title: R47H TREM2 variant increases risk of typical early-onset Alzheimer's disease but not of prion or frontotemporal dementia.
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.
  
  
  CONCLUSIONS
  We find p.R47H is a risk factor for AD, but not frontotemporal dementia or prion disease.
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Catherine F
authors.initials: CF
authors.lastname: Slattery
authors.affiliation: Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Beck
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Lorna
authors.initials: L
authors.lastname: Harper
authors.affiliation: Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Adamson
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Abdi
authors.affiliation: Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Uphill
authors.affiliation: Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
authors.forename: Tracy
authors.initials: T
authors.lastname: Campbell
authors.affiliation: Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
authors.forename: Ron
authors.initials: R
authors.lastname: Druyeh
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Mahoney
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Rohrer
authors.affiliation: Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
authors.forename: Janna
authors.initials: J
authors.lastname: Kenny
authors.affiliation: Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lowe
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Kelvin K
authors.initials: KK
authors.lastname: Leung
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Josephine
authors.initials: J
authors.lastname: Barnes
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Shona L
authors.initials: SL
authors.lastname: Clegg
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Melanie
authors.initials: M
authors.lastname: Blair
authors.affiliation: Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Nicholas
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Rita J
authors.initials: RJ
authors.lastname: Guerreiro
authors.affiliation: Department of Clinical Neurosciences, Cambridge University, UK.
authors.forename: James B
authors.initials: JB
authors.lastname: Rowe
authors.affiliation: Department of Neurology, Clinical Dementia Center, Georg-August University Göttingen, Göttingen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ponto
authors.affiliation: Department of Neurology, Clinical Dementia Center, Georg-August University Göttingen, Göttingen, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Zerr
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Kretzschmar
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gambetti
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Crutch
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Warren
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Martin N
authors.initials: MN
authors.lastname: Rossor
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.affiliation: Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schott
authors.affiliation: Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK. Electronic address: s.mead@prion.ucl.ac.uk.
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D001120:Arginine / Q000235:genetics*; D001921:Brain / Q000473:pathology; D015331:Cohort Studies; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics / Q000473:pathology; D005091:Exons / Q000235:genetics; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics / Q000473:pathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006639:Histidine / Q000235:genetics*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D011971:Receptors, Immunologic / Q000235:genetics*; D012307:Risk Factors
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; D006639:Histidine; D001120:Arginine
keywords: Alzheimer's; Frontotemporal dementia; Phenotype; Prion; TREM2