Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker–based case–control study

Autoři: Hana Saddiki aff001;  Aurore Fayosse aff001;  Emmanuel Cognat aff002;  Séverine Sabia aff001;  Sebastiaan Engelborghs aff003;  David Wallon aff005;  Panagiotis Alexopoulos aff006;  Kaj Blennow aff007;  Henrik Zetterberg aff007;  Lucilla Parnetti aff010;  Inga Zerr aff011;  Peter Hermann aff011;  Audrey Gabelle aff012;  Mercè Boada aff013;  Adelina Orellana aff013;  Itziar de Rojas aff013;  Matthieu Lilamand aff002;  Maria Bjerke aff014;  Christine Van Broeckhoven aff014;  Lucia Farotti aff010;  Nicola Salvadori aff010;  Janine Diehl-Schmid aff006;  Timo Grimmer aff006;  Claire Hourregue aff002;  Aline Dugravot aff001;  Gaël Nicolas aff005;  Jean-Louis Laplanche aff015;  Sylvain Lehmann aff016;  Elodie Bouaziz-Amar aff015aff001;  Jacques Hugon aff002;  Christophe Tzourio aff017;  Archana Singh-Manoux aff001;  Claire Paquet aff002;  Julien Dumurgier aff001
Působiště autorů: Université de Paris, Inserm U1153, Epidemiology of Ageing and Neurodegenerative diseases, Paris, France aff001;  Cognitive Neurology Center, Lariboisiere—Fernand Widal Hospital, AP-HP, Université de Paris, Paris, France aff002;  Department of Neurology, Universitair Ziekenhuis Brussel, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium aff003;  Department of Biomedical Sciences, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium aff004;  Inserm U1245, Rouen University Hospital, Department of Neurology and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France aff005;  Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Faculty of Medicine, Technical University of Munich, Munich, Germany aff006;  Department of Psychiatry and Neurochemistry, University of Gothenburg, Mölndal, Sweden aff007;  Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden aff008;  Department of Neurodegenerative Disease, Institute of Neurology, University College London, UK Dementia Research Institute, London, United Kingdom aff009;  Center for Memory Disturbances-Lab of Clinical Neurochemistry, Section of Neurology, University of Perugia, Italy aff010;  Department of Neurology, Clinical Dementia Center, University Medical Center Göttingen and German Center for Neurodegenerative Diseases, Göttingen, Germany aff011;  Department of Neurology, Memory Research and Resources Centre, University of Montpellier, Montpellier, France aff012;  Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurciències Aplicades, Universitat International de Catalunya, Barcelona, Spain aff013;  VIB Center for Molecular Neurology, Institute Born-Bunge and Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium aff014;  Department of Biochemistry and Molecular Biology, Lariboisière Hospital, APHP, Paris, France aff015;  Department of Biochemistry, University of Montpellier, Montpellier, France aff016;  Bordeaux Population Health Research Center, Team HEALTHY, UMR1219, University of Bordeaux, Inserm, Bordeaux, France aff017;  Department of Epidemiology and Public Health, University College London, London, United Kingdom aff018
Vyšlo v časopise: Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker–based case–control study. PLoS Med 17(8): e1003289. doi:10.1371/journal.pmed.1003289
Kategorie: Research Article



The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD.

Methods and findings

This case–control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44–96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44–94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1–5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4–31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was 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%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD.


In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. 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.

Klíčová slova:

Alzheimer's disease – Apolipoproteins – Biomarkers – Cardiovascular disease risk – Cerebrospinal fluid – Diagnostic medicine – Medical risk factors – Memory


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