New Risk Variant for Alzheimer's Disease Discovered

Megan Brooks

November 14, 2012

A new study strongly implicates a variant in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) in the pathogenesis of Alzheimer's disease (AD).

TREM2 has an antiinflammatory role in the brain. "Reduced TREM2 activity may lead to brain damage through increased inflammatory response," study leader Kari Stefansson, MD, PhD, chief executive officer, deCode Genetics, Reykjavik, Iceland, said in a statement.

"This is a basic science paper and the real clinical importance may not be known for a while yet," William Thies, PhD, chief medical and scientific officer, Alzheimer's Association, cautioned in an interview with Medscape Medical News.

"This paper is very interesting, it demonstrates real progress, it applies a new technology to the field and really points to the value of basic science in terms of it developing leads to potential therapies," Dr. Thies added.

The study was published online November 14 in the New England Journal of Medicine.

Few Known AD Variants

Outside of the ε4 allele of apolipoprotein E, few variants affecting the risk for the common late-onset form of AD have been found, Dr. Stefansson and colleagues note.

They obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. They imputed these variants into the genomes of 3550 patients with AD and a control population of adults who had reached age 85 without a diagnosis of AD.

The researchers identified a rare missense mutation (rs75932628-T) in the gene encoding TREM2, leading to an R47H substitution, with an allelic frequency of 0.63% in Iceland, which conferred a significant risk for AD (odds ratio [OR], 2.92; 95% confidence interval [CI], 2.09 - 4.09). The mutation had a frequency of 0.46% in the control population.

The researchers observed the same association in additional case-control series from the United States, Norway, the Netherlands, and Germany (OR, 2.90; 95% CI, 2.16 - 3.91).

They also found that carriers of rs75932628-T aged 80 to 100 years without AD had poorer cognitive function than noncarriers (P = .003).

Attractive Drug Target

"Given the involvement of TREM2 in the phagocytic role of microglia on amyloid plaques, it is possible that reduced TREM2 activity caused by the R47H substitution may lead to brain damage through the inability of the brain to clear these toxic products," the researchers say.

Dr. Stefansson thinks TREM2 is "an attractive target for drug development."

In comments to Medscape Medical News, Dr. Thies said, "We've known for some time that inflammation is associated with Alzheimer's disease but we haven't really been able to exploit that with current drugs. The nonsteroidal anti-inflammatory drugs have sort of a checkered history in being useful for Alzheimer's disease."

"This kind of genetic study with whole genome sequencing that points to a very specific gene that is attached to a metabolic pathway really opens up the possibility of finding molecules that will work to modulate that pathway to a clinical benefit," Dr. Thies said.

It's important to note, he added, this mutation is "relatively uncommon, so people shouldn't go out and get tested for it because they won't find any place that will do it and it isn't going to do them any good."

Nonetheless, "the value of basic science is clearly established here," Dr. Thies said, adding, "we have to fund this type of research through public sources, so the need for funding at the level of the National Alzheimer's plan demands seems to me very sensible."

The study was funded by the National Institute on Aging and by the Research Council of Norway and Southeastern Norway Health Authority. A complete list of author disclosures can be found at .

N Engl J Med. Published online November 14, 2012. Full text