Two international studies published this week point to a link between Alzheimer’s disease and a rare gene mutation that affects the immune system’s inflammation response. The discovery supports an emerging theory about the role of the immune system in the development of Alzheimer’s disease.

Both studies are published online this week in the New England Journal of Medicine, one led by John Hardy of University College London, and the other led by the Iceland-based global company deCode Genetics.

Alzheimer’s is a form of distressing brain-wasting disease that gradually robs people of their memories and their ability to lead independent lives. Its main characteristic is the build up of protein tangles and plaques inside and between brain cells, which eventually disrupts their ability to communicate with each other.

Both teams conclude that a rare mutation in a gene called TREM2, which helps trigger immune system responses, raises the risk for developing Alzheimer’s disease. One study suggests it raises it three-fold, the other, four-fold.

Lead author of the UCL-led study, Rita Guerreiro, a research fellow at UCL, adds:

“While the genetic mutation we found is extremely rare, its effect on the immune system is a strong indicator that this system may be a key player in the disease.”

In the UCL-led study, which included researchers from 44 institutions around the world, the researchers used data on a total of 25,000 people.

After homing in on the TREM2 gene using new sequencing techniques, they carried out further sequencing that identified a set of rare mutations that occurred more often in 1,092 Alzheimer’s disease patients than in a group of 1,107 healthy controls.

With further follow-up studies involving a large number of Alzheimer’s disease patients and controls, they evaluated the most common mutation, R47H, and confirmed that this variant of TREM2 substantially increases the risk for Alzheimer’s disease.

Co-author Minerva Carrasquillo, of the Mayo Clinic in Florida, says:

“The TREM2 variant may be rare, but it is potent.”

“In our series, it was present in 1.9 percent of the Alzheimer’s patients and in only 0.37 percent of the controls,” she adds.

The researchers on this study note, as do the researchers on the study led by deCode Genetics, that this strong effect is on a par with that of the well-established gene variant known as APOE4.

“R47H isn’t fully penetrant — meaning that not all people who have the variant will develop Alzheimer’s and in those who do, other genes and environmental factors will also play a role — but like APOE 4 it does substantially increase risk,” Carrasquillo explains.

The study led by deCode Genetics involved collaborators from Iceland, Holland, Germany and the US. It too found a strong link between the R47H variant and Alzheimer’s disease, and, in addition, discovered the variant also predicts poorer cognitive function in older people without Alzheimer’s.

In a statement, lead author Kari Stefánsson, CEO and co-founder of deCODE Genetics says:

“The discovery of variant TREM2 is important because it confers high risk for Alzheimer’s and because the gene’s normal biological function has been shown to reduce immune response that may contribute to the disease.”

“These combined factors make TREM2 an attractive target for drug development,” he adds.

The study was a massive data crunching exercise.

Using deCode’s genome sequencing and genotyping technology, Stefánsson and colleagues identified approximately 41 million markers, including 191,777 functional variants, from 2,261 Icelandic samples.

They further analyzed these variants against the genomes of 3,550 people with Alzheimer’s disease and a control group of over-85s who did not have a diagnosis of Alzheimer’s.

This led to them finding the TREM2 variant, and to make sure this was not just a feature of Icelandic people, they replicated the findings against other control populations in the United States, Germany, the Netherlands and Norway.

Stefánsson says:

“Using this approach, we have recently reported variants that greatly influence the risk of developing other diseases, including ovarian cancer, gliomas, gout and sick sinus syndrome.”

He says thanks to a new set of sophisticated research tools, access to expanded and high quality genomic data sets, and investigators with profound analytic skills, research into genetic causes of disease can now carry out “big data research” that combines sequence data and biological knowledge to find new drug targets.

Preclinical studies have found that TREM2 is important for clearing away cell debris and amyloid protein, the protein that is associated with the brain plaques that are characteristic of Alzheimer’s disease.

Studies also suggest the gene helps control the inflammation response, which has been linked to Alzheimer’s and cognitive decline.

Rosa Rademakers, a co-author in the UCL-led study, runs a lab at the Mayo Clinic in Florida that helped to pinpoint the R47H variant of TREM2. She says while their findings fit in well with those of other studies that link the immune system to Alzheimer’s disease, “additional studies are needed to establish that R47H does, in fact, act by altering immune function”.

“Fortunately, this variant changes an amino acid in TREM2 and that will greatly facilitate the biological studies that follow,” she notes.

Written by Catharine Paddock PhD