PHILADELPHIA -- An additional 42 genes connected to the development of Alzheimer's disease have been uncovered in the largest study of genetic risk for Alzheimer's to date.
"This is a landmark study in the field of Alzheimer's research and is the culmination of 30 years' work," study co-author Julie Williams, center director at the UK Dementia Research Institute at Cardiff University, said in a statement.
"Lifestyle factors such as smoking, exercise and diet influence our development of Alzheimer's, and acting to address these now is a positive way of reducing risk ourselves," she added. "However, 60-80% of disease risk is based on our genetics and therefore we must continue to seek out the biological causes and develop much-needed treatments for the millions of people affected worldwide."
The 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 hallmark proteins that build up in the brain with devastating results as Alzheimer's progresses.
"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," said Susan Kohlhaas, director of research at Alzheimer's Research UK, who was not involved in the research.
A number of the newly discovered genes focus on very detailed reactions between proteins in the body that govern how inflammation and the immune system might damage brain cells, the study found.
"The new risk variants identified in the present study are significantly associated with progression" to Alzheimer's disease, says the study, published Monday in the journal Nature Genetics.
The discovery will provide scientists with potential new targets for treatments, medications and lifestyle changes that might reduce the risk of the deadly brain disease, experts say.
"The future of Alzheimer's disease is precision medicine and prevention," said Dr. Richard Isaacson, director of the Alzheimer's Prevention Clinic in the Center for Brain Health at Florida Atlantic University's Schmidt College of Medicine.
"This paper gives us so many 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 those with genes from 677,663 cognitively healthy people. The genomes were supplied by clinics in over 15 members of the European Union, Argentina, Australia, Brazil, Canada, Iceland, Nigeria, New Zealand, the UK 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 into the roles of amyloid beta and tau.
Of the 42 new genes found to be connected to Alzheimer's, many clustered into several suspected but unconfirmed pathways for disease development. One such pathway is the body's immune system, designed to protect us from germ invaders.
A number of genes were associated with an immune regulator called LUBAC, which the body needs 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 trash" -- clearing away damaged neurons -- play a key role in people with diagnosed Alzheimer's disease.
Some of the newly discovered genes may cause microglia to be 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 kill off pathogens, but it also plays a role in removing damaged cells.
One protein that stood out in the study was tumor necrosis factor alpha, which is made by the immune system to regulate inflammation. The study found a cluster of genes associated with TNF, as it is called. Though the chemical's true role is to gather the body's defenses for a fight, it is also a culprit in many autoimmune diseases in which the body turns upon itself, such as rheumatoid and psoriatic arthritis, Crohn's disease and type 1 diabetes.
Additional complicated gene interactions were found by the study, all of which illustrate that "Alzheimer's disease is a multifactorial disease, made up of different pathologies, and each person has their own road," Isaacson said.
"Clinicians always say, 'once you've seen one person with Alzheimer's, you've seen one person with Alzheimer's.' The disease presents differently and progresses differently in different people," he said.
A common cause?
Another key insight of 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 as a whole, these data may thus emphasize a potential continuum between neurodegenerative diseases," the study said.
"The scientific and medical community view neurodegenerative disease processes as 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 and Parkinson's disease prevention at Weill Cornell Medicine and NewYork-Presbyterian.
"This emphasizes that there may be a larger 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 they might lead to Parkinson's in one person and Alzheimer's in the other," she said. "In reality, it is less relevant. What matters is understanding that this is what is going wrong in their body, so let's start early and target this pathway."
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 to predict the risk of Alzheimer's disease," Tara Spires-Jones, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, said in a statement.
"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," said Spires-Jones, who was not involved in the study.
Clinician researchers like Isaacson and Niotis know that a tool like that is precisely what patients want who are worried about their brain health.
"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'll be able to calculate a person's likelihood of developing Alzheimer's or another brain disorder in a more precise way, and that will help with precision medical and lifestyle management."
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