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, 72 (8), 920-7

R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study

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R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study

Olena Korvatska et al. JAMA Neurol.

Abstract

Importance: 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.

Design, setting, and participants: 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.

Main outcomes and measures: 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 and relevance: 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.

Conflict of interest statement

Conflict of Interest Disclosures: No other disclosures were reported.

Figures

Figure 1
Figure 1. Late-Onset Alzheimer Disease Pedigree Segregating TREM2 R47H
The dark icons denote individuals confirmed by medical records to be affected, death certificate, or examination by medical personnel. An individual suspected to have dementia is shaded pale gray. Capital letters within the icons denote the TREM2 genotype (CT = R47H and CC = R47R) and lower case letters denote the UNC5A genotype (ct = D353N and cc = D353D) for those whose DNA was available; c indicates current age (in years); d, age at death (in years); e, last evaluated; ε 3/3, ε 2/4, ε 3/4, or ε 4/4, apolipoprotein E genotype; E, exome sequencing done; and o, age at onset (in years). The circles indicate females; squares, males; diamonds, sex unknown; and a diagonal line through a symbol indicates death. The numbers within the symbols indicate the number of individuals of that sex within the sibship.
Figure 2
Figure 2. Immunoreactivity in the Hippocampus
Four areas were assessed: cornu ammonis (CA) region 1 (CA1); the hilus or CA4; the parahippocampal gyrus (PHG), and white matter (WM). Groups are compared using a 2-tailed t test. The Alzheimer disease (AD) group indicates the patients with AD with normal TREM2 (n = 6); control, the nondemented cases (n = 3); and R47H_AD, patients with AD who carry TREM2 R47H (n = 7). All R47H_AD individuals and 3 of 6 AD group individuals are from the LOAD123 family; the others are sporadic cases. Iba1 indicates ionized calcium-binding adapter molecule 1; MHCII, major histocompatibility complex class II. The error bars indicate 1 SD. aP < .05.
Figure 3
Figure 3. Immunoreactivity in the Frontal Lobe for Ionized Calcium-Binding Adapter Molecule 1 (Iba1)
Gray matter and white matter were assessed. The density of the signal was averaged from 3 areas measured for each individual. Groups are compared using a 2-tailed t test. AD group indicates patients with AD with normal TREM2 (n = 6); control, the nondemented cases (n = 3); and R47H_AD, patients with AD who carry TREM2 R47H (n = 7). All R47H_AD individuals and 3 of 6 AD group individuals are from the LOAD123 family; the others are sporadic cases. The error bars indicate 1 SD. a P < .05.
Figure 4
Figure 4. Graded Immunohistochemistry Analysis of Hippocampal White Matter
Groups are compared using 1-way analysis of variance and Tukey post-test comparison. Analysis of sections presented in Figure 2. The Alzheimer disease (AD) group indicates the patients with AD with normal TREM2 (n = 6); control, nondemented cases (n = 3); and R47H_AD, patients with AD who carry TREM2 R47H (n = 7). All R47H_AD individuals and 3 of 6 AD group individuals are from the LOAD123 family; the others are sporadic cases. Iba1 indicates ionized calcium-binding adapter molecule 1. The error bars indicate 1 SEM. a P < .05.

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