Tuesday 12 April 2022

Landmark study finds 42 new genetic risk factors for Alzheimer


A milestone study involving hundreds of scientists from around the world has identified 75 genomic regions associated with Alzheimer’s disease. A number of the newly discovered genetic pathways play a role in inflammation, adding weight to a growing hypothesis immune dysfunction can drive disease progression. Plus, the researchers raise the possibility of developing an Alzheimer’s genetic risk test to predict those most likely to develop the neurodegenerative condition.

Alzheimer’s disease is an incredibly complex and multifactorial condition. We know lifestyle factors play a major role in the development of the disease, however, over the last couple of decades researchers have estimated genetics influence the majority of a person’s risk. Between 60 and 80 percent of one’s Alzheimer’s risk is thought to come down to genes.

But even if the lion’s share of Alzheimer’s risk is driven by genetics, it is looking likely that a large number of genes play a role in driving development of the disease. Before this new study around 40 genomic regions had been linked to increased Alzheimer’s risk, and some researchers have estimated at least 100 different genes could be influencing the disease.

This massive new study, published in Nature Genetics, is the result of years of work from hundreds of scientists all over the globe. The collaborative project is the largest genome-wide association study ever conducted on the links between genetics and Alzheimer’s disease.

Genomic data from 111,326 Alzheimer’s patients was pooled and compared to a control group of 677,663 healthy subjects. Overall, the study found 75 genomic regions associated with Alzheimer’s disease, 33 of which were previously known and 42 that were new discoveries.

“This is a landmark study in the field of Alzheimer’s research and is the culmination of 30 years’ work,” said Julie Williams, a co-author on the new study from Cardiff University. “Genetics has and will continue to help us identify specific disease mechanisms which we can target therapeutically. This piece of work is a major leap forward in our mission to understand Alzheimer’s, and ultimately produce several treatments needed to delay or prevent the disease.”

As Williams explained, understanding what genetic pathways are linked to the development of Alzheimer’s helps researchers learn what mechanisms actually cause the disease. And these new findings both validate prior knowledge and point researchers in new directions.

The primary pathological sign of Alzheimer’s is the abnormal accumulation of amyloid and tau proteins in the brain. The new findings confirm that link, indicating several genomic regions associated with amyloid and tau production can influence Alzheimer’s risk.

Perhaps the most interesting part of the new research comes in looking at what mechanisms the newly discovered genetic regions are linked with. Many of these newly discovered genomic regions play a role in immune system functions, particularly influencing microglial activity, a type of central nervous system immune cell.

“Components of our immune system have a big role to play in the development of the disease,” said Williams. “For example, immune cells in the brain known as microglia are responsible for clearing out damaged tissue, but in some people that may be less efficient which could accelerate the disease.”

In the study’s most novel finding, an inflammatory pathway involving an immune protein known as TNF-alpha was found to be genetically linked to Alzheimer’s risk. This is the first time TNF-alpha has been implicated in the development of Alzheimer’s disease.

The researchers also explored the predictive capacity of these newly discovered genetic associations. The study found a genetic risk score could be calculated that predicted with 84 percent accuracy whether a patient experiencing mild cognitive impairment would progress to Alzheimer’s disease within three years.

In an interview with Alzforum, Jean-Charles Lambert, one of the study co-authors, estimated each individual gene variant could increase a person’s risk of developing Alzheimer’s disease by an average of five percent. And this risk was cumulative, so each extra gene variant increased a person’s chances of developing Alzheimer’s.

"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," Lambert said.

Susan Kohlhaas, director of Alzheimer’s Research UK, said the findings are a potent reminder of just how complex Alzheimer’s disease is, and how different combinations of genetics and environment can trigger the disease.

“Creating an extensive list of Alzheimer’s disease risk genes is like having the edge pieces of a puzzle put together, and while this work doesn’t give us the full picture, it provides a valuable framework for future developments,” explained Kohlhaas, who did not work on this new study. “The research also, however, tells us just how complex Alzheimer’s is, with several different mechanisms implicated in the development of the disease.”

Tara Spires-Jones, form the University of Edinburgh, called the new study “robust” and “important”. She said it may be some time before these kinds of genetic studies offer patients individual risk evaluations but in the short term the findings help researchers better understand the mechanisms that drive the disease, and inform ways to prevent it from developing in the first place.

“The new genes provide hints about why people develop Alzheimer’s that will be followed up in future studies to try and better understand the disease and develop treatments,” said Spires-Jones. “This more complete picture of genes that increase Alzheimer’s risk also allowed the scientists running this study to develop a new scoring system to predict the risk of Alzheimer’s disease. This tool will be useful for researchers but will not likely be used any time soon for people who are not participating in clinical trials.”

The new study was published in the journal Nature Genetics.

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