a French team identifies 75 genetic risk factors

Lille, France— Lille researchers have identified 75 regions of the genome associated with Alzheimer’s disease, 42 of which had never been associated with the disease before. Jean-Charles LambertInserm research director at the Institut Pasteur de Lille, explains to Medscape these discoveries which make it possible to envisage new avenues of treatment and diagnosis.

Risk groups

Alzheimer’s disease is a complex multifactorial pathology, which affects approximately 1,200,000 people in France. The majority of cases would be caused by the interaction of different genetic predisposition factors with environmental factors. “The genetic component of Alzheimer’s disease is particularly strong: it reaches 60 to 80% of attributable risk”, specifies Jean-Charles LambertInserm research director at the Institut Pasteur in Lille. “Characterizing the genetic component of Alzheimer’s disease is an important issue, because this type of genetic analysis makes it possible to highlight the pathophysiological processes involved, but also because it makes it possible to develop genetic risk scores to determine, in a population , if groups of people are at risk of developing the disease. For the moment, this score cannot be used in the clinic”, he nevertheless wishes to indicate.

21 million variants studied

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 study, GWAS) on the largest group of Alzheimer’s patients implemented so far.

“We compared the genome of diseased individuals with that of individuals considered healthy to determine the frequency of genetic variants. We studied 21 million variants in 111,000 patients and 677,000 controls. If the frequency of these variants is higher in patients, it is associated with an increased risk and if it is lower, it is associated with protection”, develops Jean-Charles Lambert.

The researchers were able to identify 75 regions of the genome (loci) associated with Alzheimer’s disease, of which 33 were already known and 42 had so far not been implicated. “We have doubled our knowledge of Alzheimer’s disease with this study,” says Jean-Charles Lambert.

The researchers were able to identify 75 regions of the genome (loci) associated with Alzheimer’s disease, of which 33 were already known and 42 had so far not been implicated.

Importance of the inflammatory response

In Alzheimer’s disease, two cerebral pathological phenomena have already been well documented: the accumulation of beta-amyloid peptides 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. 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 the Tau protein. “The good news is that therapeutic strategies under development are already targeting these processes,” emphasizes the research director.

This study also confirmed and extended the involvement of the inflammatory response. “Alzheimer’s disease appears to be an immune disease with a significant inflammatory response, which notably involves microglial cells (immune cells that play a role of “garbage collector” in the central nervous system), but also the TNF-alpha pathway , tumor necrosis factor alpha”, explains Jean-Charles Lambert.

Genetic risk score

For him, the main message that emerges from this analysis is that monotherapy will probably not be effective in Alzheimer’s disease. “We need a polytherapy, with different entry points depending on the individual,” he summarizes.

Based on their results, the researchers have also constructed a genetic risk score that helps to better assess who, among people with cognitive impairment, will progress to Alzheimer’s disease, within three years after the identification. disorder clinic. This score is currently intended for setting up better targeted clinical trials and not for clinical practice.

The team now wishes to continue its work in an even larger group to validate and extend its results, while developing numerous cellular and molecular biology approaches to determine the role of these genetic factors in the development of the disease. “There are still a lot of things to discover and then we have to give them biological meaning,” comments Jean-Charles Lambert.

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.

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