The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease
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A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta‐analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ 42) and total‐tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10−25). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF‐total‐tau (P = .0110) but not Aβ 42 suggesting that TREM2's role in AD may involve tau dysfunction.
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In the CSF of AD patients, the R47H variant of TREM2 or soluble TREM2 correlates with total or phosphorylated tau (Thr181), respectively, but not with Aβ42.
“In the CSF of AD patients, the R47H (rs75932628) variant of TREM2 or soluble TREM2 has been found to correlate with total or phosphorylated tau (Thr181), respectively, but not with Aβ42 [124, 125].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [124]
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Wang, T., Liu, X., Wang, X., Hua, F., & Yan, L. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1739875 · Cited by 14 · see citing works
- Authors
- Lill, C. M., Rengmark, A., Pihlstrøm, L., Fogh, I., Shatunov, A., Sleiman, P. M., Wang, L., Liu, T., Lassen, C. F., Meissner, E., Alexopoulos, P., Calvo, A., Chio, A., Dizdar, N., Faltraco, F., Forsgren, L., Kirchheiner, J., Kurz, A., Larsen, J. P., Liebsch, M., Linder, J., Morrison, K. E., Nissbrandt, H., Otto, M., Pahnke, J., Partch, A., Restagno, G., Rujescu, D., Schnack, C., Shaw, C. E., Shaw, P. J., Tumani, H., Tysnes, O., Valladares, O., Silani, V., van den Berg, L. H., van Rheenen, W., Veldink, J. H., Lindenberger, U., Steinhagen‐Thiessen, E., SLAGEN Consortium, Teipel, S., Perneczky, R., Hakonarson, H., Hampel, H., von Arnim, C. A. F., Olsen, J. H., Van Deerlin, V. M., Al‐Chalabi, A., Toft, M., Ritz, B., & Bertram, L.
- Affiliations
- Max Planck Institute for Molecular Genetics (DE)
- Oslo University Hospital (NO)
- King's College London (GB)
- Center for Applied Genomics Abramson Research Center, The Children's Hospital of Philadelphia Philadelphia PA USA
- University of Pennsylvania (US)
- Max Planck Institute for Human Development (DE)
- Danish Cancer Society (DK)
- Department of Psychiatry and Psychotherapy Technische Universität München Munich Germany
- University of Turin (IT)
- Rita Levi Montalcini Department of Neuroscience, ALS Center University of Torino Torino Italy
- Linköping University (SE)
- Goethe University Frankfurt (DE)
- Umeå University (SE)
- Universität Ulm (DE)
- Technical University of Munich (DE)
- The Norwegian Centre for Movement Disorders Stavanger University Hospital Stavanger Norway
- University Hospitals Birmingham NHS Foundation Trust (GB)
- University of Gothenburg (SE)
- Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT)
- Martin Luther University Halle-Wittenberg (DE)
- University of Sheffield (GB)
- Haukeland University Hospital (NO)
- University of Milan (IT)
- Department of Neurology, Neuromuscular Diseases Brain Center Rudolf Magnus, Netherlands ALS Center University Medical Center Utrecht Utrecht The Netherlands
- University Medical Center Utrecht (NL)
- Charité – Universitätsmedizin Berlin (DE)
- German Center for Neurodegenerative Diseases (DE)
- West London Mental Health NHS Trust (GB)
- Children's Hospital of Philadelphia (US)
- Sorbonne Université (FR)
- Department of Neurology University of Ulm Ulm Germany
- Department of Pathology and Laboratory Medicine Perelman School of Medicine at the University of Pennsylvania Philadelphia PA USA
- University of California, Los Angeles (US)
- Corresponding author
- Lill, Christina M.
- ORCID
- Lill, Christina M.
- Pihlstrøm, Lasse
- Fogh, Isabella
- Shatunov, Aleksey
- Wang, Li‐San
- Liu, Tian
- Lassen, Christina F.
- Calvo, Andrea
- Dizdar, Nil
- Faltraco, Frank
- Forsgren, Lars
- Kurz, Alexander
- Morrison, Karen E.
- Nissbrandt, Hans
- Otto, Markus
- Pahnke, Jens
- Rujescu, Dan
- Shaw, Christopher E.
- Shaw, Pamela J.
- Tumani, Hayrettin
- Tysnes, Ole‐Bjørn
- Valladares, Otto
- Silani, Vincenzo
- Veldink, Jan H.
- Lindenberger, Ulman
- Steinhagen‐Thiessen, Elisabeth
- Teipel, Stefan
- Perneczky, Robert
- Hakonarson, Hakon
- Hampel, Harald
- Olsen, Jørgen H.
- Al‐Chalabi, Ammar
- Toft, Mathias
- Ritz, Beate
- Bertram, Lars
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2015-04-29
- Volume
- 11
- Issue
- 12
- Pages
- 1407-1416
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC4627856
- OpenAlex
- W2055995786
- Cited by
- 205
- References
- 42
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 8 · 2023: 29 · 2022: 13 · 2021: 20 · 2020: 12 · 2019: 17 · 2018: 25 · 2017: 21 · 2016: 21 · 2015: 17
- FWCI
- 3.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- ePrints Soton (University of Southampton) (submittedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (submittedVersion)
- Max Planck Digital Library (submittedVersion, other-oa)
- Research Portal (King's College London) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- DZNE Pub (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, other-oa)
- Funders
- Cure Alzheimer's Fund
- Michael J. Fox Foundation for Parkinson's Research
- 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
- MeSH terms
- Aged, Alleles, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Female, Genotype, Humans, Male, Membrane Glycoproteins, Middle Aged, Parkinson Disease, Receptors, Immunologic, Risk Factors, Case-Control Studies, tau Proteins, Neurodegenerative Diseases, Genetic Predisposition to Disease, Quantitative Trait Loci, White People, Frontotemporal Lobar Degeneration
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