Professor Jean-Charles Lambert, who spearheaded the most extensive ever genome-wide association study for Alzheimer’s disease, outlines how the project has discovered 75 risk genes for Alzheimer’s disease.
Alzheimer’s disease is a progressive neurodegenerative condition and the most common form of dementia. As the population ages, cases of Alzheimer’s disease are increasing, and it is estimated that 14 million people in Europe will be affected by 2030. This poses a huge economic burden for healthcare systems, especially as there is currently no cure for the disease. However, a recent international study involving over 100,000 people with Alzheimer’s disease has revealed new insights that could inform new therapeutic interventions and preventative care. Researchers compared the genome of participants with Alzheimer’s disease with over 600,000 healthy individuals and were able to identify 75 risk genes for Alzheimer’s disease as well as 42 new genes which had not been previously linked to the condition.
Amalgamating the results of individuals’ genetic make-up means researchers now have access to a large dataset which will support efforts in identifying those at risk of developing Alzheimer’s disease in the future, even before symptoms appear. Lorna Rothery spoke to the project’s lead professor Jean-Charles Lambert, who is a research director at the French National Institute of Health and Medical Research to find out more.
How much of the disease risk for Alzheimer’s is based on genetics? What is known about the interaction between genetic, environmental and lifestyle risk factors?
Less than 1% of forms of Alzheimer’s disease (AD), mainly early-onset forms, are monogenic, i.e., a mutation in a gene that leads to the development of the disease. For the vast majority of forms, mainly late forms, the evaluation of the genetic component was carried out using large cohorts of twins in northern European countries. It appears that this component is particularly high for an age-related disease, between 60-80% of the attributable risk. However, we are talking about genetic susceptibility and subsequent probabilities in the general population, resulting in the combination of many genetic factors increasing or decreasing the risk of developing the pathology.
Incidentally, 20-40% of the attributable risk is due to environmental/lifestyle factors and their interaction with genetic risk factors. We have already characterised some of these environmental factors and most are similar to cardiovascular risk factors such as hypertension, diabetes, and obesity. There is no longer any doubt that sport is a very effective prevention tool. It is now estimated that a major change in environmental and lifestyle risks might reduce the risk of developing AD by 40% in the general population.
Understanding the interaction between the genetic and environmental determinants is difficult for essentially methodological reasons. Few studies have so far been able to convincingly apprehend this work and many efforts will be necessary to detect these interactions and assess their roles in the mechanisms leading to the development of the pathology.
Can you outline what you and your team discovered and the significance of this? What external factors – such as age, environment, and previous conditions – need to be considered in a study of this nature?
Our work aims to characterise the genetic component of Alzheimer’s disease and has enabled us to validate the association of 33 genetic determinants of the pathology and to propose 42 new ones. It is therefore a significant step forward to enhance our understanding of the genetic architecture of the pathology. However, in this type of study, we have certain constraints that do not necessarily allow us to go further in terms of examining the interaction of these determinants with environmental factors. In other words, we do not have sufficient information for most of the individuals included in our study. This is about to change, for example with the UK biobank which includes 500,000 people with follow-up and lots of epidemiological data available. However, since Alzheimer’s disease primarily affects older adults, it will take a good 10 years to obtain conclusive results.
Age is a complicated factor to take into account since the incidence of the disease increases sharply as we get older. The question is therefore whether the impact of a genetic factor can be dependent on the age at which a patient will develop the clinical expression of the pathology. In our case, we simply checked that age was not a confounding factor for the observed associations. We know that age did not bias our results. However, our study did not take into account the fact that certain genetic signals could be observed differently depending on the age of the patients. This is something we are still looking into.
How could your research help to inform future prevention strategies and new therapeutic interventions for Alzheimer’s disease?
Research on the risk genes for Alzheimer’s disease is above all basic research. Due to the very large genetic component, associated genes are expected to participate and cluster in major pathophysiological pathways of the disease. Thus, insights into genetic make-up will make it possible to propose key elements of these pathophysiological pathways and therapeutic targets. Genetics has thus unambiguously shown that microglia are essential to the development of the disease. This has opened up very promising new avenues of research. In our study, we were able to reveal, for the first time, the central role of the TNF-a pathway, opening up new therapeutic perspectives, especially since molecules targeting this pathway are already available.
Importantly, it now clearly appears from these genetic data that a polytherapeutic approach will probably be necessary because apart from a few exceptions – the monogenic forms of the disease – there are more than likely several entry points and paths to, unfortunately, develop the disease.
Our knowledge of the genetics involved in common forms of AD cannot be used as an individual diagnostic tool yet. On the other hand, what we were able to show in our paper is that this knowledge makes it possible to define groups of individuals more or less at risk of developing the pathology at the population level. It is very interesting because it will make it possible to optimise therapeutic trials and therefore accelerate the development of effective therapies. In the context of polytherapy, it will then be a question of proposing the most suitable treatments according to the pathophysiological processes involved for a given individual. Knowledge of the risk genes for Alzheimer’s disease will be the basis of personalised medicine.
This research is important today for the development of therapeutic approaches and in the not-so-distant future, the clinical management of patients at the earliest stage.
How do you hope to develop your research moving forward?
We will now seek to increase the number of patients studied but categorise our research by clinical data, brain imaging or biomarkers. The objective is to integrate large amounts of data to give us the most complete overview between the genetic determinants and the natural history of dementia. However, it will require a lot of resources.
Our studies focus predominantly on populations of European ancestries, and it is absolutely necessary for us, for obvious reasons, to extend our work to populations of different ancestries. Finally, having a list of risk genes for Alzheimer’s disease is good, but if we do not give biological and pathological meaning to this list, it is useless. We are also researching to better understand how these factors play a role at the biological level.
Jean-Charles Lambert, Ph.D.
Institut Pasteur de Lille, INSERM