Evidence map›Paper›PMID 24439484›Full record

ArticleNeurobiology of aging2014

Missense variant in TREML2 protects against Alzheimer's disease.

Bruno A Benitez, Sheng Chih Jin, Rita Guerreiro, Rob Graham, Jenny Lord, Denise Harold, Rebecca Sims, Jean-Charles Lambert, J Raphael Gibbs, Jose Bras and 37 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neurobiology of aging, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers, 6 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
75citing papers in PubMed, 6 pooled it
9.1field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

75 citing papers in PubMed, 6 syntheses or guidelines pooled it, 125 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Pooled it
  5. Pooled it
  6. Pooled it
  7. Trial
  8. Review
  9. Article
  10. Early microglial and astrocyte reactivity in preclinical Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Article
  11. Article
  12. Review
  13. Article
  14. Review
  15. Article
  16. Review
  17. The biology of TREM receptors.Nature reviews. Immunology · 2023
    Review
  18. The Alzheimer's disease-associated geneNeural regeneration research · 2023
    Article
  19. Article
  20. Article

15 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

47 authors at 14 institutions in 3 countries.

Bruno A BenitezDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Sheng Chih JinDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Rita GuerreiroDepartment of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Rob GrahamDiagnostic Discovery Department, Genentech Inc, South San Francisco, CA, USA.
Jenny LordHuman Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Denise HaroldInstitute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Rebecca SimsInstitute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Jean-Charles LambertInserm, Lille, France; Universite Lille 2, Lille, France; Institut Pasteur de Lille, Lille, France.
J Raphael GibbsDepartment of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Jose BrasDepartment of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Celeste SassiDepartment of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Oscar HarariDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Sarah BertelsenDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Michelle K LuptonInstitute of Psychiatry, King's College London, London, UK.
John PowellInstitute of Psychiatry, King's College London, London, UK.
Celine BellenguezInserm, Lille, France; Universite Lille 2, Lille, France; Institut Pasteur de Lille, Lille, France.
Kristelle BrownHuman Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Christopher MedwayHuman Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Patrick C G HaddickDiagnostic Discovery Department, Genentech Inc, South San Francisco, CA, USA.
Marcel P van der BrugDiagnostic Discovery Department, Genentech Inc, South San Francisco, CA, USA.
Tushar BhangaleDepartment of Bioinformatics and Computational Biology, Genentech Inc, South San Francisco, CA, USA.
Ward OrtmannHuman Genetics Department, Genentech Inc, South San Francisco, CA, USA.
Tim BehrensHuman Genetics Department, Genentech Inc, South San Francisco, CA, USA.
Richard MayeuxDepartment of Neurology, Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA; Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA.
Margaret A Pericak-VanceThe John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA; Dr John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA.
Lindsay A FarrerDepartment of Medicine, Boston University Schools of Medicine and Public Health, Boston, MA, USA; Department of Biomedical Genetics, Boston University Schools of Medicine and Public Health, Boston, MA, USA; Department of Neurology, Boston University Schools of Medicine and Public Health, Boston, MA, USA; Department of Ophthalmology, Boston University Schools of Medicine and Public Health, Boston, MA, USA; Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA, USA; Department of Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA.
Gerard D SchellenbergDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Jonathan L HainesDepartment of Molecular Physiology and Biophysics, Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA.
Jim TurtonHuman Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Anne BraaeHuman Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Imelda BarberHuman Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Anne M FaganDepartment of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
David M HoltzmanDepartment of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
John C MorrisDepartment of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
3C Study Group
EADI consortium
Alzheimer's Disease Genetic Consortium (ADGC)
Alzheimer's Disease Neuroimaging Initiative (ADNI)
GERAD Consortium
Julie WilliamsInstitute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
John S K KauweDepartment of Biology, Brigham Young University, Provo, UT, USA.
Philippe AmouyelInserm, Lille, France; Universite Lille 2, Lille, France; Institut Pasteur de Lille, Lille, France.
Kevin MorganHuman Genetics, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Andy SingletonHuman Genetics Department, Genentech Inc, South San Francisco, CA, USA.
John HardyHuman Genetics Department, Genentech Inc, South San Francisco, CA, USA.
Alison M GoateDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: goatea@psychiatry.wustl.edu.
Carlos CruchagaDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA; Universite Lille 2, Lille, France. Electronic address: cruchagac@psychiatry.wustl.edu.
Washington University in St. Louis · USUniversity of Nottingham · GBCardiff University · GBUniversity College London · GBInstitut Pasteur de Lille · FRKing's College London · GBBrigham Young University · USColumbia University · USInserm · FRNational Institutes of Health · USUniversité de Lille · FRUniversity of Miami · USUniversity of Pennsylvania · USVanderbilt University · US

