participants for their active contribution to the meeting and all EPAD members for their enthusiasm and dedication during the last six years. The project started in January 2015 and received a no-cost extension from IMI, setting the end date in June 2020 for many members and October 2020 for all who were part of the longitudinal cohort study closure activities.

The European Research Council has awarded an Early Career Research (ERC) starting grant to the neurologist Marc Suárez-Calvet, MD, PhD, who will use data from the EPAD Longitudinal Cohort Study for his new project entitled “Identification of age-related Human Blood factors as a therapeutic target for Alzheimer’s disease” (acronym: HeBe).

The overall aim of the project, named after the Ancient Greek goddess of eternal youth, is to discover blood factors with a rejuvenating or ageing effect on the human brain that could become therapeutic targets for Alzheimer’s disease and other age-related brain diseases.

Marc Suárez-Calvet will define extreme biological age phenotypes in participants of the Alfa + study, conducted at the Barcelonaβeta Brain Research Center (BBRC), based on the difference between biological and chronological age. Afterwards, he will use advanced proteomics and metabolomics to measure these factors in BBRC’s cohort, but also in research participants from the EPAD Longitudinal Cohort Study.

The main hypothesis of the awarded project is that higher levels of rejuvenating blood factors decrease the rate of neurodegeneration, while higher levels of ageing blood factors increase the rate of neurodegeneration.

The study will be performed at BBRC, where the researcher was working over the last two years with a Marie Skłodowska-Curie Grant, in collaboration with the University of Göteborg.

For more information, please contact Marc Suárez-Calvet via email (msuarez@barcelonabeta.org) or Twitter (@M_SuarezCalvet).

We are writing to you with the latest news of the EPAD project.

What will the world be like once the COVID-19 pandemic is over? We can all speculate, formulate, hypothesise, hope and fear – we will all have our personal crystal balls – some cloudy, some clearer, some ignored and some stared into constantly – but one thing we can all be sure of is that once this nasty little virus is gone and all we have is the scars there will still be millions upon millions of people with or at risk of Alzheimer’s disease.

The whole world is working under the proposal that: ‘Until we get the vaccine we need to do all we can to make sure we don’t get it.’ This could be paraphrased to apply to Alzheimer’s disease too – we have an ongoing and vital role to do all we can to make sure as few people get it (Alzheimer’s disease) as possible through knowledge generation that drives clinical and public health implementation.

Although the IMI period of EPAD has come to an end for many of us in June and the rest of us in October, the aims, objectives and vision of EPAD persists. National programmes are being developed to follow up all the EPAD participants in a series of linked national and local programmes, the database and biobank is in safe hands with substantial funding from the Alzheimer’s Association and the site network is poised to be substantially extended and we will be offered a wide range of trials through the emerging GAP/EPAD collaboration. It is though a huge pity that we couldn’t initiate the platform trial which – after all – was the primary objective of EPAD. Over the weeks and months ahead though we can formally analyse the reasons for this as platform trials are proving to be of massive value in testing new treatments for COVID-19. Perhaps the Alzheimer’s trials world wasn’t quite ready for us – they will be though one day, hopefully soon…

In amongst all these developments and focus on COVID – we released to the world the V1500.0 dataset on schedule and in September we will release the entire EPAD dataset to the partnership and we will work on global release and open access through our collaboration with the Alzheimer’s Disease Data Interoperability Programme which launches formally very soon.

In essence the incredible and valuable contributions we’ve all made since 2014 – including the contribution of our over 2,000 research participants – has created phenomenal momentum and has generated legacies, assets, opportunities and hope for a huge, inspired and inspirational community. The only real challenge is to make sure we each can remain motivated, committed and believing when the (virtual) world manifests such unreality and such distraction.

One thing that is real and certain though is that once this nasty little virus is gone, hundreds of thousands of people will have died from Alzheimer’s disease who shouldn’t have and millions more will still ‘get it’ in the years ahead. If you were asked – ‘what did you do during the COVID Pandemic?’. ‘I kept working to find a cure for Alzheimer’s disease….’ isn’t too shabby an answer.

We will have a virtual General Assembly meeting in September and with our friends in NEURONET, we will meet as early as we can next year face to face to talk about what we’ve done, what we’re doing and what we still need to do. Until then keep safe and keep the faith.

