title: R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study.
abstract: OBJECTIVE
  The R47H variant in the triggering receptor expressed on myeloid cells 2 gene (TREM2), a modulator of the immune response of microglia, is a strong genetic risk factor for Alzheimer disease (AD) and possibly other neurodegenerative disorders.
  
  
  OBJECTIVE
  To investigate a large family with late-onset AD (LOAD), in which R47H cosegregated with 75% of cases.
  
  
  METHODS
  This study includes genetic and pathologic studies of families with LOAD from 1985 to 2014. A total of 131 families with LOAD (751 individuals) were included from the University of Washington Alzheimer Disease Research Center. To identify LOAD genes/risk factors in the LOAD123 family with 21 affected members and 12 autopsies, we sequenced 4 exomes. Candidate variants were tested for cosegregation with the disease. TREM2 R47H was genotyped in an additional 130 families with LOAD. We performed clinical and neuropathological assessments of patients with and without R47H and evaluated the variant's effect on brain pathology, cellular morphology, and expression of microglial markers.
  
  
  METHODS
  We assessed the effect of TREM2 genotype on age at onset and disease duration. We compared Braak and Consortium to Establish a Registry for Alzheimer's Disease scores, presence of α-synuclein and TAR DNA-binding protein 43 aggregates, and additional vascular or Parkinson pathology in TREM2 R47H carriers vs noncarriers. Microglial activation was assessed by quantitative immunohistochemistry and morphometry.
  
  
  RESULTS
  Twelve of 16 patients with AD in the LOAD123 family carried R47H. Eleven patients with dementia had apolipoprotein E 4 (ApoE4) and R47H genotypes. We also found a rare missense variant, D353N, in a nominated AD risk gene, unc-5 homolog C (UNC5C), in 5 affected individuals in the LOAD123 family. R47H carriers demonstrated a shortened disease duration (mean [SD], 6.7 [2.8] vs 11.1 [6.6] years; 2-tailed t test; P = .04) and more frequent α-synucleinopathy. The panmicroglial marker ionized calcium-binding adapter molecule 1 was decreased in all AD cases and the decrease was most pronounced in R47H carriers (mean [SD], in the hilus: 0.114 [0.13] for R47H_AD vs 0.574 [0.26] for control individuals; 2-tailed t test; P = .005 and vs 0.465 [0.32] for AD; P = .02; in frontal cortex gray matter: 0.006 [0.004] for R47H_AD vs 0.016 [0.01] for AD; P = .04 and vs 0.033 [0.013] for control individuals; P < .001). Major histocompatibility complex class II, a marker of microglial activation, was increased in all patients with AD (AD: 2.5, R47H_AD: 2.7, and control: 1.0; P < .01).
  
  
  CONCLUSIONS
  Our results demonstrate a complex genetic landscape of LOAD, even in a single pedigree with an apparent autosomal dominant pattern of inheritance. ApoE4, TREM2 R47H, and rare variants in other genes, such as UNC5C D353N, are likely responsible for the notable occurrence of AD in this family. Our findings support the role of the TREM2 receptor in microglial clearance of aggregation-prone proteins that is compromised in R47H carriers and may accelerate the course of disease.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle.
authors.forename: Olena
authors.initials: O
authors.lastname: Korvatska
authors.affiliation: Lou Ruvo Center for Brain Health, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.affiliation: Department of Neurology, University of Washington, Seattle.
authors.forename: Suman
authors.initials: S
authors.lastname: Jayadev
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle4Mental Illness Research, Education, and Clinical Center, Department of Veteran Affairs, Seattle, Washington.
authors.forename: Pamela
authors.initials: P
authors.lastname: McMillan
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle.
authors.forename: Irina
authors.initials: I
authors.lastname: Kurtz
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle.
authors.forename: Xindi
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Neurology, University of Washington, Seattle.
authors.forename: Malia
authors.initials: M
authors.lastname: Rumbaugh
authors.affiliation: Department of Medicine (Medical Genetics), University of Washington, Seattle.
authors.forename: Mark
authors.initials: M
authors.lastname: Matsushita
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College7Department of Anthropology, Pennsylvania State University, State College.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Girirajan
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle8Department of Pathology, University of Washington, Seattle.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Dorschner
authors.affiliation: Department of Medicine (Medical Genetics), University of Washington, Seattle.
authors.forename: Kostantin
authors.initials: K
authors.lastname: Kiianitsa
authors.affiliation: Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington10Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle.
authors.forename: Chang-En
authors.initials: CE
authors.lastname: Yu
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Brkanac
authors.affiliation: Department of Neurology, University of Washington, Seattle8Department of Pathology, University of Washington, Seattle.
authors.forename: Gwenn A
authors.initials: GA
authors.lastname: Garden
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle4Mental Illness Research, Education, and Clinical Center, Department of Veteran Affairs, Seattle, Washington5Department of Medicine (Medical Genetics), University of Washin.
authors.forename: Wendy H
authors.initials: WH
authors.lastname: Raskind
authors.affiliation: Department of Neurology, University of Washington, Seattle5Department of Medicine (Medical Genetics), University of Washington, Seattle9Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics*
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human