Is TREM2 a genetic risk factor for FTD?

TREM2 is a gene that produces a protein known to be involved in the immune system, the part of the body that protects us against disease. In the brain, the cells with immune functions are called microglia, and these cells protect the brain from foreign invaders and remove dead nerve cells and other debris. There is increasing evidence that this immune response may occur as part of the disease process in a number of different neurodegenerative disorders.

We have known for some time that mutations in both copies of TREM2 cause a rare disorder called Nasu-Hakola disease but in the last couple of years it has been shown that this disorder can have very similar symptoms to FTD (see previous post on FTD talk). It has also recently been shown that people who have a particular rare variant in the TREM2 gene (called R47H) are at an increased risk of developing Alzheimer’s disease. Both of these factors have led to the hypothesis that TREM2 might be a risk factor for developing FTD.

The genetic association of the rare variant R47H in TREM2 with Alzheimer’s disease has been consistently replicated by groups studying different populations across the world. However, the association between TREM2 and the risk of developing FTD has not been as consistent. R47H has only been associated with the risk of developing FTD in one study assessing people in North America. Several other studies in European populations have not identified such an association. It is difficult to know exactly why there are differences between these studies. We know that the R47H variant occurs at a different frequency in different populations, and it may be this fact that underlies the differences observed between American and European studies.

Some studies also looked at different variants in the gene apart from R47H. The two key findings were, firstly, an increased risk of FTD was reported with even rarer variants (such as one called T96K), and secondly, an increased total number of variants was found in people with FTD when compared to people without any neurological problems.

These positive findings of an association with TREM2 will need to be replicated in other studies first before we can really get a clear answer of whether TREM2 is a risk factor for FTD.


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