“Lifestyle factors, such as smoking, exercise and diet, influence our development of Alzheimer’s disease, and acting to address them now is a positive way of reducing risk ourselves,” he added. “However, 60-80% of disease risk 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 worldwide.”
Previously unknown genes point to additional pathways for disease progression besides the well-known APOE e4 gene or the development of amyloid beta and tau, two distinctive proteins that accumulate in the brain with devastating results as Alzheimer’s progresses.
“Creating an extensive list of Alzheimer’s disease risk genes is like putting together the pieces of a puzzle, and while this work doesn’t give us a complete picture, it does provide a valuable framework for future developments,” said Susan Kohlhaas, research director at Alzheimer’s Research UK, which was not involved in the research.
Several of the newly discovered genes focus on highly detailed reactions between proteins in the body that govern how inflammation and the immune system might damage brain cells, the study found.
The discovery will provide scientists with new potential targets for treatments, drugs and lifestyle changes that could reduce the risk of the deadly brain disease, experts say.
“The future of Alzheimer’s disease is precision medicine and prevention,” said Richard Isaacson, MD, director of the Alzheimer’s Disease Prevention Clinic at the Center for Brain Health at Schmidt School of Medicine in Florida Atlantic University.
“This paper gives us a lot more tools in our toolbox to eventually more precisely target Alzheimer’s disease,” said Isaacson, who was not involved in the study.
New disease pathways
The global study analyzed the genomes of 111,326 people with clinically diagnosed Alzheimer’s and compared them with genes from 677,663 cognitively healthy people. The genomes were supplied by clinics in more than 15 members of the European Union, Argentina, Australia, Brazil, Canada, Iceland, Nigeria, New Zealand, the United Kingdom and the United States.
The study identified 75 genes that are linked to an increased risk of Alzheimer’s, 33 of which were already known. It also confirmed years of research on the roles of amyloid beta and tau.
Of the 42 new genes found to be linked to Alzheimer’s, many clustered in various suspected but unconfirmed pathways for the development of the disease. One such pathway is the body’s immune system, designed to protect us from invading germs.
Several genes were associated with an immune regulator called LUBAC, which is needed by the body to activate genes and prevent cell death. The study also found that microglia, immune cells in the brain that are tasked with “taking out the garbage” (cleaning up damaged neurons), play a key role in people diagnosed with Alzheimer’s disease.
Some of the newly discovered genes may make microglia less efficient, “which could speed up 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 the elimination of damaged cells.
One protein that stood out in the study was tumor necrosis factor alpha, which is produced by the immune system to regulate inflammation. The study found a group of genes associated with TNF, as it is called. Although the chemical’s true role is to rally the body’s defenses for a fight, it is also to blame for many autoimmune diseases in which the body turns against itself, such as rheumatoid and psoriatic arthritis, Crohn’s disease and diabetes Type 1.
The study found additional complicated genetic interactions, all of which illustrate that “Alzheimer’s disease is a multifactorial disease, made up of different pathologies, and each person has their own path,” Isaacson said.
“Doctors always say, ‘once you’ve seen a person with Alzheimer’s, you’ve seen a person with Alzheimer’s.’ The disease presents differently and progresses differently in different people,” he said.
A common cause?
Another key insight from the study was that brain disorders such as Parkinson’s, frontotemporal dementia, Lewy body disease and amyotrophic lateral sclerosis may have the same underlying genetic basis: “Taken together, these data may emphasize a continuing potential among neurodegenerative diseases,” the study said.
“The scientific and medical community considers neurodegenerative disease processes to be very different and distinct, and that’s how we’ve been studying them for a long time,” said Dr. Kellyann Niotis, a neurologist specializing in Alzheimer’s disease prevention and Parkinson at Weill Cornell Medicine. and NewYork-Presbyterian.
“This emphasizes that there may be a broader continuum between these disease processes than we really understood before,” said Niotis, who was not involved in the study.
“Young people may have similar underlying genetic risks, and could lead to Parkinson’s in one person and Alzheimer’s 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 down this path.”
In generating this more complete picture of genetic risk, which must be developed and defined in future studies, the study authors also developed “a new scoring system to predict the risk of Alzheimer’s disease,” said Tara Spires-Jones, deputy director of the Center for Discovery Brain Sciences at the University of Edinburgh, in a statement.
“This tool will be useful to researchers, but it probably won’t be used anytime soon for people who aren’t in clinical trials,” said Spires-Jones, who was not involved in the study.
Clinical researchers like Isaacson and Niotis know that such a tool is precisely what patients who are concerned about their brain health want.
“People want to know, ‘what are my chances?’ and then ‘what can I do about it?’ Isaacson said.”Not today, but in the near future, we will be able to calculate the probability that a person will develop Alzheimer’s or another brain disorder in a more precise way, and that will help with precision medical and lifestyle management.”