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.

3rd Department of Neurology Medical School Aristotle University of Thessaloniki Thessaloniki Greece

Alzheimer's Disease and Other Cognitive Disorders Unit Neurology Department Hospital Clínic Institut d'Investigacions Biomediques August Pi i Sunyer Barcelona Spain

Center for Neuroscience and Cell Biology University of Coimbra Coimbra Portugal

Centre for Neurodegenerative Disorders Neurology Unit Department of Clinical and Experimental Sciences University of Brescia Brescia Italy

Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas Instituto de Salud Carlos 3 Madrid Spain; Department of Neurology IIB Sant Pau Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona Barcelona Spain

Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas University of Navarra Pamplona Spain; Department of Neurology Clínica Universidad de Navarra University of Navarra School of Medicine Pamplona Spain

Department of Neurobiology Care Sciences and Society Center for Alzheimer Research Division of Neurogeriatrics Karolinska Institutet Huddinge Sweden; Department of Geriatric Medicine Genetics Unit Karolinska University Hospital Stockholm Sweden

Department of Neurology Fundación Jiménez Díaz Madrid Spain

Department of Neurosciences Faculty of Medicine KU Leuven Leuven Belgium; Department of Neurology University Hospitals Leuven Leuven Belgium

Department of Neurosciences Psychology Drug Research and Child Health University of Florence Florence Italy

Department of Pathology 1st Medical Faculty Charles University and Department of Pathology and Molecular Medicine Thomayer Hospital Prague Prague Czech Republic

Department of Psychiatry and Psychotherapy Technische Universität München München Germany

Faculty of Medicine University of Lisbon Lisbon Portugal

Fundació ACE Institut Català de Neurociències Aplicades Barcelona Spain

Institute Born Bunge University of Antwerp Antwerp Belgium; Department of Neurology and Memory Clinic Hospital Network Antwerp Middelheim and Hoge Beuken Antwerp Belgium

Memory Unit Department of Neurology University Hospital Mútua de Terrassa University of Barcelona School of Medicine Terrassa Barcelona Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas Instituto de Salud Carlos 3 Madrid Spain

Molecular Markers Laboratory Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli Brescia Italy

Neurodegenerative Brain Diseases group VIB Center for Molecular Neurology University of Antwerp Antwerp Belgium; Institute Born Bunge University of Antwerp Antwerp Belgium

Neurodegenerative Brain Diseases group VIB Center for Molecular Neurology University of Antwerp Antwerp Belgium; Institute Born Bunge University of Antwerp Antwerp Belgium; Department of Neurology Antwerp University Hospital Edegem Belgium; Department of Neurology and Memory Clinic Hospital Network Antwerp Middelheim and Hoge Beuken Antwerp Belgium

Neurological Tissue Bank of the Biobanc Hospital Clinic Institut d'Investigacions Biomediques August Pi i Sunyer Barcelona Spain

Citace poskytuje Crossref.org