Craig Ritchie, EPAD Co-coordinator

The past years were very productive and efficient for the EPAD project. In this piece, we wanted to reflect back on some of the important advances and major achievements made by each Work Package (WP).

WP1 (Scientific challenges)

• Creation of 5 Scientific Advisory Groups (SAGs) – Clinical and Cognitive Outcomes, Fluid Biomarkers, Genetics, Imaging and Life Style/Non-Pharmacological Interventions
• Development of recommendations/advices by the SAGs for the EPAD Register, Longitudinal Cohort Study (LCS) and the Proof of Concept (PoC) trial in order to recruit patients on a “risk spectrum”
• Establishment of the EPAD LCS Research Access Committee and the EPAD Research Access Process (ERAP) for data and sample access requests through the WizeHive Zengine tool
• Preparation of a state of the art report on the role of lifestyle as protective or risk factor for Alzheimer’s disease and on the perspective of non-pharmacological interventions (Lifestyle and non-pharmacological interventions SAG)
• Creation of a proposed protocol for a Primary Prevention EPAD Cohort as a post-IMI sustainability strategy

WP2 (Statistical/Methodology Engine Room)

• Disease modelling work focused on the development of Alzheimer’s disease risk models using historical/existing data, with the ultimate aim of translating and tailoring these models to the EPAD LCS
• Development of an efficient analysis method for clinical trials and using LCS data to demonstrate the improvements
• Analyses of the EPAD LCS data
• Delivery of the V500.0, V1500.0 and V500.1 data releases

WP3 (Parent Cohorts and EPAD Register)

• Creation of the EPAD Register built from a collaborating set of Parent Cohorts
• Creation of software and platform to support the discovery and/or proposing of suitable participants and provide an alternative recruitment route for rapid inclusion of certain high-value participants
• Development of an online graphic tool called ‘Subject Enrolment in EPAD’ (SEEPAD), so EPAD partners could visualise many aspects of the whole research participant recruitment process
• Publication of several manuscripts on the EPAD Registry and the prescreening for EPAD Trial-Ready Cohort

WP4 (EPAD Cohort and EPAD Trials)

• May 2016: First participant screened for the LCS
• December 2017: 10 Trial Delivery Centers opened
• February 2018: 500 participants screened for the LCS
• June 2018: First letter of intent signed by an intervention owner and first appendix writing group kick-off meeting for the PoC Platform
• July 2018: Launched PoC platform and had first EPAD booth at AAIC in Chicago
• September 2018: 1000 participants screened for the LCS
• April 2019: Second letter of intent signed by an intervention owner to join the PoC Platform
• December 2019: The number of trial ready participants (Amy + and CDR 0.5) had increased to 9.7% from 5% at the beginning of 2019.
• December 2019: 30 TDCs had been opened compared to 21 at the beginning of 2019
• March 2020: Over 2000 participants screened for the LCS before closure

WP5 (Project Management)

• 9 amendments of the IMI Grant Agreement, including 2 project no-cost extensions
• 2 amendments of the Project Agreement
• Organisation of 5 General Assembly meetings
• Coordination of 4 Periodic Reports
• Coordination of production – including formal review process – and submission of 63 deliverables
• Work Plan monitoring and follow up on milestones achievement
• Maintenance of internal repository platform (TeamworkPM), distribution lists and internal bulletin production

WP6 (Dissemination)

• Communication activities were carried out in line with the strategy outlined in the Dissemination and Communication Plan with regular updates to the EPAD website, mailing of a quarterly external newsletter and active presence on social media channels
• Numerous dissemination opportunities to present the project and its progress were taken at an increasing number of scientific conferences and events
• More than 30 EPAD videos have been uploaded on the EPAD YouTube channel (i.e. videos, webinars)
• Development of an EPAD Research Gate page to share and download EPAD publications
• Development of 5 press releases and several flyers/brochures

WP7 (Business Model and Sustainability)

• Creation of the 5-component model
• Funding secured for the maintenance of LCS data and samples
• Funding secured for communications, including maintenance of the website
• International Site Network (GAP-EPAD) & Registers– Business plan in place (funding application to happen by end 2020)
• EPAD Academy to potentially expand across the IMI Neurodegeneration portfolio with support from Neuronet

WP8 (Ethical, Legal and Social Implications)

• Developing an ethical framework for the project
• Developing a procedure and supporting materials for the communication of research results to participants as part of clinical trial recruitment
• Conducting research on ethical questions related to risk communication and the experience of EPAD research participants
• Working with sites across the project to set-up the EPAD Participants’ Panel

We would like to thank all the EPADistas and research participants for their work, enthusiasm and dedication to the EPAD initiative.

