Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimer's disease and frontotemporal dementia
Abstract
A non-synonymous genetic rare variant, rs75932628-T (p.R47H), in the TREM2 gene has recently been reported to be a strong genetic risk factor for Alzheimer's disease (AD). Also, rare recessive mutations have been associated with frontotemporal dementia (FTD). We aimed to investigate the role of p.R47H variant in AD and FTD through a multi-center study comprising 3172 AD and 682 FTD patients and 2169 healthy controls from Spain. We found that 0.6% of AD patients carried this variant compared to 0.1% of controls (odds ratio [OR] = 4.12, 95% confidence interval [CI] = 1.21-14.00, p = 0.014). A meta-analysis comprising 32,598 subjects from 4 previous studies demonstrated the large effect of the p.R47H variant in AD risk (OR = 4.11, 95% CI = 2.99-5.68, p = 5.27×10(-18)). We did not find an association between p.R47H and age of onset of AD or family history of dementia. Finally, none of the FTD patients harbored this genetic variant. These data strongly support the important role of p.R47H in AD risk, and suggest that this rare genetic variant is not related to FTD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The R47H variant of TREM2 has an effect size for increased Alzheimer's disease risk comparable to the APOEε4 allele, around a 3-fold increased risk.
“The risk from this variant has a comparable effect size with the APOEε4 allele (around 3-fold increased AD risk; 4,19–22).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [21]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984) · Neurology · doi:10.1212/wnl.34.7.939 · Cited by 27,915 · see citing works
Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria
Neary, D., Snowden, J. S., Gustafson, L., Passant, U., Stuss, D., Black, S., Freedman, M., Kertesz, A., Robert, P. H., Albert, M., et al. (1998) · Neurology · doi:10.1212/wnl.51.6.1546 · Cited by 5,047 · see citing works
<i>TREM2</i> Variants in Alzheimer's Disease
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211851 · Cited by 3,020 · see citing works
Variant of <i>TREM2</i> Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558 · see citing works
Evolution and functional impact of rare coding variation from deep sequencing of human exomes
Tennessen, J. A., Bigham, A. W., O’Connor, T. D., Fu, W., Kenny, E. E., Gravel, S., McGee, S., Do, R., Liu, X., Jun, G., et al. (2012) · Science · doi:10.1126/science.1219240 · Cited by 1,613 · see citing works
Review papers : The statistical basis of meta-analysis
Fleiss, J. (1993) · Statistical Methods in Medical Research · doi:10.1177/096228029300200202 · Cited by 1,284 · see citing works
Are Rare Variants Responsible for Susceptibility to Complex Diseases?
Pritchard, J. K. (2001) · The American Journal of Human Genetics · doi:10.1086/321272 · Cited by 1,197 · see citing works
Paloneva, J., Manninen, T., Christman, G., Hovanes, K., Mandelin, J., Adolfsson, R., Bianchin, M., Bird, T., Miranda, R., Salmaggi, A., et al. (2002) · The American Journal of Human Genetics · doi:10.1086/342259 · Cited by 683 · see citing works
Meta-Analyst: software for meta-analysis of binary, continuous and diagnostic data
Wallace, B., Schmid, C. H., Lau, J., & Trikalinos, T. A. (2009) · BMC Medical Research Methodology · doi:10.1186/1471-2288-9-80 · Cited by 658 · see citing works
Practical aspects of imputation-driven meta-analysis of genome-wide association studies
de Bakker, P. I. W., Ferreira, M. A. R., Jia, X., Neale, B. M., Raychaudhuri, S., & Voight, B. F. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn288 · Cited by 531 · see citing works
Rayaprolu, S., Mullen, B., Baker, M., Lynch, T., Finger, E., Seeley, W. W., Hatanpaa, K. J., Lomen-Hoerth, C., Kertesz, A., Bigio, E. H., et al. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-19 · Cited by 404 · see citing works
Guerreiro, R. J., Lohmann, E., Brás, J. M., Gibbs, J. R., Rohrer, J. D., Gurunlian, N., Dursun, B., Bilgic, B., Hanagasi, H., Gurvit, H., et al. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.579 · Cited by 374 · see citing works
TREM2 is associated with the risk of Alzheimer's disease in Spanish population
Benitez, B. A., Cooper, B., Pastor, P., Jin, S.-C., Lorenzo, E., Cervantes, S., & Cruchaga, C. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.12.018 · Cited by 163 · see citing works
Self-citationTREM2 R47H Variant as a Risk Factor for Early-Onset Alzheimer's Disease
