Alzheimer: new genetic risk factors identified

With approximately 1,200,000 people affected in France, Alzheimer’s disease is undoubtedly the most common form of dementia. But medicine doesn’t know how to cure it. However, a study published on Monday, April 4, allows us to understand it better, by identifying 75 genetic risk factors.

Researchers from Inserm, the Institut Pasteur de Lille, the University Hospital of Lille and the University of Lille collaborated with European, American and Australian teams to carry out this research work. Their study, published in the scientific journal Nature Geneticslists 75 regions of the human genome associated with Alzheimer’s disease, including 42 that have never been implicated in this pathology until now.

The complex multifactorial character and the strong genetic component of Alzheimer’s disease have been known for a long time. In fact, most cases would be caused by the interaction of different genetic predisposition factors with environmental factors. The characterization of the genetic elements of the pathology constitutes one of the great challenges of research, with the hope of better understanding its origins and proposing new therapies.

To do this, the international team that carried out this new study brought together the largest group of Alzheimer’s patients ever seen, in order to analyze their complete genomes. A total of 111,326 people participated: some had been diagnosed with Alzheimer’s, others had relatives affected by the disease. In parallel, 677,663 people served as healthy “controls”.

The data confirmed the important role of the accumulation of beta-amyloid peptides and the modification of the Tau protein, two brain pathological phenomena already implicated in the pathology.

According to Jean-Charles Lambert, director of research at theinsert, these analyzes also reveal “that a dysfunction of the innate immunity and of the action of the microglia (an immune cell present in the central nervous system that plays a role of ‘garbage collector’ by eliminating toxic substances) is at work in the disease of Alzheimer’s”. For the first time, the involvement of the tumor necrosis factor-alpha (TNF-alpha)-dependent signaling pathway has also been brought to light.

Improving diagnosis

These results shed new light on therapeutic research, opening new paths and confirming others. Scientists were also interested in improving the diagnostic process for Alzheimer’s disease. In light of their findings, they have constructed a genetic risk score, which makes it possible to better assess who, among people suffering from cognitive disorders, will progress to pathology in the three years after the disorders are identified.

At the moment, this tool is not dedicated to clinical practice but “it could be very useful in the implementation of therapeutic trials to categorize participants according to their risk and better assess the interest of the tested drugs”, explains Jean-Charles Lambert.

Given that until now genetic research has been carried out mainly in populations of Caucasian origin, the goal in the future will be to determine if the identified risk factors are the same from one population to another. The research team also plans to continue its work in an even larger group of patients and is interested, beyond genetics, in the involvement of cellular and molecular biology in the development of the disease.

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