A Newly Discovered Genetic Cause of Alzheimer’s Disease – Mutations of TREM2

Abstract & Commentary

By Michael Lin, MD, PhD

Assistant Professor of Neurology and Neurosciences, Weill Cornell Medical College

Dr. Lin reports no financial relationships relevant to this field of study.

Synopsis: Genome sequencing and analysis of mutations of the TREM2 gene demonstrated that homozygotes have an increased risk of developing Alzheimer’s disease, and carriers have cognitive impairments compared to age-matched controls.

Sources: Jonsson T, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 2013;368:107-116.

Guerreiro R, et al. TREM2 varients in Alzeimer’s disease. N Engl J Med 2013;368:117-127.

Inflammation is thought to play a role in alzheimer’s disease (AD) pathogenesis. Evidence of inflammation is seen in AD brains, including activated microglia, cytokines, and complement components. Providing further evidence for the role of inflammation, two recent studies presented back-to-back in the New England Journal of Medicine showed that a rare variant in TREM2 (triggering receptor expressed on myeloid cells 2) is associated with 3- to 5-fold increased risk of AD.

In the study by Jonsson et al, all the protein-changing mutations identified in whole genome sequence data from 2261 Icelanders were imputed in a case-control analysis of AD (3550 patients) and control patients. Other than ApoE and APP, the only marker that showed a significant genome-wide association with AD was a rare R47H missense mutation in TREM2 (odds ratio [OR], 2.92; 95% confidence interval [CI], 2.09-4.09; P = 3.42 x 10-10). The overall allele frequency for this mutation was 0.63% in Iceland. The association was replicated using datasets from the United States, Germany, the Netherlands, and Norway (combined OR, 2.83; CI, 1.45-5.40; P = 0.002). Finally, elderly carriers of the R47H TREM2 mutation without AD had poorer cognitive function than noncarriers (P = 0.003).

In the study by Guerreiro et al, there were significantly more mutations in TREM2 in 1092 AD cases than in 1107 controls. Of these mutations, the R47H mutation showed the strongest association with AD (P < 0.001). The association was replicated on meta-analysis of three imputed datasets of genome-wide association studies of AD (P = 0.002). The authors also directly genotyped the R47H variant in 1994 AD cases and 4062 controls, and again found a significant association with AD (OR, 5.05; 95% CI, 2.77-9.16; P = 9.0 x 10-9). TREM2 expression was increased in brains of transgenic APP mice compared to nontransgenic littermates.


Overall, the R47H mutation in TREM2 described in both papers is rare (allelic frequency < 1%), but the magnitude of risk conferred by the mutation (OR ~ 3-5) is similar to that conferred by the apoE4 allele. The pathogenesis of TREM2 in AD remains to be elucidated, but may provide some insight into AD pathogenesis in general. TREM2 is expressed in microglia, enhances phagocytosis (which may be relevant to clearance of amyloid), and promotes the “alternative activation” state of microglia, which is thought to be protective. TREM2 also suppresses proinflammatory cytokine signaling. Thus, loss of function of TREM2 could affect clearance of amyloid and promote inflammatory cascades.

Homozygous loss of function of TREM2 has previously been associated with early onset dementia and bone cysts with pathologic fractures, termed polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (Nasu-Hakola disease). It also has been associated with frontotemporal dementia with leukodystrophy. The papers above suggest that TREM2 is likely also associated with AD.