A Possible Player in Alzheimer Disease
A Possible Player in Alzheimer Disease
Jonsson T, Stefansson H, Steinberg S, et al
N Engl J Med. 2013;368:107-116
The risk for the highly prevalent late-onset form of Alzheimer disease is increased in patients with specific sequence variants, such as the epsilon-4 allele of apolipoprotein E. To date, however, few rare variants have been found to be associated with risk for late-onset Alzheimer disease.
Jonsson and colleagues identified sequence variants that were likely to affect protein function from the genome sequences of 2261 Icelanders. To test for an association with Alzheimer disease, the investigators imputed these variants into the genomes of patients with Alzheimer disease and control patients. They also used a case/control series from the United States, Norway, the Netherlands, and Germany for replication tests, and tested an elderly population without Alzheimer disease to see whether these variants were associated with cognitive function.
This testing identified a rare missense mutation (rs75932628-T), which was predicted to result in an R47H substitution in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2). Icelandic participants with the TREM2 variant had nearly triple the risk for Alzheimer disease (odds ratio [OR], 2.92; 95% confidence interval [CI], 2.09-4.09; P = 3.42 × 10).
In control participants who were at least 85 years of age, the frequency of this mutation was 0.46%. Findings were similar in the other samples studied (OR, 2.90; 95% CI, 2.16-3.91; P = 2.1 × 10 in combined discovery and replication samples). Compared with noncarriers of rs75932628-T aged 80-100 years without Alzheimer disease, carriers had poorer cognitive function (P = .003).
The findings of this study suggest that variant TREM2 plays a role in the pathogenesis of Alzheimer disease. Although this study could not determine the underlying mechanism, TREM2 has been reported to play an anti-inflammatory role in the brain and to enhance phagocytosis of amyloid plaques by microglia. The R47H substitution may therefore convey an enhanced susceptibility to Alzheimer disease through impaired control of inflammatory processes, with neuronal damage possibly resulting from reduced ability of microglia to clear amyloid plaques.
Abstract
Variant of TREM2 Associated With the Risk of Alzheimer's Disease
Jonsson T, Stefansson H, Steinberg S, et al
N Engl J Med. 2013;368:107-116
Study Summary
The risk for the highly prevalent late-onset form of Alzheimer disease is increased in patients with specific sequence variants, such as the epsilon-4 allele of apolipoprotein E. To date, however, few rare variants have been found to be associated with risk for late-onset Alzheimer disease.
Jonsson and colleagues identified sequence variants that were likely to affect protein function from the genome sequences of 2261 Icelanders. To test for an association with Alzheimer disease, the investigators imputed these variants into the genomes of patients with Alzheimer disease and control patients. They also used a case/control series from the United States, Norway, the Netherlands, and Germany for replication tests, and tested an elderly population without Alzheimer disease to see whether these variants were associated with cognitive function.
This testing identified a rare missense mutation (rs75932628-T), which was predicted to result in an R47H substitution in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2). Icelandic participants with the TREM2 variant had nearly triple the risk for Alzheimer disease (odds ratio [OR], 2.92; 95% confidence interval [CI], 2.09-4.09; P = 3.42 × 10).
In control participants who were at least 85 years of age, the frequency of this mutation was 0.46%. Findings were similar in the other samples studied (OR, 2.90; 95% CI, 2.16-3.91; P = 2.1 × 10 in combined discovery and replication samples). Compared with noncarriers of rs75932628-T aged 80-100 years without Alzheimer disease, carriers had poorer cognitive function (P = .003).
Viewpoint
The findings of this study suggest that variant TREM2 plays a role in the pathogenesis of Alzheimer disease. Although this study could not determine the underlying mechanism, TREM2 has been reported to play an anti-inflammatory role in the brain and to enhance phagocytosis of amyloid plaques by microglia. The R47H substitution may therefore convey an enhanced susceptibility to Alzheimer disease through impaired control of inflammatory processes, with neuronal damage possibly resulting from reduced ability of microglia to clear amyloid plaques.
Abstract
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