Contents lists available at ScienceDirect Mechanisms of Ageing and Development journal homepage: www.elsevier.com/locate/mechagedev Apolipoprotein E gene in physiological and pathological aging E. Ferri a, ⁎ , C. Gussago b , M. Casati a , D. Mari a,b , P.D. Rossi a , S. Ciccone a , M. Cesari a,b , B. Arosio a,b a Geriatric Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Pace 9, 20122 Milan, Italy b Department of Clinical Sciences and Community Health, University of Milan, Via Pace 9, 20122 Milan, Italy ARTICLE INFO Keywords: Centenarians Alzheimer’s disease Apolipoprotein E Longevity ABSTRACT Introduction: The genetic background plays a role on longevity. The distribution of the apolipoprotein E gene (APOE) variants (ε2, ε3, ε4) may differ across age groups, especially in the oldest old and despite geographical and ethnic specificities. Since the ε4 variant is associated with Alzheimer’s disease (AD), it might represent an opportunity for exploring the relationship of APOE with physiological and pathological aging. Aim: To explore the role played by APOE genotype/alleles on physiological and pathological brain aging. Materials and Methods: The study was conducted in a cohort of centenarians (n = 106), and two cohorts of octogenarians (without cognitive decline, n = 351 controls; and with AD, n = 294). Results: No significant differences in genotype/allele distributions were observed comparing controls to cen- tenarians. The prevalence of ε2/ε3, ε3/ε3, ε3/ε4 and ε4/ε4 genotypes were significantly different in centenarians compared to AD. The prevalence of ε2 and ε3 alleles were significantly higher in centenarians, whereas the ε4 was less frequent. The ε4 allele was positively associated with AD, whereas a negative association was found for ε2 and ε3 alleles. Conclusions: Our study indicates that ε4 allele is strongly associated with AD. APOE significantly affects AD risk, but apparently not longevity. 1. Introduction The global increase of life expectancy and the rapid aging of the population represent major epidemiological phenomena characterizing the past two centuries. They have major economic implications for public health policies due to the higher complexity of persons referred to clinical services (often affected by multiple age-related diseases, chronic conditions, and disabilities). This has led many researchers at focusing on the biology of aging for better understanding its underlying mechanisms with the final aims of preventing the onset of age-related conditions. Centenarians represent an extraordinary model for studying suc- cessful aging and identifying its biological determinants (Franceschi et al., 2017). The prevention or delayed onset of age-related conditions is the most reasonable way for reaching the considerable age of 100 years of life. Survival analyses of centenarians and their families as well as re- search on monozygotic and dizygotic twins have suggested that the longevity phenotype presents a genetic component, accounting for about 25% of the intra-population phenotypic variance (De Benedictis and Franceschi, 2006; Franceschi et al., 2007). Specific genetic patterns have also been associated to successful aging (De Benedictis and Franceschi, 2006; Kulminski et al., 2015; Franceschi and Garagnani, 2016). In this context, the apolipoprotein E gene (APOE) is probably the most thoroughly investigated. APOE is a protein involved in the lipid metabolism and the transport of cholesterol to neurons (Riedel et al., 2016; Rosenberg et al., 2016). There are three common alleles of the APOE gene (i.e., ε2, ε3, and ε4), which encode three isoforms of the protein (i.e., E2, E3, and E4) (Verghese et al., 2011). APOE is recognized as the most important gene associated with longevity in many studies across Europe and in a number of meta-analyses (Deelen et al., 2011; Fortney et al., 2015). Interestingly, the APOE gene variant ε4 is also associated with early and late onset Alzheimer’s disease (AD) (Genin et al., 2011; Lescai et al., 2011; Skillback et al., 2018). A long-lasting controversy in the literature is open about the possible antagonistic pleiotropic effects of the ε4 al- lele of the APOE gene, thus conferring to the individual advantages on cognitive tasks early in life, but cognitive and neural disadvantages at more advanced age (Albin, 1993; Han and Bondi, 2008). https://doi.org/10.1016/j.mad.2019.01.005 Received 30 October 2018; Received in revised form 2 January 2019; Accepted 15 January 2019 ⁎ Corresponding author at: Geriatric Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Via Pace 9, 20122 Milan, Italy. E-mail addresses: evelyn.ferri@guest.unimi.it (E. Ferri), cristina.gussago@unimi.it (C. Gussago), martina.casati@unimi.it (M. Casati), daniela.mari@unimi.it (D. Mari), paolo.rossi@policlinico.mi.it (P.D. Rossi), simona.ciccone@policlinico.mi.it (S. Ciccone), matteo.cesari@unimi.it (M. Cesari), beatrice.arosio@unimi.it (B. Arosio). Mechanisms of Ageing and Development 178 (2019) 41–45 Available online 15 January 2019 0047-6374/ © 2019 Elsevier B.V. All rights reserved. T