Alzheimer Disease Risk Variant Discovered

Most cases of Alzheimer disease (AD) affect people after age 65 and do not involve clear autosomal-dominant genetics. Clinicians are generally aware of the increased risk for late-onset AD conferred by the ε4 allele of apolipoprotein E (APOE ε4). Now, two groups report a new, rare variant in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) that results in an odds ratio for AD that is similar to the odds with APOE ε4. TREM2 is expressed throughout the central nervous system, particularly in the white matter. Its protein is related to immunoglobulin and acts as a phagocytic receptor for bacteria and as a control of the inflammatory response. On microglia, the protein is important for the clearance of neural debris.

The two research teams each used a complicated series of genetics methods, including direct sequencing of DNA from AD patients and controls, genome-wide association studies with imputation, and assays of gene expression across regions of the human brain and in mouse models. Jonsson and colleagues found that the R47H variant of TREM2 was associated with a significantly increased risk for AD in a relatively homogenous Icelandic group (odds ratio, 2.92), and in other, more heterogenous, populations. Similarly, among people of European and North American ancestry, Guerreiro and colleagues found a significantly increased risk for AD associated with the R47H variant (OR, 4.5).