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19-11-2012 | Genetics | Article

New genetic insight into Alzheimer’s disease

medwireNews: A rare mutation in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has a potent effect on the risk for late-onset Alzheimer's disease, two studies published in The New England Journal of Medicine suggest.

The findings show that people heterozygous for this mutation, which causes a substitution of histidine for arginine at position 47, have an increased risk for Alzheimer's disease, with the effect shown across several European and North American populations.

Earlier research has established that patients with homozygous mutations resulting in complete loss of TREM2 function develop severe early-onset dementia, but with no signs of amyloid plaques. In an editorial accompanying the studies, Harald Neumann (University of Bonn, Germany) and Mark Daly (Massachusetts General Hospital, Boston, USA) suggest that TREM2 mutations may therefore contribute to dementia via an inflammatory process.

Evidence from other genetic conditions that indirectly involve TREM2 indicates that this could center on the microglial phagocytosis or inflammatory pathway, they add.

The latest findings "provide a new path for experimental inquiry into the biologic roots of Alzheimer's disease," they write.

In one study, Kari Stefansson (University of Iceland, Reykjavik) and team found the TREM2 mutation nearly tripled the odds for Alzheimer's disease in 2261 Icelandic people. This association was also apparent in replication cohorts from the USA, Germany, the Netherlands, and Norway.

And in the second study, John Hardy (UCL Institute of Neurology, London, UK) and colleagues found this same relationship in 1092 patients with Alzheimer's disease and 1107 controls of European or North American descent. When replicating the findings in a further 1994 patients and 4062 controls, they found the mutation to be associated with about a fivefold increased risk for Alzheimer's disease.

The mutation was rare, being present in just 0.63% of the Icelandic population. However, Stefansson et al note that, in their study, its effect on an individual's risk for Alzheimer's disease was similar to that associated with carrying the ε4 allele of apolipoprotein E.

Furthermore, they found that the TREM2 mutation affected cognition even if people did not have Alzheimer's. In 3752 people older aged at least 80 years who did not have dementia, those with the mutation had a significantly poorer performance on the Cognitive Performance Scale, by an average of 0.87 units relative to those without.

medwireNews ( is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2012

By Eleanor McDermid, Senior medwireNews Reporter

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