Authors: Carol Routledge (Alzheimer's Research UK), Bart de Strooper (UK Dementia Research Institute) & James Pickett (Alzheimer's Society)
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.
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.