Besides the rationale for postulating ApoE as a candidate to influence EL, a major strength of our study was the clear definition we used for the criterion of EL (with all cases being centenarians). A novelty with regards to previous research on EL and ApoE stems from the fact that (i) the analyses were conducted in three independent cohorts (with one of them, the Japanese cohort, including a very large sample of centenarians) and(ii) we studied both normal and super-healthy (Italian) centenarians. Nonetheless, it must be kept in mind that the cross-sectional nature of our design precludes comments on causality, and we only concentrated on EL as a categorical trait (i.e., to be centenarian or not) rather than on the continuous life-span, which runs the risk of losing some information. On the other hand, some caution is needed when attempting to extrapolate our findings to the whole Italian, Spanish or Japanese population because we used mostly convenience samples, which raises the risk of bias due to population stratification. Another limitation of our study is the relatively high rate of genotyping failure in the Spanish cohort, particularly in cases. The main reason might lie in the fact that DNA extraction from saliva in frail individuals such as centenarians might result in small amounts of DNA available for analyses (we did not collect blood samples based on ethical constraints). Thus, blood sampling is likely preferable in this population segment. Also, two different methodologies were used in the Spanish cohort, i.e., TaqMan and real-time PCR. With regard to the two aforementioned limitations, we believe the fact that genotype distributions met HWE in the two Spanish groups (cases and controls) and allele/genotype frequencies were similarI cannot see any text enclosed in ``` ```. Please provide the text to be proofread and improved.Tikkanen, M.J., Miettinen, T.A., Tilvis, R.S., Aging and genetic variation of plasma apolipoproteins. Relative loss of the apolipoprotein E phenotype in centenarians. Arteriosclerosis. Thromb. Vasc. Biol., Louhija, J., Viitanen, M., Aguero-Torres, H., Tilvis, R., Survival in Finnish centenarians in relation to apolipoprotein E polymorphism. J. Am. Geriatr. Soc., Maruszak, A., Peplonska, B., Safranow, K., Chodakowska-Zebrowska, M., Barcikowska, M., Zekanowski, C., TOMM rs polymorphism's role in late-onset Alzheimer's disease and in longevity. J. Alzheimer's Dis., Nebel, A., Kleindorp, R., Caliebe, A., Nothnagel, M., Blanche, H., Junge, O., Wittig, M., Ellinghaus, D., Flachsbart, F., Wichmann, H.E., Meitinger, T., Nikolaus, S., Franke, A. In summary, our data corroborate that ApoE genotypes are associated with exceptional longevity (EL). The 4-allele appears to decrease the likelihood of reaching EL among individuals of different ethnic/geographic backgrounds. An additional finding of our report was that the 2-allele seems to favor EL in the Italians and Japanese cohorts we studied. Moreover, the 2-allele appears to specifically favor healthy EL in the Italian cohort we assessed although this finding remains to be corroborated in other cohorts of disease-free centenarians from the same country and other parts of the world and especially in longitudinal studies.

Conflict of interest: The authors declare that they have no conflict of interest regarding this manuscript.

Acknowledgments: This study was funded by the Fondo de Investigaciones Sanitarias (FIS, ref. # PI12/00914 and FIS # PI12/00045) and Fundación Reina Sofía.

References: Asada, T., Kariya, T., Yamagata, Z., Kinoshita, T., Asaka, A., 1996. Apolipoprotein E allele in centenarians. Neurology, Beekman, M., Blanche, H., Perola, M., Hervonen, A., Bezrukov, V., Sikora, E., Flachsbart, F., Christiansen, L., De Craen, A.J., Kirkwood, T.B., Rea, I.M., Poulain, M., Robine, J.M., Valensin, S., Stazi, M.A., Passarino, G., Deiana, L., Gonos,E.S., Paternoster,L.,Sorensen,T.I.,Tan,Q.,Helmer,Q.,van den Akker,E.B., Deelen,J., Martella,F., Cordell,H.J., Ayers,K.L. Vaupel,J.W. Tornwall,O. Johnson,T.E. Schreiber,S. Lathrop,M. Skytthe,A. Westendorp,R.G. Christensen,K. Gampe,J. Nebel,A. Houwing-Duistermaat,J.J. Slagboom,P.E. Franceschi,C. consortium,G. Genome-wide linkage analysis for human longevity: genetics of healthy aging study. Aging cell,Bennet,A.M.Di Angelantonio,E.Ye,Z.Wensley,F.Dahlin,A.Ahlbom,A.Keavney,B.Collins,R.Wiman,B.de Faire,U. Danesh,J. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA, Blanche, H., Cabanne, L., Sahbatou, M., Thomas, G. A study of French centenarians: are ACE and APOE associated with longevity? C. R. Acad. Sci. III, Calero, O., Hortigela, R., Bullido, M.J., Calero, M. Apolipoprotein E genotyping method by real-time PCR, a fast and cost-effective alternative to the TaqMan and FRET assays. J. Neurosci. Methods,Capurso,C.,Solfrizzi,V.,D'Introno,A.,Colacicco,A.M.,Capurso,S.A.,Semeraro,C.,Capurso,A.,Panza,F. Interleukin-G/C promoter gene polymorphism in centenarians: no evidence of association with human longevity or interaction with apolipoprotein alleles. Exp. Gerontol., Castro, E., Ogburn, C.E., Hunt, K.E., Tilvis