Although Alzheimer’s disease is not hereditary in 99% of cases, genetic factors can increase the risk of developing it. Therefore, Inserm estimates that among the cases that occur in people under 65, only 10% are in people with rare inherited familial forms of the disease. In these inherited forms, it is the mutation of a particular gene that systematically causes the disease in the person that carries this modification of the genome. Today, faced with the lengthening of life span and the continuous increase in the number of cases resulting from it, the main challenge is to predict the early onset of the disease in order to cure it before the first symptoms appear. The presence of amyloid plaques (aggregates of disease-defining proteins) in the brains of older people without cognitive decline has been shown to significantly increase the risk of developing Alzheimer’s disease in later years.
In fact, the degeneration of neurons that occurs in Alzheimer’s disease is partly due to the abnormal accumulation of a protein called beta-amyloid peptide (Aß peptide) outside nerve cells. This accumulation of proteins leads to the formation of “amyloid plaques” or “senile plaques”. Their presence can help determine which people are affected and especially which people will develop the disease. But to date, the detection of these plaques in the brain can only be done with an expensive imaging method, unusable in routine medicine, called PET-MRI (Positron Emission Tomography-Magnetic Resonance Imaging), a medical imaging examination by scintigraphy performed. in a nuclear medicine ward) or by dosing in plasma or cerebrospinal fluid (lumbar puncture). On the other hand, detection is only possible late, when amyloid plaques are present in the brain, just before the onset of symptoms.
A score associated with the presence of amyloid plaques in the brain
In a study published in the scientific journal “Neurology”, researchers from the Institut du Cerveau * started from the observation that although Alzheimer’s disease is not hereditary (except in 1% of cases), it has been shown that there were factors of genetic predisposition, that is, increasing the risk of developing the disease. Previous studies have shown in particular that people who carry a particular allele of the APOE gene, APOEe4, have a 3 to 15 times greater risk than non-carriers, but also that some patients with Alzheimer’s disease do not carry this allele. Since then, other studies based on comparing the frequencies of genetic variants among several thousand patients and control individuals have made it possible to identify more than 40 predisposing variants to the disease. Each of these variants being neither necessary nor sufficient, only a combination of several of them (multigenic risk) gives the individual a greater risk of developing the disease.
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Based on this knowledge, the scientific team hypothesized that a multigene score could be associated with the future appearance of amyloid plaques in the brain, thus enabling early targeting of those at greatest risk of developing the disease. The study initially focused on a cohort called “INSIGHT” from the Institute for Memory and Alzheimer’s Disease, which included 291 asymptomatic elderly people, 83 of whom had brain amyloid plaques. Researchers demonstrated that an optimized polygenic score comprising 17 Alzheimer’s disease predisposition variants other than APOE is associated with the presence of amyloid plaques in the cohort, knowing that this score could be validated in an independent cohort. Although these results are preliminary, the researchers still believe so show an association between the presence of brain amyloid plaques and a combination of 17 genetic variants, of which the individuals studied are carriers. “
It also turns out that this score is valid in people who “carry” APOE4 as well as in “non-carriers”, a result which therefore demonstrates that there are many other genetic factors besides APOE involved in the formation of amyloid plaques. This finding is important as the genetic load conferred by these 17 variants is assessed, prior to a possible detection of amyloid plaques in the brain or plasma, ” it would make it possible to identify the patients most at risk of developing amyloid plaques very early and therefore to be able to prevent the onset of the disease thanks to a more interventional follow-up. concludes the scientific group. Because if there is no cure for Alzheimer’s disease, adequate treatment can slow its progression and improve the life of the patient and those around him. It is still necessary to act in time, thanks to the earliest possible diagnosis. Note that health insurance estimates Alzheimer’s disease to be the most common neurodegenerative disease in France, with 1.2 million people affected.
* The team “Alzheimer’s disease, prion diseases” co-directed by Marie-Claude POTIER, CNRS researcher at the Institut du Cerveau,