They discover 42 previously unknown genes linked to Alzheimer’s disease

(CNN) — Another 42 genes linked to the development of Alzheimer’s disease have been discovered in the largest study to date on the genetic risk of the disease.

“This is a landmark study in Alzheimer’s disease research and the culmination of 30 years of work,” said study co-author Julie Williams, director of the UK Dementia Research Institute. from Cardiff University, in a statement.

“Certain lifestyle factors, such as smoking, exercise and diet, influence the development of Alzheimer’s disease. And taking action now to address them is a positive way to reduce risk to ourselves. “, he added. “However, between 60% and 80% of the risk of the disease is based on our genetics. And, therefore, we must continue to search for biological causes and develop much-needed treatments for the millions of people affected around the world.” he finished.

The previously unknown genes point to other disease progression pathways besides the well-known APOE e4 gene or the development of amyloid beta and tau proteins, which accumulate in the brain with devastating results as Alzheimer’s disease is progressing.

“Coming up with a long list of risk genes for Alzheimer’s disease is like having the pieces of a puzzle put together. And while this work doesn’t give us the complete picture, it does provide a framework. valuable for future development,” said Susan Kohlhaas, director of Alzheimer’s Research UK, who was not involved in the research.

According to the study, a set of newly discovered genes target very detailed reactions between proteins in the body that regulate how inflammation and the immune system can damage brain cells.

“The new risk variants identified in the present study have a significant association with the progression” of Alzheimer’s disease, explains the research published this Monday in the journal Natural genetics.

The discovery will provide scientists with potential new targets for treatments, drugs and lifestyle changes that could reduce the risk of fatal brain disease, experts say.

“The future of Alzheimer’s disease lies in precision medicine and prevention,” said Richard Isaacson, MD, director of the Alzheimer’s Disease Prevention Clinic at the Center for Brain Health at the University of Florida. Atlantic Schmidt College of Medicine.

“This work gives us a lot more tools to target Alzheimer’s disease more precisely over time,” said Isaacson, who was not involved in the study.

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New pathological pathways

The global study analyzed the genomes of 111,326 people with a clinical diagnosis of Alzheimer’s disease and compared them to the genes of 677,663 cognitively healthy people. The genomes were provided by clinics in more than 15 countries in the European Union, Argentina, Australia, Brazil, Canada, Iceland, Nigeria, New Zealand, the United Kingdom and the United States. United.

The research identified 75 genes linked to an increased risk of Alzheimer’s disease, 33 of which were already known. It also confirmed years of research on the role of amyloid beta and tau proteins.

Of the 42 new genes linked to Alzheimer’s disease, many cluster in various suspected but unconfirmed pathways of disease development. One of these pathways is the body’s immune system, which is designed to protect us from invading germs.

Several genes were associated with an immune regulator called LUBAC, which the body needs to turn genes on and prevent cell death. The study also found that microglia – immune cells in the brain responsible for ‘taking out the trash’, i.e. cleaning up damaged neurons – play a vital role in people with Alzheimer’s disease. .

Some of the newly discovered genes can make microglia less efficient. “Which could accelerate the disease,” Williams said.

Another key pathway, according to the study, involves genes associated with inflammation. The body uses inflammation as a defense mechanism to eliminate pathogens. But it also plays a role in eliminating damaged cells.

One protein that stood out in the study was tumor necrosis factor alpha (TNF), which the immune system makes to regulate inflammation. The study discovered a cluster of genes associated with this factor. The true function of this chemical is to rally the body’s defenses to fight. But it’s also the culprit of many autoimmune diseases, in which the body attacks itself, such as rheumatoid and psoriatic arthritis, Crohn’s disease and type 1 diabetes.

The study uncovered other complicated genetic interactions, illustrating that “Alzheimer’s disease is a multifactorial disease, made up of different pathologies, and each person has their own path,” Isaacson said.

“Clinicians always say, ‘Once you’ve seen one person with Alzheimer’s disease, you’ve only seen one person with Alzheimer’s disease.’ The disease presents differently and progresses differently in each person.”

A common cause?

Another key finding from the study is that brain disorders such as Parkinson’s disease, frontotemporal dementia, Lewy body disease and amyotrophic lateral sclerosis may have the same underlying genetic basis. “Taken together, these data may underscore a potential continuum among neurodegenerative diseases,” the study says.

“The scientific and medical community sees the processes of neurodegenerative diseases as very different and distinct. And that’s how we’ve studied them for a long time,” said Dr. Kellyann Niotis, a neurologist specializing in the prevention of Alzheimer’s disease and Parkinson’s at Weill Cornell Medicine. and NewYork-Presbyterian.

“This highlights that there may be more continuity between these disease processes than we really knew before,” said Niotis, who was not involved in the study.

“Young people may have similar underlying genetic risks and could lead to Parkinson’s disease in one person and Alzheimer’s disease in another,” he said. “It’s actually less relevant. What matters is understanding that this is what’s wrong with your body, so let’s start early and aim for that.”

By generating this more complete picture of genetic risk – which needs to be fleshed out and defined in future studies – the study authors also developed “a new scoring system for predicting the risk of Alzheimer’s disease”, he said. he said in a statement. Spiers-Jones, deputy director of the Center for Discovery Brain Sciences at the University of Edinburgh.

“This tool will be useful for researchers. But it probably won’t be used in the near future for people who aren’t in clinical trials,” said Spires-Jones, who was not part of the research.

Clinician researchers like Isaacson and Niotis know that such a tool is precisely what brain-health-conscious patients want.

“People want to know, ‘What chance do I have?’ and then ‘what can I do about it?’, says Isaacson. “Not today, but in the near future we will be able to calculate the likelihood of a person developing Alzheimer’s disease or another brain disorder more accurately, which will help with medical and mode management. precision life.”

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