R47H TREM2 variant increases risk of typical early-onset Alzheimer's disease but not of prion or frontotemporal dementia

Alzheimers Dement. 2014 Nov;10(6):602-608.e4. doi: 10.1016/j.jalz.2014.05.1751. Epub 2014 Aug 23.

Abstract

Background: Rare TREM2 variants are significant risk factors for Alzheimer's disease (AD).

Methods: We used next generation sequencing of the whole gene (n = 700), exon 2 Sanger sequencing (n = 2634), p.R47H genotyping (n = 3518), and genome wide association study imputation (n = 13,048) to determine whether TREM2 variants are risk factors or phenotypic modifiers in patients with AD (n = 1002), frontotemporal dementia (n = 358), sporadic (n = 2500), and variant (n = 115) Creutzfeldt-Jakob disease (CJD).

Results: We confirm only p.R47H as a risk factor for AD (odds ratio or OR = 2.19; 95% confidence interval or CI = 1.04-4.51; P = .03). p.R47H does not significantly alter risk for frontotemporal dementia (OR = 0.81), variant or sporadic CJD (OR = 1.06 95%CI = 0.66-1.69) in our cohorts. Individuals with p.R47H associated AD (n = 12) had significantly earlier symptom onset than individuals with no TREM2 variants (n = 551) (55.2 years vs. 61.7 years, P = .02). We note that heterozygous p.R47H AD is memory led and otherwise indistinguishable from "typical" sporadic AD.

Conclusion: We find p.R47H is a risk factor for AD, but not frontotemporal dementia or prion disease.

Keywords: Alzheimer's; Frontotemporal dementia; Phenotype; Prion; TREM2.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Arginine / genetics*
  • Brain / pathology
  • Cohort Studies
  • Creutzfeldt-Jakob Syndrome / genetics
  • Creutzfeldt-Jakob Syndrome / pathology
  • Exons / genetics
  • Female
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / pathology
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation*
  • Genome-Wide Association Study
  • Genotype
  • Histidine / genetics*
  • Humans
  • Male
  • Membrane Glycoproteins / genetics*
  • Middle Aged
  • Phenotype
  • Receptors, Immunologic / genetics*
  • Risk Factors

Substances

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