Meta-analysis of existing genome-wide association studies on Alzheimer's disease (AD) showed subgenome-wide association of an intronic variant in the sequestosome 1 (SQSTM1) gene with AD. We performed targeted resequencing of SQSTM1 in Flanders-Belgian AD patients selected to be enriched for a genetic background (n = 435) and geographically matched nonaffected individuals (n = 872) to investigate the role of both common and rare SQSTM1 variants. Results were extended to the European early-onset dementia cohorts (926 early-onset Alzheimer's disease [EOAD] patients and 1476 nonaffected individuals). Of the 61 detected exonic variants in SQSTM1, the majority were rare (n = 57). Rare variant (minor allele frequency <0.01) burden analysis did not reveal an increased frequency of rare variants in EOAD patients in any of the separate study populations nor when meta-analyzing all cohorts. Common variants p.D292= and p.R312= showed nominal association with AD (odds ratiop.D292= = 1.11 [95% confidence interval = 1-1.22], p = 0.04), only when including the Flanders-Belgian cohort in the meta-analysis. We cannot exclude a role of SQSTM1 genetic variability in late-onset AD, but our data indicate that SQSTM1 does not play a major role in the etiology of EOAD.

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

Center of Clinical Neurosciences Department of Neurology 1st Medical Faculty Charles University Prague Czech Republic; Department of Pathology and Molecular Medicine Thomayer Hospital Prague Czech Republic

Center of Clinical Neurosciences Department of Neurology 1st Medical Faculty Charles University Prague Czech Republic; Department of Pathology and Molecular Medicine Thomayer Hospital Prague Czech Republic; Institute of Pathology 3rd Medical Faculty of Charles University Prague Prague Czech Republic

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

Départements de Médicine Interne Réhabilitation and Gériatrie et de Sante Mentale and Psychiatrie Hôpitaux Universitaires de Genève et Université de Genève Geneva Switzerland; Alzheimer's Neuroimaging and Epidemiology Laboratory IRCCS Fatebenefratelli Brescia Italy

Department of Molecular Genetics VIB Antwerp Belgium; Laboratory of Neurogenetics Institute Born Bunge University of Antwerp Antwerp Belgium; Laboratory of Neurochemistry and Behavior Institute Born Bunge University of Antwerp Antwerp Belgium

Department of Neurobiology Care Sciences and Society Center for Alzheimer Research Division of Neurogeriatrics Karolinska Institutet Huddinge Sweden

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 Neurological and Movements Sciences Section of Neurology University Hospital G B Rossi University of Verona Verona Italy

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

Department of Old Age Psychiatry and Memory Clinic University of Leuven and University Hospitals Leuven Gasthuisberg Leuven Belgium

Department of Psychiatry and Psychotherapy Technische Universität München München Germany

Faculty of Medicine and Institute of Molecular Medicine University of Lisbon Lisbon Portugal

Laboratory for Cognitive Neurology Department of Neurology University of Leuven and University Hospitals Leuven Gasthuisberg Leuven Belgium

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

Laboratory of Neurogenetics Institute Born Bunge University of Antwerp Antwerp Belgium; Laboratory of Neurochemistry and Behavior Institute Born Bunge University of Antwerp Antwerp Belgium; Department of Neurology and Memory Clinic Hospital Network Antwerp Middelheim and Hoge Beuken Antwerp Belgium; Department of Neurology and Alzheimer Research Center University of Groningen and University Medical Center Groningen Groningen The Netherlands

Memory Clinic of Fundaciò ACE Institut Català de Neurociències Aplicades Barcelona Spain

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

Neurogenetics Laboratory Division of Neurosciences Center for Applied Medical Research Universidad de Navarra Pamplona Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas Instituto de Salud Carlos 3 Madrid Spain

Neurogenetics Laboratory Division of Neurosciences Center for Applied Medical Research Universidad de Navarra Pamplona Spain; Department of Neurology Hospital Universitari Mutua de Terrassa Terrassa Barcelona Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas Instituto de Salud Carlos 3 Madrid Spain

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

Neurology Unit University of Brescia Brescia Italy

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