Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia

Neurobiol Aging. 2014 Mar;35(3):726.e11-9. doi: 10.1016/j.neurobiolaging.2013.09.009. Epub 2013 Oct 9.


Homozygous mutations in exon 2 of TREM2, a gene involved in Nasu-Hakola disease, can cause frontotemporal dementia (FTD). Moreover, a rare TREM2 exon 2 variant (p.R47H) was reported to increase the risk of Alzheimer's disease (AD) with an odds ratio as strong as that for APOEε4. We systematically screened the TREM2 coding region within a Belgian study on neurodegenerative brain diseases (1216 AD patients, 357 FTD patients, and 1094 controls). We observed an enrichment of rare variants across TREM2 in both AD and FTD patients compared to controls, most notably in the extracellular IgV-set domain (relative risk = 3.84 [95% confidence interval = 1.29-11.44]; p = 0.009 for AD; relative risk = 6.19 [95% confidence interval = 1.86-20.61]; p = 0.0007 for FTD). None of the rare variants individually reached significant association, but the frequency of p.R47H was increased ~ 3-fold in both AD and FTD patients compared to controls, in line with previous reports. Meta-analysis including 11 previously screened AD cohorts confirmed the association of p.R47H with AD (p = 2.93×10(-17)). Our data corroborate and extend previous findings to include an increased frequency of rare heterozygous TREM2 variations in AD and FTD, and show that TREM2 variants may play a role in neurodegenerative diseases in general.

Keywords: Alzheimer's disease; Frontotemporal dementia; IgV-set domain; Meta-analysis; Rare variants; TREM2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / epidemiology
  • Alzheimer Disease / genetics*
  • Belgium / epidemiology
  • Cohort Studies
  • Female
  • Frontotemporal Dementia / epidemiology
  • Frontotemporal Dementia / genetics*
  • Genetic Variation*
  • Heterozygote*
  • Humans
  • Male
  • Membrane Glycoproteins / genetics*
  • Meta-Analysis as Topic
  • Middle Aged
  • Prospective Studies
  • Receptors, Immunologic / genetics*


  • Membrane Glycoproteins
  • Receptors, Immunologic
  • TREM2 protein, human