The identification ofgenetics of is a crucial research issue to better understand the and deal with it better. The progress of the analysis of the human, coupled with the implementation of large pan-genomic association studies — these studies consist of analyzing the entire genome of thousands, or even tens of thousands of individuals, healthy or sick, to identify risk factors associated with specific traits of the disease — today allow important advances in the field.
Alzheimer’s disease is the most common ofaffecting approximately 1,200,000 people in France. It is a complex multifactorial pathology, which generally appears after the age of 65 and for which there is a strong genetic component. The majority of cases would be caused by the interaction of from genetics with .
If the disease is better and better understood, there is currently no treatment to cure it. The drugs available are mainly aimed at slowing down cognitive decline and reducing certain behavioral problems. One of the major challenges of research is to better characterize the genetic risk factors of the disease, to better understand its origins by identifying the physiopathological processes involved (all the functional problems caused by a disease or a particular condition), and thus propose.
As part of an international collaboration, and under the coordination of Inserm research director Jean-Charles Lambert, researchers from Inserm, the Institut Pasteur de Lille, the Lille University Hospital and the University of Lille ledgenome-wide association Genome-wide association studyGWAS) on the largest group of Alzheimer’s patients set up so far — the researchers here looked at the genetic data of 111,326 people who received a Alzheimer’s disease or having relatives affected by the disease and 677,663 healthy “controls”. These data come from several large European countries grouped together within the consortium European Alzheimer and Dementia Biobank (BDEA).
Encouraged by progress in the analysis ofthese studies consist of analyzing the entire genome of tens of thousands, or even hundreds of thousands of individuals, healthy or sick, to identify genetic risk factors associated with specific traits of the disease.
Using this method, the scientists were able to identify 75 regions of the genome (called loci) associated with Alzheimer’s, 42 of which had not previously been implicated in this disease. ” After this important discovery, the rest of our work consisted in characterizing these regions of the genome that we had identified to give them meaning in relation to our biological and clinical knowledge, and therefore better understand the cellular mechanisms and the processesat work “, emphasizes Jean-Charles Lambert.
Highlighting pathological phenomena
In Alzheimer’s disease, two pathological cerebral phenomena have already been well documented: the accumulation ofbeta-amyloids and modification of Tau, a which is found in the form of aggregates in neurons.
Scientists here have confirmed the importance of these pathological processes. Indeed, their analyzes of the different regions of the genome confirm that some are involved in the production of amyloid peptides and in the functioning of.
Moreover, these analyzes also reveal that a dysfunction ofinnate and the action of (immune cell present in the which acts as a “garbage collector” by eliminating toxic substances) is at work in Alzheimer’s disease.
Finally, this study demonstrates for the first time the involvement in disease of the tumor necrosis factor-alpha (TNF-alpha)-dependent signaling pathway — tumor necrosis factor-alpha is aprotein of involved in the stunt of the particularly in tissue damage mechanisms.
These results confirm and strengthen our knowledge of the pathological processes involved in the disease, and open up new avenues for therapeutic research. For example, they confirm the interest of conducting clinical trials on treatments targeting theto continue work on microglial cells, initiated a few years ago, but also to target the TNF-alpha signaling pathway.
The usefulness of the genetic risk score
Based on their findings, the researchers also constructed a genetic risk score that helps to better assess who among people withwill progress to Alzheimer’s disease, within three years after the clinical demonstration of the disorders. ” This tool is currently not intended for clinical practice at all, but it could be very useful in setting up therapeutic trials to categorize participants according to their risk and better assess the benefit of the drugs tested. », explains Jean-Charles Lambert.
The team now wishes to continue their work in an even larger group to validate and extend their results. Beyond this exhaustive characterization of the genetic factors of Alzheimer’s disease, the team is also developingfrom and molecular to determine their roles in the development of the disease.
Moreover, since genetic research has for the moment mainly been carried out on populations of Caucasian origin, one of the future challenges will be to carry out the same type of study in other groups to determine whether the risk factors are the same from one population to another, which would reinforce their importance in the physiopathological process.