,

–

Jacobsen,R.,Martinussen,T.,Christiansen,L.,Jeune,B.,Andersen-Ranberg,K.,Vaupel,J.W., Christensen, K.,

Increased effect of the Ap

gene on survival at advanced age in healthy and long-lived Danes: two nationwide cohort studies. Aging Cell

,

–

Kolovou, G., Yiannakouris, N., Hatzivassiliou, M., Malakos, J., Daskalova, D., Hatzigeorgiou, G., Cariolou, M.A., Cokkinos, D.V.,

Association of apolipoprotein E polymor- phism with myocardial infarction in Greek patients with coronary artery disease. Curr. Med. Res. Opin.

,

–

Kumar,N.T.,Liestol,K.,Loberg,E.M.,Reims,H.M.,Brorson,S.H.,Maehlen,J.,

Theapo- lipoprotein E polymorphism and cardiovascular diseases—an autopsy study. Cardiovasc. Pathol.

,

–

Lewis, S.J., Brunner, E.J.,

Methodological problems in genetic association studies of longevity—the apolipoprotein E gene as an example. Int. J. Epidemiol.

,

–

Lindahl-Jacobsen, R., Tan, Q., Mengel-From, J., Christensen, K., Nebel, A., Christiansen, L.,

Effects of the APOE ε

allele on mortality and cognitive function in the oldest. J. Gerontol. A Biol. Sci. Med. Sci.

,

–

Liu, C.C., Kanekiyo, T., Xu, H., Bu, G.,

Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol.

,

–

Louhija, J., Miettinen, H.E., Kontula, K., Tikkanen, M.J., Miettinen, T.A., Tilvis, R.S.,

Aging and genetic variation of plasma apolipoproteins. Relative loss of the apolipo- protein E

phenotype in centenarians. Arterioscler. Thromb.

,

–

Louhija, J., Viitanen, M., Aguero-Torres, H., Tilvis, R.,

Survival in Finnish cente- narians 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. Alzheimers 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 EL. The ε4-allele appears to decrease the likelihood of reaching EL among individuals of different ethnic/geographic backgrounds. An addi- tional finding of our report was that the ε2-allele seems to favor EL in the Italians and Japanese cohorts we studied. Moreover, the ε2-allele seems 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 from other parts of the world, and especially in longitudinal studies.

Conflict of interests

The authorsdeclare that noneof them has any conflict of interest re- to 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 46, 1484.

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., Hortigüela, R., Bullido, M.J., Calero, M.,

Apolipoprotein E genotyping method by real time PCR, a fast and cost-effective alternative to the Ta

an 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/Cpromotergenepolymorphismincentenarians: no evidence of association with human longevity or interaction with apolipoprotei

alleles. Exp. Gerontol.

,

–

Castro, E., Ogburn, C.E., Hunt, K.E., Tilvis, R., Louhija, J., Penttinen, R., Erkkola, R., Panduro, A., Riestra, R., Piussan, C., Deeb, S.S., Wang, L., Edland, S.D., Martin, G.M., Oshima, J.,

Polymorphismsatth

ernerlocus:I.Newlyidentifiedpolymorphisms,ethnic variability of

Cys/Arg, and its stability in a population of Finnish centenarians. Am. J. Med. Genet.

,

–

Christensen, K., Johnson, T.E., Vaupel, J.W.,

The quest for genetic determinants of human longevity: challenges and insights. Nat. Rev. Genet.

,

–

Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W., Roses, A.D., Haines, J.L., Pericak-Vance, M.A.,

Gene dose of apolipoprotein E type

allele and the risk of Alzheimer's disease in late onset families. Science

,

–

Dallongeville, J., Lussier-Cacan, S., Davignon, J.,

Modulation of plasma triglyceride levels by ap

phenotype: a meta-analysis. J. Lipid Res.

,

–

Drenos, F., Kirkwood, T.B.,

Selection on alleles affecting human longevity and late-life disease: the example of apolipoprotein E. PL

One

, e

Emanuele, E., Fontana, J.M., Minoretti, P., Geroldi, D.,

Preliminary evidence of a ge- netic association between chromosome

p

and human longevity. Rejuvenation Res.

,

–

Feng,J.,Xiang,L.,Wan,G.,Qi,K.,Sun,L.,Huang,Z.,Zheng,C.,Lv,Z.,Hu,C.,Yang,Z.,