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Age Modifies the Association Between Apolipoprotein E Genotype and Alzheimer's Disease: A CSF Biomarker-Based Multicentric Case-Control Study

32 Pages Posted: 14 Jul 2019

See all articles by Hana Sadikki

Hana Sadikki

Université Paris I Panthéon-Sorbonne - Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases

Aurore Fayosse

Université Paris I Panthéon-Sorbonne - Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases

Emmanuel Cognat

Hôpital Lariboisiere, AP-HP

Séverine Sabia

Université Paris I Panthéon-Sorbonne - Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases

Sebastiaan Engelborghs

Vrije Universiteit Brussel (VUB)

David Wallon

University of Rouen - Rouen University Hospital

Panagiotis Alexopoulos

Technische Universität München (TUM) - Klinikum Rechts der Isar

Kaj Blennow

University of Gothenburg - Institute of Neuroscience and Physiology; University of Gothenburg - Sahlgrenska University Hospital

Henrik Zetterberg

University of Gothenburg - Institute of Neuroscience and Physiology

Lucilla Parnetti

University of Perugia - Department of Medicine

Inga Zerr

University of Goettingen (Gottingen) - Department of Neurology

Peter Hermann

University of Goettingen (Gottingen) - Department of Neurology

Audrey Gabelle

University of Montpellier

Merce Boada

Carlos III Institute of Health

Adelina Orellana

Carlos III Institute of Health

Itziar de Rojas

Carlos III Institute of Health

Matthieu Lilamand

Hôpital Lariboisiere, AP-HP

Maria Bjerke

University of Antwerp - Department of Biomedical Sciences

Christine Van Broeckhoven

University of Antwerp - Department of Biomedical Sciences

Lucia Farotti

University of Perugia - Department of Medicine

Nicola Salvadori

University of Perugia - Department of Medicine

Janine Diehl-Schmid

Technische Universität München (TUM)

Timo Grimmer

Technische Universität München (TUM)

Claire Hourregue

Hôpital Lariboisiere, AP-HP

Aline Dugravot

Université Paris I Panthéon-Sorbonne - Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases

Gaël Nicolas

University of Rouen - Rouen University Hospital

Jean-Louis Laplanche

Hôpital Lariboisière

Sylvain Lehmann

University of Montpellier

Elodie Bouaziz-Amar

Hôpital Lariboisière

Jacques Hugon

Lariboisiere Hospital, AP-HP

Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Christopher Tzourio

University of Bordeaux - Bordeaux Population Health Research Center

Archana Singh-Manoux

Université Paris I Panthéon-Sorbonne - Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases

Claire Paquet

Hôpital Lariboisiere, AP-HP

Julien Dumurgier

Université Paris I Panthéon-Sorbonne - Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases

More...

Abstract

Background: We investigated the global and age-specific association between Apolipoprotein E (APOE) genotype and Alzheimer's disease (AD) in a large multicentric case-control study, using cerebrospinal fluid (CSF) biomarkers-based diagnostic criteria for AD.

Methods: In this case-control design, data on 1,599 Caucasian AD cases with abnormal values of CSF biomarkers came from 9 European memory clinics and the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. AD cases were compared to 11,724 dementia-free controls, drawn from two longitudinal cohort studies (Whitehall II and 3-City). Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were reported, overall and by 5-year age categories. Findings. 63*4% of CSF biomarker-defined AD patients and 22*6% of population controls carried at least one APOE ε4 allele; respective percentages for APOE ε4 homozygotes were 16*7% and 1*4%. Compared to nonε4 carriers, heterozygous ε4 carriers had a 4*6 (95% confidence interval: 4*1 - 5*2) and ε4/ε4 homozygotes a 25*4 (20*5 - 31*3) higher OR of AD. This association was strongly modified by age (p for interaction < 0*001). The PAF associated with carrying at least one ε4 allele was greatest in the 65-70 age group (69*7%), and weaker before 55 years (14*2%) and after 85 years (22*6%). There was some evidence of a stronger effect of APOE on AD risk in women.

Interpretation: Incorporating biomarkers for diagnosis of AD led to a stronger association with APOE ε4 than previously reported, perhaps due to better diagnostic accuracy. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level.

Funding Statement: US National Institutes of Health, Fondation Plan Alzheimer.

Declaration of Interests: ASM is supported by NIH/NIA R01AG056477. IZ is supported by the Robert-Koch-Institute through funds of Federal Ministry of Health (grant no. 1369-341) and DZNE (German Center for Neurodegenerative Diseases). KB reports consulting fees from Fujirebio Europe, IBL International, Roche Diagnostics. HZ is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. MB has been a consultant for Araclon, Avid, Bayer, Elan, Grifols, Janssen/Pfizer, Lilly, Neuroptix, Nutricia, Roche, Sanofi, and Servier. All other authors declare no competing interests.

Ethics Approval Statement: Ethical clearance was obtained by the institutional review boards of all participating sites (European memory centers and ADNI Study sites) and all participants provided written, informed consent.

