Volume 14, Issue 7 p. 913-924
Featured Article

Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease

Niklas Mattsson

Corresponding Author

Niklas Mattsson

Clinical Memory Research Unit, Clinical Sciences Malmö, Lund University, Lund, Sweden

Corresponding author. Tel.: +46 46 171000; Fax: +46 46 222 4720.

Corresponding author. Tel.: +31 20 444 0816; Fax: +31 20 444 0816.

E-mail address: [email protected] (N.M.), [email protected] (R.O.)

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Colin Groot

Colin Groot

Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands

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Willemijn J. Jansen

Willemijn J. Jansen

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands

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Susan M. Landau

Susan M. Landau

Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA

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Victor L. Villemagne

Victor L. Villemagne

Department of Nuclear Medicine and Centre for PET, Austin Health, Melbourne, Australia

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Sebastiaan Engelborghs

Sebastiaan Engelborghs

Reference Center for Biological Markers of Dementia (BIODEM), University of Antwerp, Antwerp, Belgium

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Mark M. Mintun

Mark M. Mintun

Avid Radiopharmaceuticals, Philadelphia, PA, USA

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Alberto Lleo

Alberto Lleo

Neurology Department, Hospital de Sant Pau, Barcelona, Spain

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José Luis Molinuevo

José Luis Molinuevo

Alzheimer's Disease and Other Cognitive Disorders Unit, IDIBAPS, Clinic University Hospital, Barcelona, Spain

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William J. Jagust

William J. Jagust

Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA

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Giovanni B. Frisoni

Giovanni B. Frisoni

Memory Clinic and LANVIE- Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Geneva, Switzerland

Laboratory of Alzheimer's Neuroimaging and Epidemiology, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy

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Adrian Ivanoiu

Adrian Ivanoiu

Memory Clinic and Neurochemistry Laboratory, Saint Luc University Hospital, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium

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Gaël Chételat

Gaël Chételat

Inserm, Inserm UMR-S U1237, Université de Caen-Normandie, GIP Cyceron, Caen, France

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Catarina Resende de Oliveira

Catarina Resende de Oliveira

Center for Neuroscience and Cell Biology, Faculty of Medicine, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal

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Karen M. Rodrigue

Karen M. Rodrigue

Center for Vital Longevity, School of Behavioral and Brain Sciences, The University of Texas at Dallas, Dallas, TX, USA

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Johannes Kornhuber

Johannes Kornhuber

Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen- Nuremberg, Erlangen, Germany

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Anders Wallin

Anders Wallin

Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden

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Aleksandra Klimkowicz-Mrowiec

Aleksandra Klimkowicz-Mrowiec

Jagiellonian University College of Medicine, Krakow, Poland

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Ramesh Kandimalla

Ramesh Kandimalla

Department of Biochemistry, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

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Julius Popp

Julius Popp

Department of Psychiatry, Service of Old Age Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland

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Pauline P. Aalten

Pauline P. Aalten

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands

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Dag Aarsland

Dag Aarsland

Center for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway

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Daniel Alcolea

Daniel Alcolea

Neurology Department, Hospital de Sant Pau, Barcelona, Spain

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Ina S. Almdahl

Ina S. Almdahl

Department of Neurology, Akershus University Hospital, Lørenskog, Norway

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Inês Baldeiras

Inês Baldeiras

Center for Neuroscience and Cell Biology, Faculty of Medicine, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal

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Mark A. van Buchem

Mark A. van Buchem

Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands

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Enrica Cavedo

Enrica Cavedo

Laboratory of Alzheimer's Neuroimaging and Epidemiology, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy

AXA Research Fund & UPMC Chair, Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Inserm, CNRS, Institut du Cerveau et de la Moelle Épinière (ICM), Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Hôpital Pitié-Salpêtrière, Paris, France

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Kewei Chen

Kewei Chen

Banner Alzheimer's Institute, Phoenix, AZ, USA

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Ann D. Cohen

Ann D. Cohen

University of Pittsburgh School of Medicine, Department of Psychiatry, Pittsburgh, PA, USA

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Stefan Förster

Stefan Förster

Department of Nuclear Medicine, Technische Universitaet München, Munich, Germany

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Juan Fortea

Juan Fortea

Neurology Department, Hospital de Sant Pau, Barcelona, Spain

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Kristian S. Frederiksen

Kristian S. Frederiksen

Danish Dementia Research Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Yvonne Freund-Levi

