Editors' ChoiceAlzheimer's Disease

Remembering the Variants in Alzheimer’s Disease

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Science Translational Medicine  12 Dec 2012:
Vol. 4, Issue 164, pp. 164ec226
DOI: 10.1126/scitranslmed.3005444

Alzheimer’s disease, the most common cause of dementia, leaves its victims with a progressive loss of both memory and cognitive function. Rare forms of the disease are hereditary, caused by mutations in specific genes. But the causes of the more common sporadic type of Alzheimer’s disease are largely elusive. To determine whether variants in the genome modulate risk for development of Alzheimer’s disease, two international consortia sequenced the genomes of large groups of patients and controls.

In two concurrent articles, Jonsson et al. and Guerreiro et al. report the genome-wide sequencing of over 4000 individuals, approximately half of whom had Alzheimer’s disease. Both groups found that variants in the gene encoding TREM2 (triggering receptor expressed on myeloid cells 2) were associated with markedly increased risk of developing Alzheimer’s disease. People carrying one variant in particular (rs75932628-T) had the highest risk of Alzheimer’s. This finding was validated in several thousand additional cases and controls, when taking into account both studies. Individuals with this TREM2 variant were more than three times more likely to develop Alzheimer’s disease than were individuals without it. Even carriers of the rs75932628-T variant without Alzheimer’s disease fared worse on cognitive testing than did noncarriers, especially after the age of 80.

TREM2 is a transmembrane protein that participates in signaling pathways that modulate the immune response in several cell types, including microglia, the resident phagocytic cell of the brain. Although exactly how the rs75932628-T version of TREM2 changes microglia function is unknown, the authors postulate that it could perturb the cell’s ability to clear debris and amyloid aggregates, which are thought to be pivotal in the pathogenesis of Alzheimer’s disease.

Although these studies present compelling evidence for the contribution of TREM2 variants to the development of Alzheimer’s disease, the vast majority of patients still have no identifiable genetic marker. The quest to understand and therapeutically target the drivers of Alzheimer’s disease is not over.

T. Jonsson et al., Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med., published online 14 November 2012 (10.1056/NEJMoa1211103). [PubMed]

R. Guerreiro et al., TREM2 variants in Alzheimer’s disease. N. Engl. J. Med., published online 14 November 2012 (10.1056/NEJMoa1211851). [PubMed]

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