Alzheimer’s disease: 75 genetic risk factors

The identification of genetic risk factors for Alzheimer’s disease is a crucial research challenge to better understand the pathology and better treat it. Advances in the analysis of the human genome, together with the implementation of large pan-genome association studies [1] they are now enabling major advances in the field: 75 regions of the genome associated with Alzheimer’s disease have been identified, providing hope for new avenues of treatment.

Researchers from Inserm, the Institut Pasteur de Lille, the University Hospital of Lille and the University of Lille within the U1167 laboratory “Risk factors and molecular determinants of age-related diseases” -in collaboration with European, American and Australian teams- have thus identified 75 regions of the genome associated with Alzheimer’s disease, which, as we know, is characterized by a progressive loss of memory and cognitive functions. Among them, 42 are new, as they have never been implicated in the disease before. The results, published in the journal Nature Geneticsreinforce the knowledge of the biological mechanisms involved in the pathology and enable the consideration of new ways of treatment and diagnosis.

Alzheimer’s disease is the most common dementia, affecting 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. Most of the cases would be caused by the interaction of different genetic predisposition factors with environmental factors.

If the disease is increasingly better understood, there is currently no treatment to cure it. The available drugs are mainly aimed at slowing cognitive decline and reducing certain behavioral disorders. One of the main research challenges is to better characterize the genetic risk factors of the disease, to better understand its origins by identifying the pathophysiological processes involved. [2]and thus propose new therapeutic targets.

As part of an international collaboration, researchers from Inserm, the Institut Pasteur de Lille, the University Hospital of Lille and the University of Lille conducted a pan-genomic association study (in English, genome-wide association studyGWAS) in the largest group of Alzheimer’s patients established so far [3]under the coordination of the research director of Inserm, Jean-Charles Lambert.

Encouraged by progress in genome analysis, these studies consist of analyzing the entire genome of tens of thousands, or even hundreds of thousands of individuals, healthy or diseased, to identify genetic risk factors associated with specific diseases.

Using this method, the scientists were able to identify 75 regions of the genome (called “loci”) associated with Alzheimer’s disease, 42 of which had not previously been implicated in this disease. ” After this important discovery, the rest of our work consisted of characterizing these regions of the genome that we had identified in order to make sense of them in relation to our biological and clinical knowledge, and thus better understand the cellular mechanisms and pathological processes at work. “, emphasizes Jean-Charles Lambert.

Highlighting pathological phenomena.

In Alzheimer’s disease, two brain pathological phenomena have already been well documented: the accumulation of beta-amyloid peptides (small proteins) and the modification of Tau, a protein, which is found in the form of aggregates in neurons.
Scientists here have confirmed the importance of these pathological processes. In fact, 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 the Tau protein.

In addition, these analyzes also reveal that a dysfunction of innate immunity and the action of microglia (an immune cell present in the central nervous system that plays a “garbage collector” role by eliminating toxic substances) is at work in Alzheimer’s disease .

Finally, this study shows for the first time the involvement of the signaling pathway dependent on tumor necrosis factor alpha (TNF-alpha) in the disease. [4].

These results allow confirming and reinforcing the knowledge of the pathological processes involved in the disease, and open new avenues of therapeutic research. They confirm, for example, the value of carrying out clinical trials on treatments directed at the amyloid precursor protein, of continuing the work on microglial cells, begun a few years ago, and also of TNF-alpha.

risk score

Based on their results, the researchers also constructed a genetic risk score that helps better assess who, among people with cognitive impairment, will progress to Alzheimer’s disease within three years of clinical identification of the disorder. ” This tool is not currently intended for clinical practice at all, but it could be very useful for 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 scale up their results. Beyond this comprehensive characterization of the genetic factors of Alzheimer’s disease, the team is also developing numerous molecular and cell biological approaches to determine their role in the development of the disease.

In addition, given that at the moment genetic research has been carried out mainly in populations of Caucasian origin, one of the future challenges will be to carry out the same type of study in other groups to determine if the risk factors are the same from one population to another. . another, which would reinforce its importance in the pathophysiological process.

[1] In English, we talk about genome-wide association study, GWAS. These studies consist of analyzing the entire genome of thousands or even tens of thousands of individuals, healthy or sick, to identify genetic risk factors associated with specific features of the disease.
[2] All functional problems caused by a particular disease or condition.
[3] The researchers here looked at genetic data from 111,326 people who had been diagnosed with Alzheimer’s disease or who had relatives affected by the disease, and 677,663 healthy “controls.” These data come from several large European cohorts grouped within the European Alzheimer & Dementia BioBank (EADB) consortium.
[4] Tumor necrosis factor alpha is a cytokine, an immune system protein involved in the inflammatory cascade, particularly in tissue damage mechanisms. TNFα (Tumor Necrosis Factor) is a protein secreted by T lymphocytes (a variety of white blood cells) that is involved in the inflammatory process and in immune reactions.

header photo : In Alzheimer’s disease, two brain pathological phenomena are already well documented: the accumulation of beta-amyloid peptides and the modification of Tau, a protein found in the form of aggregates in neurons. © NIH/Public domain

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