Yvonne Freund-Levi

Department of Geriatrics, Karolinska University Hospital Huddinge, Section of Clinical Geriatrics, Institution of NVS, Karolinska Institutet, Stockholm, Sweden

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Kiran Dip Gill

Kiran Dip Gill

Department of Biochemistry, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

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Olymbia Gkatzima

Olymbia Gkatzima

Third Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece

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Timo Grimmer

Timo Grimmer

Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar der Technischen Universitaet München, Munich, Germany

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Harald Hampel

Harald Hampel

AXA Research Fund & UPMC Chair, Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Inserm, CNRS, Institut du Cerveau et de la Moelle Épinière (ICM), Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Hôpital Pitié-Salpêtrière, Paris, France

Department of Psychiatry, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Ludwig-Maximilian University, Munich, Germany

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Sanna-Kaisa Herukka

Sanna-Kaisa Herukka

Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland

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Peter Johannsen

Peter Johannsen

Memory Clinic, Danish Dementia Research Center, Rigshospitalet, Copenhagen, Denmark

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Koen van Laere

Koen van Laere

Department of Imaging and Pathology, Catholic University Leuven, Leuven, Belgium

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Mony J. de Leon

Mony J. de Leon

School of Medicine, Center for Brain Health, New York University, New York, NY, USA

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Wolfgang Maier

Wolfgang Maier

Department of Psychiatry and Psychotherapy, University of Bonn, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

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Jan Marcusson

Jan Marcusson

Geriatric Medicine, Department of Clinical and Experimental Medicine, University of Linköping, Linköping, Sweden

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Olga Meulenbroek

Olga Meulenbroek

Department of Geriatric Medicine, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen, the Netherlands

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Hanne M. Møllergård

Hanne M. Møllergård

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA

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John C. Morris

John C. Morris

Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

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Barbara Mroczko

Barbara Mroczko

Department of Neurodegeneration Diagnostics, Leading National Research Centre in Białystok (KNOW), Medical University of Białystok, Białystok, Poland

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Arto Nordlund

Arto Nordlund

Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden

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Sudesh Prabhakar

Sudesh Prabhakar

Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

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Oliver Peters

Oliver Peters

Department of Psychiatry and Psychotherapy, Charité Berlin, German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany

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Lorena Rami

Lorena Rami

Alzheimer's Disease and Other Cognitive Disorders Unit, IDIBAPS, Clinic University Hospital, Barcelona, Spain

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Eloy Rodríguez-Rodríguez

Eloy Rodríguez-Rodríguez

Neurology Service, Universitary Hospital Marqués de Valdecilla, CIBERNED, IDIVAL, Santander, Spain

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Catherine M. Roe

Catherine M. Roe

Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

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Eckart Rüther

Eckart Rüther

Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University, Göttingen, Germany

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Isabel Santana

Isabel Santana

Center for Neuroscience and Cell Biology, Faculty of Medicine, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal

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Johannes Schröder

Johannes Schröder

Sektion Gerontopsychiatrie, Universität Heidelberg, Heidelberg, Germany

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Sang W. Seo

Sang W. Seo

Clinical Memory Research Unit, Clinical Sciences Malmö, Lund University, Lund, Sweden

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Hilkka Soininen

Hilkka Soininen

Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

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Luiza Spiru

Luiza Spiru

Department of Geriatrics-Gerontology-Gerontopsychiatry, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

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Erik Stomrud

Erik Stomrud

Clinical Memory Research Unit, Clinical Sciences Malmö, Lund University, Lund, Sweden

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Hanne Struyfs

Hanne Struyfs

Reference Center for Biological Markers of Dementia (BIODEM), University of Antwerp, Antwerp, Belgium

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Charlotte E. Teunissen

Charlotte E. Teunissen

Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands

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Frans R.J. Verhey

Frans R.J. Verhey

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands

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Stephanie J.B. Vos

Stephanie J.B. Vos

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands

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Linda J.C. van Waalwijk van Doorn

Linda J.C. van Waalwijk van Doorn

Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen, the Netherlands

Department of Laboratory Medicine, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen, the Netherlands

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Gunhild Waldemar

Gunhild Waldemar

Danish Dementia Research Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Åsa K. Wallin

