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ApoE gene and exceptional longevity: Insights from three independent cohorts

Garatachea a,j, , Enzo Emanuele b, Miguel Calero c,k, Noriyuki Fuku d, Yasumichi Arai e, Yukiko Abe Murakami f, Motohiko Miyachi f, Thomas Yvert g, Zoraida Verde g, Ma Ascensión Zea c, Venturini b, Catalina Santiago g, Alejandro Santos-Lozano h,j, Gabriel Rodríguez-Romo i, Ricevuti b, Nobuyoshi Hirose e, Alberto Rábano c,1, Alejandro Lucia g,j,1

Faculty of Health and Sport Science, University of Zaragoza, Ronda Misericordia 5, 22001 Huesca, Spain b Department of Health Sciences, University of Pavia, Via Bassi, 21, I-27100 Pavia, Italy c Fundación CIEN, Fundación Reina Sofía, Instituto de Salud Carlos III, Calle Valderrebollo 5, 28031 Madrid, Spain d Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, e Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan f Department of Health Promotion and Exercise, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjuku-ku, 162-8636 Tokyo, Japan g European University of Madrid, Villaviciosa de Odón, 28670 Madrid, Spain h Department of Biomedical Sciences, University of León, Campus de Vegazana s/n, 24071 León, Spain i INEF, Universidad Politécnica, c/ Martín Fierro s/n, 28040 Madrid, Spain

Hospital Universitario 12 de Octubre, Research Institute (i+12), Avda. de Córdoba s/n, 28041 Madrid, Spain UFIEC, Fundación CIEN-Fundación Reina Sofía, and CIBERNED - Instituto de Salud Carlos III, Madrid, Spain



The ApoE gene is associated with the risk of Alzheimer or cardiovascular disease but its influence on exceptional longevity (EL) is uncertain. Our primary purpose was to determine, using a case–control design, if the ApoE gene is associated with EL. We compared ApoE allele/genotype frequencies among the following cohorts: cases (centenarians, most with 1+ major disease condition; n = 163, 100–111 years) and healthy controls (n = 1039,20–85 years) fromSpain;disease-freecases(centenarians; n= 79,100–104 years)and healthy controls (n = 597, age 27–81 years) from Italy; and cases (centenarians and semi-supercentenarians, most with 1+ major disease condition; n = 729, 100–116 years) and healthy controls (n = 498, 23–59 years) from Japan.Ourmainfindingsweretwofold.First,theε4-allelewasnegativelyassociatedwithELinthethreecohorts, with the following odds ratio (OR) values (adjusted by sex) having been found: 0.55 (95% confidence interval (CI): 0.33, 0.94), P = 0.030 (Spain); 0.41 (95%CI: 0.18, 0.99), P = 0.05 (Italy); and 0.35 (95%CI: 0.26, 0.57), P b 0.001 (Japan). Second, although no association was found in the Spanish cohort (OR = 1.42 (95%CI: 0.89, 2.26), P = 0.145), the ε2-allele was positively associated with EL in the Italian (OR = 2.14 (95%CI: 1.18, 3.45), P = 0.01) and Japanese subjects (OR = 1.81 (95%CI: 1.25, 2.63), P = 0.002). Notwithstanding the limitations ofcase–controldesigns,ourdatasuggestthattheApoEmightbeacandidatetoinfluenceEL.Theε4-alleleappears todecreasethelikelihood ofreachingELamongindividualsofdifferentethnic/geographic origins.Anadditional, novel finding of our study was that the ε2-allele might favor EL, at least in the Italian and Japanese cohorts.

finding of our study was that the ε2-allele might favor EL, at least in the Italian and Japanese cohorts. © 2014 Elsevier Inc. All rights reserved.

genotypes (ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4 and ε4/ε4). The ApoE is associated with the risk of having several age-related conditions, such ascardiovasculardisease(CVD,includingcoronaryheartdiseaseandce- rebrovascular disease) (Kumar et al., 2012) and Alzheimer's disease (AD) (Liu et al., 2013) including also late-onset AD (Sadigh-Eteghad et al., 2012), with the ε4-allele being the unfavorable allele. Thus, the latter variant increases mortality risk (Christensen et al., 2006). Recent data also support an association of ApoE and mortality in long-lived indi- viduals. A genome-wide linkage analysis with nonagenarians identified ApoE as a longevity gene (Beekman et al., 2013), which is in agreement with the results of a recent case–control genome-wide association study comparing long-lived individuals (mean age: 99.7 years) and

1. Introduction

Apolipoprotein E (ApoE) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. The ApoE gene is polymor- phic, and the vast majority of population studies have focused on the three most common alleles (ε2, ε3 and ε4) that result in six possible

⁎ Corresponding author at: Faculty of Health and Sport Science, Department of Physiotherapy and Nursing, University of Zaragoza, Ronda Misericordia 5, 22001- Huesca, Spain.Tel.: +34 976761000; fax: +34 976761720.

younger controls from Germany (Nebel et al., 2011). However, whether ApoE influences exceptional longevity (EL), i.e., reaching 100+ years of age, is more controversial.