Could you tell us a bit about you?

I am an expert psychologist with a special interest in cognition and its measurement. I have recently been appointed Chief Science Officer at Neurotrack and am Principal Consultant at Metis Cognition, a psychology practice established to advise with the selection and successful integration of cognitive testing into therapeutic development programs. I am also an Associate Professor at the Alzheimer Center of the VUmc in Amsterdam and Visiting Professor at King’s College London.

You are a member of the EPAD Clinical and Cognitive Outcomes Scientific Advisory Group (CCO-SAG). Could you please tell us more about this group, its work and outcomes?

Cognition has a key role and I was delighted when Karen Ritchie and Michael Ropacki asked me to join the CCO-SAG. We were very keen to ensure the work was a transparent process and the initial research reviewing the literature was really helpful as a place to start as we put a natural boundary on the possible ways of thinking about this. After the CCO-SAG met, we published a paper which was essentially an overview of our discussions as well as details of the assessments that we finally determined would be the most useful ones. I think the most obvious immediate outcome was that paper, which has since been very widely cited. You can find the paper here. A further publication followed recently and both papers have hopefully been helpful to people working in the field, both inside and outside of EPAD.

Now we are working into the opportunity to review our work and data. Just a couple of months ago, we completed an analysis of the EPAD baseline data and we have picked out a number of useful pieces of information. We now know much more about EPAD cohort cognitive performance and we are now determining which combination of tests will be the most useful for institutions who want to screen for Alzheimer’s disease. I think we had some reasonably good ideas, but the EPAD process has allowed us to evaluate and test those ideas. We are at the point where we are able to share the findings of the studies we have conducted.

What value do you see in public-private collaboration and networking with related initiatives?

I think one of the really rewarding things about this experience is that you have a strong feeling when you are connected to EPAD, that everybody’s opinion is going to be accounted for, and everybody has a lot to contribute. I’ve long believed that public-private collaborations are amongst the best ways to make progress. This has been true of my own activities, as I spend part of my time conducting academic collaborations and the rest of the time I am working from private organisations, typically pharmaceutical companies. My consultancy is very much a blend of a public-private interaction and I have followed this approach very successfully for the last 20 years. I think this is because the academic side is feeding new information, new findings, new ways of thinking about these issues and the private side, particularly the pharmaceutical and biotech companies, are very good at getting the job done, the combination is very potent.

What are the most prominent challenges you see in Alzheimer’s disease research?

We still have a good number of compounds in the pipeline and we have already seen some value in terms of either preventing progression or giving people some symptomatic relief. The main challenge I see is the need to detect early as possible signs that people are at risk for developing the disease. I think the general public still think that it is a disease of the elderly and our experience is that it is absolutely not always the case. We are seeing much younger people receiving confirmed diagnosis. The big challenge for me is trying to find a methodology that ensures we pick up cases as early as we possibly can, and then make interventions that will slow and perhaps even stop progression.

We are pleased to inform you that the 2020 William Farr Medal of the Worshipful Society of Apothecaries was awarded to our Project Co-coordinator Craig Ritchie in recognition of the substantial impact made at a global level on the wellbeing of older people through leadership of dementia prevention research and service innovation, merging expertise in translational epidemiology with psychopharmacology and clinical trials design and delivery, noting determination to see research from own projects and elsewhere rapidly embedded in clinical practice and public health policy.

Congratulations Craig on receiving this year’s William Farr Medal Award – well deserved!

This medal is awarded to medical practitioners who have made an outstanding contribution to the care of elderly people as part of their clinical and/or research work in the United Kingdom. The award was instituted in 2006 and consists of a cheque for £1,000 and a medal.

The SPEAR (Study of Participant Experience of Alzheimer’s disease Research) study was carried out as part of EPAD’s Work Package on the Ethical, Legal and Social Implications of the project (ELSI). In the early stages of EPAD, the ELSI team pointed to the extent and intensity of tests and measurements deemed necessary to provide a sufficiently detailed picture of disease progression in contemporary Alzheimer’s disease research.

