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

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

Author information

  • 1Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
  • 2Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
  • 3Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
  • 4Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
  • 5Department of Clinical Neurosciences, Cambridge University, UK.
  • 6Department of Neurology, Clinical Dementia Center, Georg-August University Göttingen, Göttingen, Germany.
  • 7Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
  • 8Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
  • 9Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK. Electronic address:



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


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).


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.


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

Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.


Alzheimer's; Frontotemporal dementia; Phenotype; Prion; TREM2

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