Pottier, C. P., collaborators, G., Wallon, D., Rousseau, S., Rovelet‐Lecrux, A., Richard, A., Rollin‐Sillaire, A., Frébourg, T., Campion, D., & Hannequin, D. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-122311 · Cited by 162 · see citing works
Giraldo, M., Lopera, F., Siniard, A. L., Corneveaux, J. J., Schrauwen, I., Carvajal, J., Muñoz, C., Ramirez-Restrepo, M., Gaiteri, C., Myers, A. J., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.02.016 · Cited by 147 · see citing works
The synergy factor: a statistic to measure interactions in complex diseases
Cortina‐Borja, M., Smith, A. D., Combarros, O., & Lehmann, D. J. (2009) · BMC Research Notes · doi:10.1186/1756-0500-2-105 · Cited by 125 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Yuan, P., Condello, C., Keene, C. D., Wang, Y., Bird, T. D., Paul, S. M., Luo, W., Colonna, M., Baddeley, D., & Grutzendler, J. (2016) · Neuron · doi:10.1016/j.neuron.2016.05.003 · Cited by 817 · see citing works
Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques
Condello, C., Yuan, P., Schain, A., & Grutzendler, J. (2015) · Nature Communications · doi:10.1038/ncomms7176 · Cited by 718 · see citing works
TREM2 — a key player in microglial biology and Alzheimer disease
Ulland, T. K., & Colonna, M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0072-1 · Cited by 735 · see citing works
New insights into the role of TREM2 in Alzheimer’s disease
Gratuze, M., Leyns, C. E. G., & Holtzman, D. M. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0298-9 · Cited by 489 · see citing works
TREM2, microglia, and neurodegenerative diseases
Yeh, F. L., Hansen, D. V., & Sheng, M. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.03.008 · Cited by 440 · see citing works
TREM2 variants: new keys to decipher Alzheimer disease pathogenesis
Colonna, M., & Wang, Y. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2016.7 · Cited by 418 · see citing works
Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
de Rojas, I., Moreno-Grau, S., Tesi, N., Grenier-Boley, B., Andrade, V., Jansen, I. E., Pedersen, N. L., Stringa, N., Zettergren, A., Hernández, I., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22491-8 · Cited by 324 · see citing works
Self-citationTREM2 regulates microglial cell activation in response to demyelination in vivo
Cantoni, C., Bollman, B., Licastro, D., Xie, M., Mikesell, R., Schmidt, R., Yuede, C. M., Galimberti, D., Olivecrona, G., Klein, R. S., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1388-1 · Cited by 296 · see citing works
The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders
Carmona, S., Zahs, K., Wu, E., Dakin, K., Bras, J., & Guerreiro, R. (2018) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30232-1 · Cited by 244 · see citing works
Bi, D., Wen, L., Wu, Z., & Shen, Y. (2020) · Alzheimer's & Dementia · doi:10.1002/alz.12088 · Cited by 232 · see citing works
Liu, W., Taso, O., Wang, R., Bayram, S., Graham, A. C., Garcia-Reitboeck, P., Mallach, A., Andrews, W. D., Piers, T. M., Botia, J. A., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa209 · Cited by 214 · see citing works
“The risk from this variant has a comparable effect size to the APOEe4 allele (around 3-fold increased AD risk; Benitez et al. 2013; Jin et al. 2014; Jonsson et al. 2013; Murray et al. 2018; Ruiz et al. 2014).”
BackgroundLill, C. M., Rengmark, A., Pihlstrøm, L., Fogh, I., Shatunov, A., Sleiman, P. M., Wang, L., Liu, T., Lassen, C. F., Meissner, E., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.12.009 · Cited by 205 · see citing works
Genetics ignite focus on microglial inflammation in Alzheimer’s disease
Malik, M., Parikh, I., Vasquez, J. B., Smith, C., Tai, L., Bu, G., LaDu, M. J., Fardo, D. W., Rebeck, G. W., & Estus, S. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0048-1 · Cited by 161 · see citing works
TREM2 is associated with increased risk for Alzheimer’s disease in African Americans
Jin, S. C., Carrasquillo, M. M., Benitez, B. A., Skorupa, T., Carrell, D., Patel, D., Lincoln, S., Krishnan, S., Kachadoorian, M., Reitz, C., et al. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0016-9 · Cited by 153 · see citing works
Microglia-Mediated Neuroprotection, TREM2, and Alzheimer’s Disease: Evidence From Optical Imaging
Condello, C., Yuan, P., & Grutzendler, J. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.10.007 · Cited by 131 · see citing works
Slattery, C. F., Beck, J. A., Harper, L., Adamson, G., Abdi, Z., Uphill, J., Campbell, T., Druyeh, R., Mahoney, C. J., Rohrer, J. D., et al. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.05.1751 · Cited by 119 · see citing works
