ALZHEIMER: Identification of 75 genetic risk factors

The authors point out that Alzheimer’s disease is the most widespread form of dementia. It is estimated that more than 150 million people could be affected by 2050. The disease is multifactorial but has a strong genetic component. Today, there is no cure, the drugs available aiming mainly to slow cognitive decline and reduce certain behavioral disorders.

By better characterizing risk factors, it becomes possible to prevent modifiable factors and to target genetic factors.

Target, through new therapies, the molecular pathways involved in the disease.

The study: the international team therefore focused on these genetic factors and is conducting here a genome-wide association study (GWAS: Genome Wide Association Study) in a large sample of Alzheimer’s patients. This type of study makes it possible to analyze the entire genome of tens of thousands or hundreds of thousands of individuals, healthy or sick, and to identify the genetic risk factors associated with specific aspects of the disease.

  • 75 regions or “loci” of the genome have been identified as associated with Alzheimer’s disease, 42 of which had never been implicated in the disease before;
  • these regions were then characterized by the researchers, in order to better understand their clinical and biological implications, and therefore the cellular mechanisms and pathological processes involved.

Several pathological brain phenomena are here confirmed with the identification of these loci:

  • the accumulation of amyloid-beta peptides already well documented in the disease;
  • and modification of the Tau protein, whose aggregates in neurons are equally characteristic of the disease;
  • some of the identified genomic regions appear to be involved in the production of amyloid peptides and in the function of the Tau protein;
  • dysfunction of innate immunity and the action of microglia (immune cells present in the CNS which play a role in the elimination of waste and toxic substances);
  • the involvement in the disease of a signaling pathway dependent on tumor necrosis factor alpha (TNF-alpha), a cytokine involved in the maintenance of immune system homeostasis.

These findings provide a better overview of different disease processes involved in the disease and open new therapeutic avenues, such as the targeting of the amyloid precursor protein, the protection of microglia or even the targeting of TNF-alpha.

Towards a predictive biological signature of the disease? Based on these biological data, the researchers developed a genetic risk score model that will help identify people at high risk of developing Alzheimer’s disease.

The team now plans to replicate these findings on a larger sample, also including participants from diverse ethnic backgrounds.

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