Åsa K. Wallin

Clinical Memory Research Unit, Clinical Sciences Malmö, Lund University, Lund, Sweden

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Jens Wiltfang

Jens Wiltfang

Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen- Nuremberg, Erlangen, Germany

Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University, Göttingen, Germany

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Rik Vandenberghe

Rik Vandenberghe

Laboratory for Cognitive Neurology and Alzheimer Research Centre KU Leuven, Catholic University Leuven, Leuven, Belgium

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David J. Brooks

David J. Brooks

Division of Neuroscience, Medical Research Council Clinical Sciences Centre, Imperial College London, London, UK

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Tormod Fladby

Tormod Fladby

Department of Neurology, Akershus University Hospital, Lørenskog, Norway

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Christopher C. Rowe

Christopher C. Rowe

Department of Nuclear Medicine, Technische Universitaet München, Munich, Germany

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Alexander Drzezga

Alexander Drzezga

Department of Nuclear Medicine, University of Cologne, Cologne, Germany

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Marcel M. Verbeek

Marcel M. Verbeek

Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen, the Netherlands

Department of Laboratory Medicine, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen, the Netherlands

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Marie Sarazin

Marie Sarazin

Neurologie de la Mémoire et du Langage, Centre Hospitalier Sainte-Anne, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

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David A. Wolk

David A. Wolk

Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA

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Adam S. Fleisher

Adam S. Fleisher

Department of Neurology, Akershus University Hospital, Lørenskog, Norway

Eli Lilly, Indianapolis, IN, USA

Department of Neurosciences, University of California, San Diego, CA, USA

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William E. Klunk

William E. Klunk

University of Pittsburgh School of Medicine, Department of Psychiatry, Pittsburgh, PA, USA

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Duk L. Na

Duk L. Na

Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

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Pascual Sánchez-Juan

Pascual Sánchez-Juan

Neurology Service, Universitary Hospital Marqués de Valdecilla, CIBERNED, IDIVAL, Santander, Spain

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Dong Young Lee

Dong Young Lee

Department of Neuropsychiatry, Seoul National University, College of Medicine, Seoul, South Korea

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Agneta Nordberg

Agneta Nordberg

Department NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Karolinska Institutet and Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden

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Magda Tsolaki

Magda Tsolaki

Third Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece

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Vincent Camus

Vincent Camus

CHRU de Tours, CIC INSERM 1415, INSERM U930, Université François Rabelais de Tours, Tours, France

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Juha O. Rinne

Juha O. Rinne

Turku PET Centre and Division of Clinical Neurosciences Turku, University of Turku and Turku University Hospital, Turku, Finland

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Anne M. Fagan

Anne M. Fagan

Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

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Henrik Zetterberg

Henrik Zetterberg

Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK

UK Dementia Research Institute, London, UK

Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden

Sweden and Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

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Kaj Blennow

Kaj Blennow

Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden

Sweden and Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

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Gil D. Rabinovici

Gil D. Rabinovici

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA

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Oskar Hansson

Oskar Hansson

Clinical Memory Research Unit, Clinical Sciences Malmö, Lund University, Lund, Sweden

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Bart N.M. van Berckel

Bart N.M. van Berckel

Department of Radiology and Nuclear Medicine, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands

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Wiesje M. van der Flier

Wiesje M. van der Flier

Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands

Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands

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Philip Scheltens

Philip Scheltens

Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands

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Pieter Jelle Visser

Pieter Jelle Visser

Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands

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Rik Ossenkoppele

Corresponding Author

Rik Ossenkoppele

Clinical Memory Research Unit, Clinical Sciences Malmö, Lund University, Lund, Sweden

Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands

Department of Radiology and Nuclear Medicine, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands

Corresponding author. Tel.: +46 46 171000; Fax: +46 46 222 4720.

Corresponding author. Tel.: +31 20 444 0816; Fax: +31 20 444 0816.

E-mail address: [email protected] (N.M.), [email protected] (R.O.)

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First published: 27 March 2018
Citations: 49

Abstract

Introduction

Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology.

Methods

We included 3451 Aβ+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location.

Results

The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aβ+ cognitively normal and Aβ+ mild cognitive impairment (P < .05) but not in Aβ+ AD dementia (P = .66). The prevalence was highest in Northern Europe but did not vary by sex or education.

Discussion

The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aβ pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.