Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort

Jan Verheijen, Julie van der Zee, Ilse Gijselinck, Tobi Van den Bossche, Lubina Dillen, Bavo Heeman, Estrella Gómez-Tortosa, Albert Lladó, Raquel Sanchez-Valle, Caroline Graff, Pau Pastor, Maria A. Pastor, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, Jordi Clarimon, Alexandre de Mendonça, Ellen Gelpi, Magda Tsolaki, Janine Diehl-SchmidBenedetta Nacmias, Maria Rosário Almeida, Barbara Borroni, Radoslav Matej, Agustín Ruiz, Sebastiaan Engelborghs, Rik Vandenberghe, Peter P. De Deyn, Marc Cruts, Christine Van Broeckhoven, Kristel Sleegers, Johan Goeman, Dirk Nuytten, Mathieu Vandenbulcke, Patrick Santens, Jan De Bleecker, Anne Sieben, Bart Dermaut, Jan Versijpt, Alex Michotte, Olivier Deryck, Bruno Bergmans, Christiana Willems, Adrian Ivanoiu, Eric Salmon, Panagiotis Alexopoulos, Sandro Sorbi, Valentina Bessi, Silvia Bagnoli, Isabel Santana, Frederico Simões do Couto, Madalena Martins, Håkan Thonberg, Laura Fratiglioni, Alessandro Padovani, Zdenek Rohan, Cristina Razquin, Elena Lorenzo, Elena Iglesias, Manuel Seijo-Martínez, Ramon Rene, Jordi Gascon, Jaume Campdelacreu, Maria Koutroumani, Alberto Lleó, Juan Fortea, Rafael Blesa

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15 Citations (Scopus)


© 2017 The Author(s) TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer's disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls. We identified only 1 LoF mutation (p.Thr79del) in a patient clinically diagnosed with Alzheimer's disease and a positive family history of ALS. We did not observe enrichment of rare variants in EOAD patients compared to controls, nor of rare variants affecting NFκB induction. Of 3 common coding variants, rs7486100 showed evidence of association (OR 1.46 [95% CI 1.13–1.9]; p-value 0.01). Homozygous carriers of the risk allele showed reduced expression of TBK1 (p-value 0.03). Our findings are not indicative of a significant role for TBK1 mutations in EOAD. The association between common variants in TBK1, disease risk and reduced TBK1 expression warrants follow-up in FTD/ALS cohorts.
Original languageEnglish
Pages (from-to)245.e1-245.e7
JournalNeurobiology of Aging
Publication statusPublished - 1 Feb 2018


  • Early onset Alzheimer's disease
  • Frontotemporal dementia
  • Loss-of-function
  • RNA sequencing
  • TBK1


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