A new gene that has a powerful effect on the immune system and nearly triples the risk of Alzheimer's disease has been discovered after a decade of international research, according to findings released Wednesday in The New England Journal of Medicine.
Using whole genome sequencing, researchers at deCODE genetics in Iceland found a variant of TREM2 more often in patients with Alzheimer's compared with a control group. They replicated the findings at other institutions in the USA, Germany, Norway and the Netherlands.
The discovery, researchers say, gives them a better understanding of one of the potential causes of late-onset Alzheimer's disease and can open doors to potentially develop therapies for treating or preventing the disease. There is no cure or treatment to slow the destruction from Alzheimer's, a brain-wasting illness that affects 5.2 million people in the USA.
"This gives us another target for the disease,'' says Allan Levey, one of the project's authors and director of the Emory Alzheimer's Disease Center of Excellence in Atlanta. "It might turn out to be something that is an ideal target for drug therapy if you could alter it to make it protective" rather than destructive.
The TREM2 variant impairs the functioning of microglia cells and supports the long-held belief that inflammation plays a role in Alzheimer's, Levey says. "These (microglia) cells are of two minds,'' he says. "They can help get rid of debris in the brain, or they can cause progressive injury."
When protective, microglias can prevent inflammation and eliminate amyloid plaque, a substance that attaches to and kills brain cells in many people with Alzheimer's. The TREM2 variant causes the microglia to become destructive, releasing inflammation causing cytokines and failing to remove plaque.
"It is possible that reduced TREM2 activity may lead to brain damage through the inability of the brain to clear these toxic products," the authors write, adding that inflammation is a "downstream effect" of damage done by amyloid plaque.
The first treatments for removing plaque are in the final trial phase and are showing some promise in people who haven't developed mild to severe cases of Alzheimer's. New trials are getting started on people who carry genes that mean they will eventually develop a form of dementia called early-onset Alzheimer's. If the therapies can prevent those people from getting Alzheimer's, researchers think therapies can be used to prevent or slow late-onset cases as well.
Having TREM2 does not mean you will get the disease. "People shouldn't rush out to be tested for this gene,'' says Bill Thies, chief medical officer of the Alzheimer's Association. "It only increases your risk. It is an incredibly rare gene, also."
While there have been other recent genetic links to the disease, Levey says only TREM2 appears to play as strong a role as APOE 4, which was discovered 20 years ago. AP0E 4 impairs the brain's vascular system in many people with Alzheimer's.
The findings of the Iceland study were replicated by another group of researchers at the National Institute on Aging in Bethesda, Md., and the Reta Lila Weston Research Laboratories in London. NIA also helped fund the Iceland study.
"This is a very important finding because it gives us another target for the disease,'' says Andrew Singleton, a neuroscientist at NIA who worked on the study with John Hardy. "The best way to understand the disease is to understand the process and develop therapies from there."
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