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

Hana Saddiki, Aurore Fayosse, Emmanuel Cognat, Séverine Sabia, Sebastiaan Engelborghs,
David Wallon, Panagiotis Alexopoulos, Kaj Blennow, Henrik Zetterberg, Lucilla Parnetti,
Inga Zerr, Peter Hermann, Audrey Gabelle, Julien Dumurgier



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.


Apolipoprotein E (APOE) ε4 allele is the strongest known genetic risk factor for Alzheimer disease (AD) in the general population [1]. The three most common alleles of the APOE gene are ε2, ε3, and ε4; they encode for three isoform proteins differing in two single cysteine-to-arginine amino acid substitution at positions 112 and 158 [2]. The ε3 allele is the most common allele in the population and is used as the reference to estimate risk of AD. Current evidence suggests that ε4 heterozygote carriers have an overall 3-fold increased risk of AD, whereas ε4 homozygote carriers have up to a 15-fold increased risk [3]. Conversely, the ε2 allele is associated with nearly 50% lower risk of AD [4]. The mechanisms underlying the relationship between APOE ε4 and AD are thought to be complex [5], involving β-amyloid (Aβ) peptide clearance [6] as well as a direct role on neuronal death [7,8] and on phosphorylation of tau [9].


This study is reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (S1 STROBE Checklist). The study objectives and analysis plan were developed prior to data manipulation as an MSc internship project (S1 Text). The analyses undertaken in response to reviewers’ suggestions are presented in post hoc analyses.


In this large multicentric study that included 1,600 biomarker-positive AD cases, we showed that the association between APOE ε4 and AD is modified by age. The impact of ε4 was less pronounced before the age of 60, strongest between 65 and 70 years, and then declined progressively at older ages. APOE ε4 carriers were more likely to develop AD at younger ages, with a difference of 4.9 years for ε4/ε4 and 1.4 years for one ε4 carriers when compared with median age at AD diagnosis in non-ε4 carriers (75.2 years). The PAF associated with APOE ε4 for AD was 53% overall, but it varied strongly with age, following a bell-curve relationship that ranged from less than 20% in the youngest and the oldest age groups and reaching 70% between 65 and 70 years. The protective effect of APOE ε2 allele was unaffected by age. The association between APOE genotype and AD was first reported in 1993 [28], and age is thought to play a role in this association [29,30]. Our use of a large, multicentric study of patients with AD defined by the new A/T/N criteria allows the risk of misclassification bias to be addressed, as it can be critical in such analyses. A further advantage of our study is the use of population controls from two large longitudinal cohorts in which the follow-up allowed us to remove incident cases of dementia. Because this control group without clinical dementia may be positive on AD biomarkers, we also considered a second group of controls drawn from the same memory clinics as the AD cases. This group of controls had a normal CSF AD biomarker profile, and results using these two independent sets of controls were similar, suggesting that our findings are robust.


Some of the data used in preparation of this article were obtained from the ADNI database ( As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. The Three-City Study is conducted under a partnership agreement between the Institut National de la Santé et de la Recherche Médicale (INSERM), the Victor Segalen-Bordeaux II University, and the Sanofi-Synthélabo Company.

Citation: Saddiki H, Fayosse A, Cognat E, Sabia S, Engelborghs S, Wallon D, et al. (2020) Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker–based case–control study. PLoS Med 17(8): e1003289.

Academic Editor: Raquel C. Gardner, University of California San Francisco, UNITED STATES

Received: November 15, 2019; Accepted: July 22, 2020; Published: August 20, 2020

Copyright: © 2020 Saddiki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Data coming from the European memory clinics used in this study are freely available at: The Whitehall-II Study is managed by the Department of Epidemiology and Public Health of the University College of London (UCL). The list of the principal investigators of the study can be shown here: Data coming from the Whitehall-II Study can be made freely available to interested researchers upon request: Contact information: The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a longitudinal multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimers disease. The principal investigator is Pr Michael W. Weiner, Professor of Radiology, Medicine, Psychiatry, and Neurology at the University of California San Francisco. Data coming from the ADNI study can be made freely available to interested researchers upon request: Contact information: The 3-City Study is managed by the INSERM Unit U708, Université Victor Segalen, Bordeaux, France. The principal investigators are Pr Jean-François Dartigues and Pr Christophe Tzourio. Data coming from the 3-City Study can be made freely available to interested researchers upon request: Contact information:

Funding: The authors received no specific funding for this work.

Competing interests: No conflicts of interest with regards to this paper. Outside the submitted work, TG reported having received consulting fees from Actelion, Biogen, Eli Lilly, Iqvia/ Quintiles; MSD; Novartis, Quintiles, Roche Pharma, lecture fees from Biogen, Lilly, Parexel, Roche Pharma, and grants to his institution from Actelion and PreDemTech.

Abbreviations: Aβ, β-amyloid; ABCA7, ATP-binding cassette, sub-family A, member 7; AD, Alzheimer disease; ADNI, American Alzheimer’s Disease Neuroimaging Initiative; APOE, apolipoprotein E; APP, amyloid precursor protein gene; A/T/N, β-amyloid deposition, pathologic tau, neurodegeneration; AUC, area under ROC curve; CI, confidence interval; CSF, cerebrospinal fluid; MMSE, Mini-Mental Status Examination; OR, odds ratio; PAF, population attributable fraction; PSEN1, presenilin-1 gene; PSEN2, presenilin-2 gene; p-Tau 181, tau phosphorylated at threonine 181; ROC, receiver operating characteristic; SORL1, sortilin-related receptor; STROBE, Strengthening the Reporting of Observational Studies in Epidemiology; TREM2, triggering receptor expressed on myeloid cells-2.

Latest Issue
Get instant
access to our latest e-book