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Researchers from across Europe team up to decode the interplay between genetics and environment

For scientists studying the origins and pathways of Alzheimer’s disease, experimental animal and cell models are a critical tool. These models mimic the processes thought to be at play in human patients and allow researchers to assess possible treatments before moving into clinical trials. Yet most models of Alzheimer’s disease are unable to take into account the complex genetic and environmental factors involved in what’s known as late-onset ‘sporadic’ Alzheimer’s disease, which is the most common type of the disease.

An international research collaboration called DACAPO-AD is trying to change this. Led by Gabor Petzold, a professor at the German Center for Neurodegenerative Diseases (DZNE), DACAPO-AD (short for ‘Deciphering Interactions of Acquired Risk Factors and ApoE-mediated Pathways in Alzheimer’s Disease’), aims to elucidate the complex interactions between known genetic and environmental risk factors, with the goal of establishing the reliable new models of Alzheimer’s disease that scientists need to identify potential treatments.

At the intersection of genetics and environment
Researchers classify Alzheimer’s disease in different groups according to the age at onset. Early-onset inherited (or ‘familial’) Alzheimer’s disease is very rare, but half of the cases have a genetic cause that is relatively well understood. Then there’s what is known as late-onset sporadic Alzheimer’s disease. This type is far more common — accounting for more than 98% of cases — but the pathways leading to sporadic Alzheimer’s disease are much less well understood and look far more complex. The most important known genetic risk factor for sporadic Alzheimer’s disease is a gene called APOE-ε4, although not everyone with sporadic Alzheimer’s disease carries the gene, and some people who do carry the APOE-ε4 gene ultimately die without ever developing Alzheimer’s disease. Indeed, around a third of sporadic Alzheimer’s patients are APOE-ε4 -negative.

For the DACAPO-AD project, the challenge is to better understand the reasons for this heterogeneity, and the researchers are focusing on the role of environmental (or ‘acquired’) risk factors. They’re trying to uncover how a range of these different factors  — such as a high-fat diet, cardiovascular disease, traumatic brain injury, systemic inflammation and sleep problems — interact with the APOE-ε4 gene to result in an increased risk of Alzheimer’s disease. “It would be a real breakthrough in the field if we could understand, on a cellular or molecular level, how these risk factors trigger the onset and contribute to the progression of sporadic Alzheimer’s disease,” Petzold explained from his lab in Bonn, Germany. “Our hope is that this research will ultimately lead to better preventive strategies and novel treatment options.”

Pooling resources to speed up discovery
The high-level skills and technologies needed to approach these questions meant that international collaboration was not just beneficial but necessary. DACAPO-AD, which was selected for support in the 2015 JPco-fuND call, brings together research teams from four countries: in addition to Germany, researchers in Denmark, France and Sweden are bringing different expertise to the project. “We are a team of five labs from four different countries that are sharing technologies and data to more rapidly address the same common goals,” Petzold said.
The project partners were selectively identified to ensure that the combination of each lab’s unique skill set would enable the collaborators to work on questions that the individual labs wouldn’t have been able to take on alone. Moreover, all of the partners have agreed to share preliminary findings and technological developments freely within the team, with one of the consortium’s explicit goals being knowledge transfer. “We will give young researchers from each lab the possibility to travel to partner labs, Petzold explained. “This will allow our teams to learn new techniques, exchange data and get to know other researchers.”

Calling young researchers!
The Alzheimer’s field is quickly evolving and offers scientists and clinicians a host of exciting challenges. To early-career researchers who are considering specializing in Alzheimer’s disease, Petzold recommends surveying a broad range of researchers, including PIs and postdocs as well as students, to see what they think the most pressing questions are facing the field and where it’s headed. “In other words,” he explained, “what novel research finding would be a real breakthrough, and how do we get there?” He advises joining a lab with a hands-on PI who has the technological and financial resources to tackle these big questions. From there, a mix of perseverance and openness, he says, is most likely to yield success: “It’s important be diligent and work hard, but also to stay flexible for new research avenues and technologies that may emerge in the future.”

“I would be a bit sad if JPND only focused on projects with 3-5 countries involved. In these projects the researchers continue in the same way as they did before, and they do not experience these cultural influences from different specialists and you would not get this circular effect that can spread around to all the countries. So I say to JPND that you should support projects that involve as many of the participating countries as possible.”

What impact do you think JPND is having?
At the start I was not so sure about JPND because I felt it was more of a top-down idea where it is decided more-or-less from the Management Board what areas should be focused on, with the input of the Scientific Advisory Board. I was afraid that the research councils and funding organisations in each country would reduce their interest. Now, I can only give the example from my own country, Sweden, but I can say that they have been extremely positive to JPND, and they have put in extra funds, in addition to the support that already existed. This extra addition of funding is due to JPND, and I am sure that this is the case in most other countries. Globally, I think there is growing interest worldwide in JPND – we can see the collaborations starting with Canada, with interest also now coming from Asia and America.

What do you think are the most pressing issue in this area of research?
This is a field that is really evolving. From a societal perspective, disorders like Alzheimer’s, Parkinson’s and Vascular dementia are very common and are a high cost to society. That means in the future, with aging populations, greater efforts are required to stimulate research, and to simulate clinical work with these patients. Due to the increasing demand, and increasing age of populations, if we don’t do anything in research, there will be a collapse of our healthcare systems. So we need to focus not only on diagnostic processes, but we need to also develop new pharmacological treatment strategies for these patients.

What is the general feeling you get from researchers in this field?
There are different views from different categories of people. If you look from the GP/Doctor perspective, I can see that GPs are rather nihilistic. They have not yet seen any great success from the new drugs that are really the first-generation of pharmacological treatments in this area, so they may be a bit negative. However, from a society perspective we are forming teams of carers for community care. With more research these teams are really increasing their knowledge, and that gives back very positive feelings. From the specialist clinicians I think it is noticed that Nobel prizes are regularly given out in this field (e.g. prion-like properties, signalling systems in the brain, MRI and PET, new microscopes to study the interaction of neurons + chemical substances in the brain). It is a fascinating research area, and an area that is more and more recognised.

What would your advice be to younger researchers?
For young people who want to come into research, the brain is fascinating. The explosion in molecular biology, cell biology, genetic findings combined with the technological advancements seen now with MRI, functional imaging, positron emission tomography are very exciting for brain research. So even if we are not solving the ultimate question in the short term, we will see great progress through these new technologies coming into this field. I really want to combine fundamental knowledge about the diseases with technology and biochemical research, and to also give young people future possibilities not only for a clinical or academic career, but also to work with industry in the future. It is not only important for them but also for Europe. Europe has many strengths – we have good clinical work, good pre-clinical work, but have lost part of the industry. If we could really integrate these three, we would play a stronger part in developing new drugs and developing ideas within Europe.

Click here to read Bengt Winblad’s biography.