2.2. Eligibility and enrollment

The Family Longevity Selection Score (FLoSS) was developed by the LLFS study to rank longevity among families based on birth-year cohort survival probabilities of the proband and siblings (Sebastiani et al., 2009). On screening, an FLoSS of 7 or more was required for a family to be eligible. If a proband's family was FLoSS-eligible, they also had to meet the following criteria: the proband N. Schupf et al./Neurobiology of Aging 34 (2013) 1287e1291 Table 2 independent effect on longevity (Deelen et al., 2011; Nebel et al., 2011; Sebastiani et al., 2012). To examine this possibility, we repeated the analysis for TOMM40 including APOE in the model as a covariate and also among those with the APOE 3/3 genotype.

Likelihood of carrying the APOE 4 allele and APOE 2 allele by relative group

Participants At risk, 4 Allele Odds ratio, Odds ratio, n (n, %) model Aa model Bb Likelihood of the APOE 4 allele Offspring generation 2307 471 (20.4) 0.75 (0.6-0.9) 0.75 (0.6-0.9) Spouse controls 764 198 (25.9) 1.0 (reference) 1.0 (reference) Participants At risk, 2 Allele Odds ratio, Odds ratio, n (n, %) model Aa model Bb Likelihood of the APOE 2 allele Offspring generation 2307 415 (18.0) 1.5 (1.1-2.0) 1.5 (1.1-1.9) Spouse controls 764 101 (13.2) 1.0 (reference) 1.0 (reference)

3. Results

LLFS offspring and their spouse controls did not differ in mean age at assessment (60.5 vs. 60.9, respectively). The average number of years of education was slightly but significantlyLower APOE 4 allele frequency was observed in a relatively young cohort of offspring of long-lived individuals before substantial mortality occurred. This suggests that the reduced frequency of the 4 allele in the oldest old might not be due to early mortality but to a heritable lower frequency of the risk allele, which reduces the risk for APOE-related disease. Previous studies have suggested that the APOE 2 allele is associated with longevity, although inconsistently (Hirose et al., 1997; Louhija et al., 1994; Schachter et al., 1994). We also observed a significantly higher frequency of the 2 allele in offspring of long-lived individuals, consistent with an association of the 2 allele and longevity in the parental generation. In some studies of older cohorts, however, including studies of Canadian, British, and Italian elders and a randomly chosen Han Chinese population, the frequency of the 2 allele was similar in the older and younger cohorts, and the frequency of the 4 allele was not consistently lower in the older cohort (Bader et al., 1998; Davignon et al.,1988; Galinsky et al.,1997; Jian-Gang et al.,1998).

In the multiethnic Washington Heights Inwood Columbia Aging Project (WHICAP) cohort, mortality risks associated with APOE genotype differed significantly by ethnic group (Lee et al., 2001). These differences underscore the importance of taking ethnicity into account when interpreting associations of genetic data with specific phenotypes and suggest that the effect of APOE risk alleles is likely to be influenced by other genetic and environmental factors. 

We also found that the frequency and likelihood of carrying a G allele in rs2075650 of TOMM40 was lower among offspring in the Long Life Family Study (LLFS), compared with married-in controls. Recent genome-wide association studies in German, Dutch, Danish, and U.S. Caucasian cohorts of long-lived individuals identified rs2075650 in TOMM40 as associated with longevity (Deelen et al., 2011; Nebel et al., 2011; Sebastiani et al., 2012), but also close to and in linkage disequilibrium with the rs429358, the APOE 4 allele. The investigators suggested that rs2075650 might not have an independent effect on longevity. Consistent with these analyses, we found that the addition of the 4 allele to our models attenuated the association between offspring and the likelihood of carrying the G allele. When the analysis was restricted to those with the APOE 3/3 genotype, the association of offspring with the likelihood of carrying the G allele was not attenuated but failed to reach statistical significance.

The limitations of this study include relatively small sample sizes and restriction of the analysis to Caucasians. It would be interesting to replicate this association in other long-lived cohorts. 

Disclosure statement: All procedures were done in accordance with the ethical standards of the Committee on Human Experimentation and were approved by the Institutional Review Boards of Columbia University Medical Center and all participating sites.

Acknowledgments: The work is supported by the National Institute on Aging (NIA cooperative agreements U01-AG023712, U01-AG23744, U01- AG023746, U01-AG023749, and U01-AG023755). The Danish 1905-cohort is funded by NIH/NIA, P01 AG08761. The Danish Aging Research Center is funded by the VELUX Foundation.

References:
Bader, G., Zuliani, G., Kostner, G.M., Fellin, R. (1998). Apolipoprotein E is not associated with longevity or disability in a sample of Italian octogenarians and nonagenarians. Gerontology, 44, 349–354.
De Benedictis, G., Tan, Q., Jeune, B., Christensen, K., Ukraintseva, S.V., Bonafe, M., Franceschi, C., Vaupel, J.W., Yashin, A.I. (2001). Recent advances in human gene-longevity association studies. Mech. Ageing Dev., 122, 909–920.
Ewbank, D.C. (2002). Mortality differences by APOE genotype estimated from demographic synthesis. Genet. Epidemiol., 22, 146–155.
Ewbank, D.C. (2003). Differences in the association between apolipoprotein E genotype and mortality across populations. J. Gerontol. A Biol. Sci. Med. Sci., 58, 741–750.
Finch, C.E., Tanzi, R.E. (1997). Genetics of aging. Science, 278, 407–411.
Galinsky, D., Tysoe, C., Brayne, C.E., Easton,gene locus in a French population. Biochem. Biophys. Res. Commun.,  e 

Kerber, R.A., O'Brien, E., Smith, K.R., Cawthon, R.M.,  Familial longevity excess in Utah genealogies. J. Gerontol. A Biol. Sci. Med. Sci.,  e