López González, I., Garcia-Esparcia, P., Llorens, F., & Ferrer, I. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17020206 · Cited by 101 · see citing works
Roussos, P., Katsel, P., Fam, P., Tan, W., Purohit, D. P., & Haroutunian, V. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.10.013 · Cited by 103 · see citing works
Lista, S., Imbimbo, B. P., Grasso, M., Fidilio, A., Emanuele, E., Minoretti, P., López-Ortiz, S., Martín-Hernández, J., Gabelle, A., Caruso, G., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03163-y · Cited by 81 · see citing works
Microglia, Trem2, and Neurodegeneration
Shi, Q., Gutierrez, R. A., & Bhat, M. A. (2025) · The Neuroscientist · doi:10.1177/10738584241254118 · Cited by 69 · see citing works
Carrasquillo, M. M., Allen, M., Burgess, J. D., Wang, X., Strickland, S. L., Aryal, S., Siuda, J., Kachadoorian, M. L., Medway, C., Younkin, C. S., et al. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.10.005 · Cited by 58 · see citing works
Frontobasal gray matter loss is associated with the TREM2 p.R47H variant
Luis, E. O., Ortega-Cubero, S., Lamet, I., Razquin, C., Cruchaga, C., Benitez, B. A., Lorenzo, E., Irigoyen, J., Pastor, M. A., & Pastor, P. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.06.007 · Cited by 47 · see citing works
Self-citationZhu, C., Herrmann, U. S., Li, B., Abakumova, I., Moos, R., Schwarz, P., Rushing, E. J., Colonna, M., & Aguzzi, A. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.02.019 · Cited by 44 · see citing works
Alzheimer’s disease: rare variants with large effect sizes
Del-Aguila, J. L., Koboldt, D. C., Black, K., Chasse, R., Norton, J., Wilson, R. K., & Cruchaga, C. (2015) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2015.07.008 · Cited by 41 · see citing works
Li, R., Wang, X., & He, P. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.9778 · Cited by 39 · see citing works
Olive, C., Ibanez, L., Farias, F. H. G., Wang, F., Budde, J. P., Norton, J. B., Gentsch, J., Morris, J. C., Li, Z., Dube, U., et al. (2020) · Journal of Alzheimer’s Disease · doi:10.3233/jad-200019 · Cited by 32 · see citing works
Su, W., Shi, Z., Liu, S., Wang, X., Liu, S., & Ji, Y. (2018) · Annals of Human Genetics · doi:10.1111/ahg.12241 · Cited by 16 · see citing works
- Authors
- Ruiz, A., Dols-Icardo, O., Bullido, M. J., Pastor, P., Rodríguez-Rodríguez, E., López de Munain, A., de Pancorbo, M. M., Pérez-Tur, J., Álvarez, V., Antonell, A., López-Arrieta, J., Hernández, I., Tárraga, L., Boada, M., Lleó, A., Blesa, R., Frank-García, A., Sastre, I., Razquin, C., Ortega-Cubero, S., Lorenzo, E., Sánchez-Juan, P., Combarros, O., Moreno, F., Gorostidi, A., Elcoroaristizabal, X., Baquero, M., Coto, E., Sánchez-Valle, R., & Clarimón, J.
- Affiliations
- Hospital Universitario Central de Asturias (ES)
- Hospital Clínic de Barcelona (ES)
- Fundació ACE (ES)
- Universitat Autònoma de Barcelona (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Universidad de Cantabria (ES)
- University of the Basque Country (ES)
- Hospital Universitari i Politècnic La Fe (ES)
- Corresponding author
- Clarimón, Jordi
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 35
- Issue
- 2
- Pages
- 444.e1-444.e4
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2082945994
- Cited by
- 118
- References
- 16
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 3 · 2023: 4 · 2022: 6 · 2021: 10 · 2020: 9 · 2019: 13 · 2018: 10 · 2017: 10 · 2016: 13 · 2015: 14 · 2014: 10
- FWCI
- 8.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Instituto de Salud Carlos III (PI12/01311, 12/00013)
- Ministry of Science (SAF2010-15558, SAF2009-10434)
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
- Consolider (CSD2010-00045)
- Ayudas a proyectos de investigación sanitaria (2009111083)
- Department of Health of the Government of Navarra (13085, 3/2008)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- TREM2, Alzheimer's disease, frontotemporal dementia, genetic risk factors, recessive mutations, age of onset, family history of dementia
- MeSH terms
- Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Female, Genes, Recessive, Genotype, Humans, Male, Membrane Glycoproteins, Middle Aged, Mutation, Polymorphism, Genetic, Receptors, Immunologic, Risk Factors, Spain, Meta-Analysis as Topic, Cohort Studies, Multicenter Studies as Topic, Genetic Predisposition to Disease, Genome-Wide Association Study, Frontotemporal Dementia
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