The SPEAR sub-study aimed to better understand participation in Alzheimer’s disease research, in order to improve study experience, informing future approaches to recruitment and retention and provide evidence for the assessment of ethical questions related to study participation. SPEAR was a mixed-method study. Both quantitative and qualitative arms of the study consider:

• Motivations for taking part in EPAD and prior experience of research
• Experience and ‘burden’ of EPAD research tests and assessments
• Willingness or ‘readiness’ to take part in future clinical trials.

The SPEAR findings provide insight into motivations, expectations and experiences of research participation. They emphasise the importance of altruism as a motivation for participation, but also that motivations overlap, change over time and may differ as participants consider clinical trial participation. Both quantitative and qualitative data emphasise that participants’ experiences of the EPAD LCS were positive, despite the intensity and discomfort of some tests. The qualitative data in particular suggest the importance to this of the interactions and relations with researchers and staff throughout the study process. Finally, the findings suggest that the majority of EPAD LCS participants would be willing to take part in a clinical trial, but that the timing, location and duration of such trials is critical.

Sincere thanks are due to all the EPAD participants who took part in both arms of the SPEAR sub-study, to the local EPAD sites for their help circulating the survey, to members of the EPAD ELSI workpackage and to members of the EPAD consortium for contributing to the development of the study questionnaire.

You can download the report on our study of participant experience in EPAD here.

For any further details, please contact Richard Milne (rjm231@medschl.cam.ac.uk) and Natassia Brenman (nkf23@medschl.cam.ac.uk).

Lucy Stirland has been awarded the 2020 Porto Research Award from the European Federation of Psychiatric Trainees (EFPT) for her paper using EPAD V500.0 data, published last year in the Journal of Alzheimer’s Disease. The aims of this award are to encourage psychiatric trainees to conduct research and contribute to the engagement of psychiatry trainees in the EFPT.

The article for which Lucy received recognition was conducted within the EPAD project using the V500.0 dataset of the EPAD Longitudinal Cohort Study. This was the first study to explore the association between multimorbidity and cerebrospinal fluid amyloid-β42 (CSF Aβ). The results were surprising as the more conditions people had, the less likely they were to have a positive result for amyloid. She will be presenting her work at the EFPT Forum held virtually in early July.

Lucy Stirland is a trainee in Old Age Psychiatry in Edinburgh, UK. She recently defended her thesis titled “Epidemiology of multimorbidity and polypharmacy in ageing: a complementary analysis of mental and brain health in three datasets”. Her thesis focused on the mental and brain health of people with multiple physical conditions. Most people with one long-term condition have more than one illness, so it’s important to study combinations of diseases. Lucy looked at data from three sources: EPAD, the PREVENT Dementia study and routinely collected data from the Scottish National Health Service.

Congratulations Lucy! Well-deserved!

Lucy Stirland received the 2020 Porto Research Award for the following paper:

Title: Associations Between Multimorbidity and Cerebrospinal Fluid Amyloid: A Cross-Sectional Analysis of the European Prevention of Alzheimer’s Dementia (EPAD) V500.0 Cohort

Abstract: Background: Multimorbidity (the co-occurrence of multiple chronic conditions) is increasingly common, especially among people with dementia. Few neuroimaging studies have explored amyloid biomarkers in people with multimorbidity. Objective: We aimed to conduct the first study of the association between multimorbidity and cerebrospinal fluid amyloid-β42 (CSF Aβ). Method: The European Prevention of Alzheimer’s Dementia (EPAD) Longitudinal Cohort Study V500.0 dataset includes volunteers aged ≥50 years from 12 sites. Participants undergo detailed phenotyping, including CSF measures and a self-reported medical history. Using logistic and linear regression analyses, we explored the association between multimorbidity and continuous chronic condition count with CSF Aβ positivity (Aβ42 <1000pg/ml) and continuous CSF Aβ concentration. All models were adjusted for age, sex, APOE status, education, and family history of dementia. Results: Among 447 eligible participants without dementia, the mean (SD) age was 66.6 (6.6) years, 234 (52.3%) were women, and 157 (35.1%) were amyloid positive. With chronic conditions regarded as pseudo-continuous, each additional condition carried a decreased likelihood of amyloid positivity (OR = 0.82, 95% CI: 0.68–0.97; p = 0.026). With CSF Aβ as a continuous variable, each additional condition was associated with an increase of 54.2 pg/ml (95% CI: 9.9–98.5, p = 0.017). Having ≥2 conditions was inversely associated with amyloid positivity (OR 0.59, 95% CI: 0.37–0.95, p = 0.030) compared to one or none. Conclusion: Our findings suggest that the established association between multimorbidity and dementia may be due to a pathway other than amyloid. However, this cross-sectional study does not allow us to make causal inferences. Longitudinal work is required to confirm the inverse association found.