Funding

National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)U24AG021886 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI TATIANA M. FOROUD · 2002 to 2026
$119.8M
NATIONAL ALZHEIMERS COORDINATING CENTER (NACC)U01AG016976 · NIA · UNIVERSITY OF WASHINGTON · PI KUKULL, WALTER ANTHONY · 1999 to 2020
$72.8M
Smartphone-Based "Burst" Cognitive AssessmentsP01AG003991 · NIA · WASHINGTON UNIVERSITY · PI Tammie Lee Smith Benzinger · 1985 to 2026
$69.5M
Alzheimer's Disease Genetics ConsortiumU01AG032984 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID · 2009 to 2024
$60.4M
THERAPEUTIC EFFECTS OF INTRA-NASAL INSULIN DETEMIRP50AG005136 · NIA · UNIVERSITY OF WASHINGTON · PI JAYADEY, SUMAN · 1985 to 2019
$57.2M
VIRUS-INDUCED BRAIN PATHOLOGYP50AG005131 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI LAGIER-TOURENNE, CLOTILDE · 1985 to 2018
$55.4M
WASHINGTON UNIVERSITY ALZHEIMERS DISEASE RESEARCH CENTERP50AG005681 · NIA · WASHINGTON UNIVERSITY · PI MORRIS, JOHN · 1985 to 2019
$52.1M
The natural history of AB accumulation in preclinical ADP01AG026276 · NIA · WASHINGTON UNIVERSITY · PI SCHINDLER, SUZANNE ELIZABETH · 2005 to 2025
$49.5M
Furthering scientific understanding of mechanisms underlying resilience to the effects of AD pathology by incorporating state of the art quantification of gliosis, inflammation, & synaptic toxicityU01AG006781 · NIA · UNIVERSITY OF WASHINGTON · PI CRANE, PAUL K, LARSON, ERIC B · 1986 to 2020
$39.3M
UPenn ADCC Biomarker CoreP30AG010124 · NIA · UNIVERSITY OF PENNSYLVANIA · PI XIE, SHARON XIANGWEN · 1991 to 2020
$35.1M
The National Institute on Aging (NIA) Late Onset of Alzheimer's Disease (LOAD) Family-Based Study (FBS)U24AG056270 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI Gary Wayne Beecham, TATIANA M. FOROUD · 2017 to 2026
$31.4M
Neuropathology CoreP30AG013846 · NIA · BOSTON UNIVERSITY MEDICAL CAMPUS · PI KOWALL, NEIL W. · 1996 to 2020
$29.1M
Medical Research Council G0902227Medical Research Council MC_G1000735Medical Research Council MR/K013041/1Medical Research Council MR/L010305/1Medical Research Council MR/L501517/1NCATS NIH HHS UL1 TR001108NHGRI NIH HHS U01 HG006375NIA NIH HHS AG010124NIA NIH HHS AG05136NIA NIH HHS P01 AG003991NIA NIH HHS P01 AG026276NIA NIH HHS P01-AG026276NIA NIH HHS P01-AG03991NIA NIH HHS P01-AG05131NIA NIH HHS P30 AG010124NIA NIH HHS P30 AG013846NIA NIH HHS P50 AG005131NIA NIH HHS P50 AG005136NIA NIH HHS P50 AG005681NIA NIH HHS P50-AG05681NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG016208NIA NIH HHS R01 AG035083NIA NIH HHS R01-AG035083NIA NIH HHS R01 AG041797NIA NIH HHS R01 AG042611NIA NIH HHS R01-AG042611NIA NIH HHS R01 AG044546NIA NIH HHS R01-AG044546NIA NIH HHS R01-AG16208NIA NIH HHS RF1 AG044546NIA NIH HHS U01 AG006781NIA NIH HHS U01 AG016976NIA NIH HHS U01 AG032984NIA NIH HHS U01-AG032984NIA NIH HHS U24 AG021886NIA NIH HHS U24 AG056270NINDS NIH HHS P30 NS069329NINDS NIH HHS P30-NS069329E01Wellcome Trust 089698
6 · The paper itself

Abstract

TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p.R47H) in TREM2 that confers a high risk for Alzheimer's disease (AD). In addition, common single nucleotide polymorphisms in this genomic region are associated with cerebrospinal fluid biomarkers for AD and a common intergenic variant found near the TREML2 gene has been identified to be protective for AD. However, little is known about the functional variant underlying the latter association or its relationship with the p.R47H. Here, we report comprehensive analyses using whole-exome sequencing data, cerebrospinal fluid biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p.S144G (rs3747742) as a potential driver of the meta-analysis AD-associated genome-wide association studies signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD.

Indexed as

Genome-Wide Association StudyAlzheimer DiseaseBiomarkersChromosomes, Human, Pair 6Genetic VariationHumansMeta-Analysis as TopicMutation, MissensePolymorphism, Single NucleotideReceptors, ImmunologicRiskBiomarkersReceptors, ImmunologicTREML2 protein, humanAlzheimer's diseaseAssociationConditional analysisEndophenotypeGeneGenome-wide association studiesTREM2

Identifiers

PMID24439484
PMCPMC3961557
OpenAlexW2062901418

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.