Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late-onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole-genome sequence data of a patient with autopsy confirmed Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early-onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency <1%, 20 missense and two splicing mutations. Burden analysis did not provide significant evidence for an enrichment of rare PLD3 variants in EOAD patients in any of the patient/control cohorts. Also, meta-analysis of the PLD3 data, including a published dataset of a German EOAD cohort, was not significant (P = 0.43; OR = 1.53, 95% CI 0.60-3.31). Consequently, our data do not support a role for PLD3 rare variants in the genetic etiology of EOAD in European EOAD patients. Our data corroborate the negative replication data obtained in LOAD studies and therefore a genetic role of PLD3 in AD remains to be demonstrated.

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

Center of Clinical Neurosciences Department of Neurology 1st Medical Faculty Charles University Prague Czech Republic

Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas Instituto de Salud Carlos 3 Madrid Spain

Department of Geriatric Medicine Genetics Unit Karolinska University Hospital Stockholm Sweden

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

Department of Neurology and Memory Clinic Hospital Network Antwerp Middelheim and Hoge Beuken Antwerp Belgium

Department of Neurology Antwerp University Hospital Edegem Belgium

Department of Neurology Clínica Universidad de Navarra University of Navarra School of Medicine Pamplona Spain

Department of Neurology Hospital Universitari Mutua de Terrassa Terrassa Barcelona Spain

Department of Neurology IIB Sant Pau Hospital de la Santa Creu i Sant Pau Universidad Autònoma de Barcelona Barcelona Spain

Department of Neurology University Hospitals Leuven Leuven Belgium

Department of Neurosciences Faculty of Medicine KU Leuven Leuven Belgium

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 Leuven Belgium

Department of Pathology and Molecular Medicine Thomayer Hospital Prague Czech Republic

Department of Psychiatry and Psychotherapy Technische Universität München München Germany

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

Institute Born Bunge University of Antwerp Antwerp Belgium

Institute of Pathology 3rd Medical Faculty of Charles University Prague Prague Czech Republic

Laboratory of Biochemistry Department of Chemistry Aristotle University of Thessaloniki Thessaloniki Greece

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

Neurodegenerative Brain Diseases Group Department of Molecular Genetics VIB Antwerp Belgium

Neurogenetics Laboratory Division of Neurosciences Center for Applied Medical Research Universidad de Navarra Pamplona Spain

Neuroimaging Laboratory Division of Neurosciences Center for Applied Medical Research University of Navarra Pamplona 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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