The paper is available at: https://doi.org/10.3233/JAD-190222 (open access here).

Could you tell us a bit about you and your work?
After studying Cognitive Neuroscience and Neuropsychology in Rome I started my PhD in Amsterdam as part of the EPAD project. My work within EPAD consists in analysing neuroimaging outcomes to first create a shared and publicly available dataset for internal and external researchers and second extract useful information about brain organization in preclinical Alzheimer’s disease. As a researcher, I’m particularly interested in studying brain network abnormalities through different MRI sequences and investigate how these relate to Alzheimer’s dementia.

You are a member of the EPAD Imaging Scientific Advisory Group (iSAG). Could you please tell us more about this group, its work and outcomes?
EPAD iSAG is a group of expert researchers in the field of neuroimaging which I have the luck of being part. The first goal we pursue in our work is the creation of a standardise pipeline for pre-processing and quality control of EPAD MRI data. This semi-automated pipeline will deal with the high diversity and variability of the EPAD cohort and deliver to researchers an high-quality imaging dataset. Furthermore, we aim for the identification of changes in brain structural and functional organisation due to the early development of Alzheimer’s disease.

How VUmc is contributing to facilitate the EPAD imaging data access?
At the VUmc, we work on setting up and maintaining the access to the EPAD xNAT platform: the online platform to access EPAD imaging data. When a data request is accepted by the EPAD committee, we provide researchers with credentials to access the system and support on the possible problems they can encounter. Moreover, we’re working on creating numeric derivatives describing brain morphology and function that can directly be used by researchers with no experience with MRI processing.

What are the most prominent challenges you see in Alzheimer’s disease research?
The creation of disease-specific therapies, still too few, is the challenge of our time. To date, diagnosed people have low expectation and bleak prognosis with no real solution. Disease onset, progression and spreading through the brain are still poorly known processes. With EPAD and in my future works we hope to bring evidence from different research fields together to help develop an accurate and unified model of Alzheimer’s disease progression that will have an impact on clinical and pharmacological trials. My hope is that research and clinical world will start collaborating more closely making sure to progress together toward an unique goal.

The European Prevention of Alzheimer’s Dementia (EPAD) project is very pleased to announce the external release of its second wave of data including the baseline data from the first 1.500 research participants (V1500.0).

“This most recent and substantial data release from the EPAD cohort will undoubtedly have a major impact on our understanding of Alzheimer’s disease at very early stages of its development. Releasing this data to the global research community for free and rapid access marks a major milestone for EPAD and will hopefully set a standard for open data access that will ultimately benefit the millions of people worldwide at risk of developing Alzheimer’s dementia.”, said Craig Ritchie, EPAD Co-coordinator.

The previous V500.0 data release went into open access in November 2019. All the data set will be made available via secure online workspaces in order to facilitate collaboration between people and teams with similar research aims. To access the data, you will need to make an online request by visiting the EPAD website, where you will find a variety of resources to support your research.

In the chosen nomenclature

• V1500.0: V=version, “1500” is the number of sequentially recruited research participants in each dataset and ‘.0’ refers to the study visit the dataset includes up (visit 0 refers to the baseline data).
• V500.0: V=version, “500” is the number of sequentially recruited research participants in each dataset and ‘.0’ refers to the study visit the dataset includes up (visit 0 refers to the baseline data).

In addition, we are pleased to let you know that the MRI imaging data access for the first 500 participants at baseline (V500.0) is now available to both internal and external researchers. All requests for EPAD LCS MRI data will be recorded by the EPAD LCS Research Access Process. EPAD partners and external researchers will have the possibility to transfer the MRI data and images from the EPAD LCS XNat to their own databases.

If you experience any technical issues or if you want more information please submit your query to epadlcsra.admin@ed.ac.uk.