In line with World Alzheimer’s Month this September, we’ve brought together a panel of experts to discuss the genetics of Alzheimer’s disease in a 3-part debate. How much do genetics contribute to Alzheimer’s risk? What are the research priorities in this field? And could routine genetic screening and personalized treatments one day be a reality for patients? With Alzheimer’s now classed as the most feared disease in the aging global population, our experts address these questions and more. Together bringing insights from across research, social and charity perspectives, our experts are Kevin Morgan (University of Nottingham, UK), Rita Guerreiro (UCL, UK) and Clare Walton (Alzheimer’s Society, UK).
You can read the third and final installment of the debate below, which looks ahead at future research trends and the potential for personalized medicine.
Catch up on Part 1, covering the contribution of genetics to Alzheimer’s risk, the differences between early- and late-onset disease, and how new technologies have advanced our understanding of this ever-expanding field, here, and Part 2, which focused on current research priorities, challenges and ethical concerns, here.
Looking ahead, with an ever increasing knowledge of the genetics underlying Alzheimer’s disease (AD), how do you anticipate this could change the way the disease is diagnosed in the next 10 years?
Rita Guerreiro: The combination of genetic and other factors seems to be having positive outcomes on the prediction of disease risk. LOAD has recently been confirmed to be enriched with a polygenic component and an area under the receiver operating curve (AUC) of 78% has been reached by using a model integrating a polygenic score in addition to information on age, sex and APOE haplotype. Prediction accuracy is expected to improve with the identification of novel genes, mutations and variants involved in the disease.
For EOAD caused by APP, PSEN1 and PSEN2 mutations, the main potential problems associated with a genetic diagnosis come from the possibility of reduced penetrance and unclear pathogenicity of the mutations. This will be overcome by the increase in the size of databases containing population- and disease-specific genetic data, by continuously curating variants of clinical relevance and by integrating these data with other sequencing strategies (such as ChIP-seq and RNA-Seq), proteomics and metabolomics.
To accurately predict a person’s risk of developing AD is absolutely essential for diagnosis, but also very important for the improvement of clinical trials.
We are seeing an increasing shift towards personalized medicine for a number of neurological disorders – could this be a reality for AD patients in the next decade?
RG: Yes. Even though pharmacogenomics and effective personalized therapies applied to AD may take more than a decade to be developed and implemented, I believe genome editing for monogenic AD cases can be a reality sooner than that. This became more feasible after the description of the base-editing CRISPR technique that does not need to cut both strands of the DNA double-helix to alter the genetic code, being able to convert a single base to another. This is particularly important because the vast majority of AD associated mutations in APP, PSEN1, PSEN2 and APOE are missense changes. Even though this technique is not without unintended changes and it originally worked in ~70% of tested cells, it is very promising. Future improvements of the technique can lead to a better specificity and precision of CRISPR/Cas9 genome editing and even the alteration of only ~70% of cells might be sufficient to minimize symptoms in certain cases. The reverse logic can be applied to mutations known to be protective for AD. This is the case of APP p.Ala673Thr that could be introduced in people known to be at high risk for the disease. Additionally, information obtained from advances in understanding and predicting AD risk can be used to modulate early-life behaviour and subsequently influence the onset and progression of AD with the goal to delay or prevent the disease. Many challenges need to be overtaken to make these approaches a reality for AD, and it may take longer than a decade, but nonetheless these are interesting possibilities that could make a real impact in our fight against AD.
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About the experts
Kevin Morgan – University of Nottingham, UK
Kevin Morgan is Professor of Human Genomics and Molecular Genetics at the University of Nottingham and works on the genetics of AD. His research team has extensive experience analyzing large datasets from GWAS’, Chip and Next Generation Sequencing (NGS) – this has resulted in over 90 publications in the last 7 years. He has established the ARUK DNA Bank (6500-plus samples) and together with the Mayo Resource (6000-plus) has access to one of the largest collections of samples worldwide. This has resulted in instrumental roles in designing, implementing and analyzing output from GWAS and NGS in LOAD, which to-date has identified over 30 new genetic associations with AD.
Rita Louro Guerreiro – UCL, UK
Rita Guerreiro is a proleptic Lecturer and an Alzheimer’s Society Senior Research Fellow working in the Department of Molecular Neuroscience, Institute of Neurology, University College London. She has recently been appointed a Foundation Programme leader within the UK Dementia Research Institute at UCL.
She received her BSc in Biomedical Sciences in 2002, her MSc in Biomolecular Methods in 2005 from the University of Aveiro, and her PhD in 2010 from the University of Coimbra, Portugal. Her PhD was supervised by John Hardy and Catarina Oliveira and was conducted at the Laboratory of Neurogenetics, National Institute on Aging, NIH, USA.
Her current interests include the analysis of genetic variability in several neurological diseases. This is being driven by the application of recently developed genetic and genomic technologies, like whole-genome genotyping and next generation sequencing, to the study of families and population cohorts.
Dr Guerreiro has published 119 journal articles, is a reviewer for several scientific journals and funding institutions and is part of the Specialist Advisory Committee for the Lewy Body Society. Dr Guerreiro was awarded the 2014 European Grand Prix for Young Researcher by the Fondation pour la Recherche sur Alzheimer/SCOR; the 2015 Alzheimer’s Society Dementia Research Leaders Award in the category ‘Academic Achievement’; the Fondazione Gino Galletti Neuroscience Prize 2015; and the 2016 Alzheimer’s Research UK Young Investigator of the Year Award.
Clare Walton – Alzheimer’s Society, UK
Dr Clare Walton is Research Communications Manager at Alzheimer’s Society where she leads the charity’s communications strategy for dementia research. Her role involves engaging a wide range of stakeholders with the Society’s research portfolio worth £30m and developing the Society’s positions on the latest advances in dementia research. Clare has an MA in Biochemistry from the University of Oxford (UK) and a PhD in Cellular Neuroscience from the Rockefeller University in New York (USA). Her PhD thesis investigated the ability of endogenous stem cells to functionally repair damage in the adult brain using songbirds. Before joining Alzheimer’s Society, Clare worked in the stroke field and has several years’ experience in communicating science to non-scientific audiences.