Investigation of the role of rare TREM2 variants in frontotemporal dementia subtypes

Mathias Thelen, Cristina Razquin, Isabel Hernández, Ana Gorostidi, Raquel Sánchez-Valle, Sara Ortega-Cubero, Steffen Wolfsgruber, Dmitriy Drichel, Klaus Fliessbach, Tanja Duenkel, Marinella Damian, Stefanie Heilmann, Anja Slotosch, Martina Lennarz, Manuel Seijo-Martínez, Ramón Rene, Johannes Kornhuber, Oliver Peters, Christian Luckhaus, Holger JahnMichael Hüll, Eckart Rüther, Jens Wiltfang, Elena Lorenzo, Jordi Gascon, Alberto Lleó, Albert Lladó, Jaume Campdelacreu, Fermin Moreno, Hojjat Ahmadzadehfar, Juan Fortea, Begoña Indakoetxea, Michael T. Heneka, Axel Wetter, Maria A. Pastor, Mario Riverol, Tim Becker, Lutz Frölich, Lluís Tárraga, Mercè Boada, Michael Wagner, Frank Jessen, Wolfgang Maier, Jordi Clarimón, Adolfo López de Munain, Agustín Ruiz, Pau Pastor, Alfredo Ramirez

    Research output: Contribution to journalArticleResearchpeer-review

    32 Citations (Scopus)


    © 2014 Elsevier Inc. Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. Rare TREM2 variants have been recently identified in families affected by FTD-like phenotype. However, genetic studies of the role of rare TREM2 variants in FTD have generated conflicting results possibly because of difficulties on diagnostic accuracy. The aim of the present study was to investigate associations between rare TREM2 variants and specific FTD subtypes (FTD-S). The entire coding sequence of TREM2 was sequenced in FTD-S patients of Spanish (. n= 539) and German (. n= 63) origin. Genetic association was calculated using Fisher exact test. The minor allele frequency for controls was derived from in-house genotyping data and publicly available databases. Seven previously reported rare coding variants (p.A28V, p.W44X, p.R47H, p.R62H, p.T66M, p.T96K, and p.L211P) and 1 novel missense variant (p.A105T) were identified. The p.R47H variant was found in 4 patients with FTD-S. Two of these patients showed cerebrospinal fluid pattern of amyloid beta, tau, and phosphorylated-tau suggesting underlying Alzheimer's disease (AD) pathology. No association was found between p.R47H and FTD-S. A genetic association was found between p.T96K and FTD-S (. p= 0.013, odds ratio= 4.23, 95% Confidence Interval [1.17-14.77]). All 6 p.T96K patients also carried the TREM2 variant p.L211P, suggesting linkage disequilibrium. The remaining TREM2 variants were found in 1 patient, respectively, and were absent in controls. The present findings provide evidence that p.T96K is associated with FTD-S and that p.L211P may contribute to its pathogenic effect. The data also suggest that p.R47H is associated with an FTD phenotype that is characterized by the presence of underlying AD pathology.
    Original languageEnglish
    Pages (from-to)2657.e13-2657.e19
    JournalNeurobiology of Aging
    Issue number11
    Publication statusPublished - 1 Nov 2014


    • Alzheimer's disease
    • Case-control studies
    • Frontotemporal dementia
    • Genetic association studies


    Dive into the research topics of 'Investigation of the role of rare TREM2 variants in frontotemporal dementia subtypes'. Together they form a unique fingerprint.

    Cite this