Study sheds light on genetic causes of Alzheimer’s disease and other dementias

If we want to enhance our knowledge and treatment of Alzheimer’s disease, we need to identify genetic risk factors. Major advancements in the field are now being made thanks to advances in human genome analysis and genome-wide association studies.

Alzheimers

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75 regions of the genome have been linked to Alzheimer’s disease by researchers in Europe, the United States, and Australia. 42 of these regions are novel, which means they have never been linked to the disease before. The findings, which were published in the journal Nature Genetics, add to our understanding of the biological mechanisms at work and provide new treatment and diagnostic options.

Alzheimer’s disease is the most prevalent form of dementia in France, affecting over 1,200,000 people. This multifactorial disease with a significant genetic component generally occurs after the age of 65. The interplay of several genetic predisposition factors with environmental circumstances is assumed to be the cause of the majority of instances.

Even though the understanding of the disease is improving, there is yet no treatment. The drugs on the market are primarily intended to decrease cognitive decline and reduce certain behavioral issues. One of the primary research objectives is to better describe the disease’s genetic risk factors by identifying the pathophysiological mechanisms at work and therefore offer novel treatment targets, to better understand the disease’s origins.

Under the direction of Inserm Research Director Jean-Charles Lambert, researchers from Inserm, Institut Pasteur de Lille, Lille University Hospital, and Université de Lille conducted a genome-wide association analysis (GWAS) on the biggest Alzheimer’s patient group yet assembled.

These investigations, which have been assisted by improvements in genome sequencing, include studying the complete genome of tens of thousands or hundreds of thousands of people, both healthy and sick, to discover genetic risk factors linked to specific characteristics of the disease.

The scientists were able to find 75 areas (loci) of the genome connected with Alzheimer’s disease using this strategy, 42 of which had never been linked to the condition before.

Following this major discovery, we characterized these regions in order to give them meaning in relation to our clinical and biological knowledge, and thereby gain a better understanding of the cellular mechanisms and pathological processes at play.”

Jean-Charles Lambert, Research Director, Institut Pasteur de Lille, Lille University Hospital, Université de Lille, INSERM

Highlighting pathological phenomena

Two pathological brain events are already well recognized in Alzheimer’s disease: the buildup of amyloid-beta peptides and the alteration of the protein Tau, which accumulates in neurons.

The experts validated the significance of these pathogenic processes in their study. Their examinations of several genomic areas reveal that some are involved in the creation of amyloid peptides and the activity of Tau proteins.

Furthermore, these studies show that Alzheimer’s disease is caused by a malfunction of innate immunity and the action of microglia (immune cells found in the central nervous system that operate as “trash collectors” by removing hazardous compounds).

Finally, our research demonstrates for the first time that the TNF-alpha-dependent signaling pathway is implicated in disease.

These discoveries add to the understanding of the disease’s pathological processes and open up new options for therapeutic study. Researchers support, for example, the conduct of clinical trials of amyloid precursor protein-targeted therapies, the continuing microglial cell research that began a few years ago, and the targeting of the TNF-alpha signaling system.

Risk score

The researchers also developed a genetic risk score based on their findings to better assess whether individuals with cognitive impairment would acquire Alzheimer’s disease within three years of clinical manifestation.

While this tool is not at all intended for use in clinical practice at present, it could be very useful when setting up therapeutic trials in order to categorize participants according to their risk and improve the evaluation of the medications being tested.”

Jean-Charles Lambert, Research Director, Institut Pasteur de Lille, Lille University Hospital, Université de Lille, INSERM

The researchers would want to continue their research in a larger population to confirm and broaden their findings. Aside from detailed identification of Alzheimer’s disease genetic variables, the group is also developing several cellular and molecular biology tools to evaluate their roles in the disease’s progression.

Furthermore, because genetic research has primarily focused on Caucasian populations, one of the future considerations will be to conduct similar studies in other groups to see if the risk factors are the same from one population to the next, thereby reinforcing their importance in the pathophysiological process.

Source:
Journal reference:

Bellenguez, C., et al. (2022) New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nature Genetics. doi.org/10.1038/s41588-022-01024-z.

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