Suggested Citation

Sadikki, Hana and Fayosse, Aurore and Cognat, Emmanuel and Sabia, Séverine and Engelborghs, Sebastiaan and Wallon, David and Alexopoulos, Panagiotis and Blennow, Kaj and Zetterberg, Henrik and Parnetti, Lucilla and Zerr, Inga and Hermann, Peter and Gabelle, Audrey and Boada, Merce and Orellana, Adelina and de Rojas, Itziar and Lilamand, Matthieu and Bjerke, Maria and Van Broeckhoven, Christine and Farotti, Lucia and Salvadori, Nicola and Diehl-Schmid, Janine and Grimmer, Timo and Hourregue, Claire and Dugravot, Aline and Nicolas, Gaël and Laplanche, Jean-Louis and Lehmann, Sylvain and Bouaziz-Amar, Elodie and Hugon, Jacques and (ADNI), Alzheimer’s Disease Neuroimaging Initiative and Tzourio, Christopher and Singh-Manoux, Archana and Paquet, Claire and Dumurgier, Julien, Age Modifies the Association Between Apolipoprotein E Genotype and Alzheimer's Disease: A CSF Biomarker-Based Multicentric Case-Control Study (July 10, 2019). Available at SSRN: https://ssrn.com/abstract=3417885 or http://dx.doi.org/10.2139/ssrn.3417885

Hana Sadikki

Université Paris I Panthéon-Sorbonne - Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases

Paris
France

Aurore Fayosse

Université Paris I Panthéon-Sorbonne - Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases

Paris
France

Emmanuel Cognat

Hôpital Lariboisiere, AP-HP

2 Rue Ambroise Paré
Paris, 75010
France

Séverine Sabia

Université Paris I Panthéon-Sorbonne - Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases

Paris
France

Sebastiaan Engelborghs

Vrije Universiteit Brussel (VUB)

Pleinlaan 2
http://www.vub.ac.be/
Brussels, 1050
Belgium

David Wallon

University of Rouen - Rouen University Hospital

37 Boulevard Gambetta
Rouen, 76000
France

Panagiotis Alexopoulos

Technische Universität München (TUM) - Klinikum Rechts der Isar

Ismaninger Straße 22
München, 81675
Germany

Kaj Blennow

University of Gothenburg - Institute of Neuroscience and Physiology

PO Box 430
Göteborg, SE405 30
Sweden

University of Gothenburg - Sahlgrenska University Hospital

PO Box 400
Göteborg, SE405 30
Sweden

Henrik Zetterberg

University of Gothenburg - Institute of Neuroscience and Physiology

PO Box 430
Göteborg, SE405 30
Sweden

Lucilla Parnetti

University of Perugia - Department of Medicine

Severi Square, 1
University of Perugia
Perugia, I-06129
Italy

Inga Zerr

University of Goettingen (Gottingen) - Department of Neurology

Goettingen
Germany

Peter Hermann

University of Goettingen (Gottingen) - Department of Neurology

Goettingen
Germany

Audrey Gabelle

University of Montpellier

163 rue Auguste Broussonnet
France

Merce Boada

Carlos III Institute of Health

Spain

Adelina Orellana

Carlos III Institute of Health

c/ Monforte de Lemos 5
Madrid, Madrid 28029
Spain

Itziar De Rojas

Carlos III Institute of Health

c/ Monforte de Lemos 5
Madrid, Madrid 28029
Spain

Matthieu Lilamand

Hôpital Lariboisiere, AP-HP

2 Rue Ambroise Paré
Paris, 75010
France

Maria Bjerke

University of Antwerp - Department of Biomedical Sciences

Prinsstraat 13
Antwerp, Antwerp 2000
Belgium

Christine Van Broeckhoven

University of Antwerp - Department of Biomedical Sciences

Prinsstraat 13
Antwerp, Antwerp 2000
Belgium

Lucia Farotti

University of Perugia - Department of Medicine

Severi Square, 1
University of Perugia
Perugia, I-06129
Italy

Nicola Salvadori

University of Perugia - Department of Medicine

Severi Square, 1
University of Perugia
Perugia, I-06129
Italy

Janine Diehl-Schmid

Technische Universität München (TUM)

Arcisstrasse 21
Munich, DE 80333
Germany

Timo Grimmer

Technische Universität München (TUM)

Arcisstrasse 21
Munich, DE 80333
Germany

Claire Hourregue

Hôpital Lariboisiere, AP-HP

2 Rue Ambroise Paré
Paris, 75010
France

Aline Dugravot

Université Paris I Panthéon-Sorbonne - Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases

Paris
France

Gaël Nicolas

University of Rouen - Rouen University Hospital

37 Boulevard Gambetta
Rouen, 76000
France

Jean-Louis Laplanche

Hôpital Lariboisière

Paris
France

Sylvain Lehmann

University of Montpellier

163 rue Auguste Broussonnet
France

Elodie Bouaziz-Amar

Hôpital Lariboisière

Paris
France

Jacques Hugon

Lariboisiere Hospital, AP-HP

2 Rue Ambroise Paré
Paris, 75010
France

Christopher Tzourio

University of Bordeaux - Bordeaux Population Health Research Center

France

Archana Singh-Manoux

Université Paris I Panthéon-Sorbonne - Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases

Paris
France

Claire Paquet

Hôpital Lariboisiere, AP-HP

2 Rue Ambroise Paré
Paris, 75010
France

Julien Dumurgier (Contact Author)

Université Paris I Panthéon-Sorbonne - Inserm U1153, Epidemiology of Ageing and Neurodegenerative Diseases ( email )

Paris
France

No contact information is available for Alzheimer’s Disease Neuroimaging Initiative (ADNI)

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