eLP/Si8Sc6crs!Block 1 (0 kh}os9s/ocsi 

Table 1

Demographic characteristics

Characteristic Spouse controls Offspring generation Sample size (n) 764 2307 Age (mean om Ae1+ SD) 60.9 J+ § 8.6 60.5   8.2 Education (mean  SD)a 12.1  3.4 12.6   3.0 Sex (n, %)a Male 403 (52.7) 975 (42.3) Female 361 (47.3) 1332 (57.7) APOE Genotype (n, %)a 2/2 5 (0.7) 15 (0.7) 2/3 79 (10.3) 360 (15.6) 2/4 17 (2.2) 40 (1.7) 3/3 482 (63.1) 1461 (63.3) 3/4 163 (21.3) 407 (17.6) 4/4 18 (2.4) 24 (1.0) One or more APOE ε4 alleles (n, %)b 198 (25.9) 471 (20.4) One or more APOE ε2 alleles, (n, %)a 101 (13.2) 415 (18.0) TOMM40 Genotypes (n, %)b Sample size (n) 746 2274 GG 17 (2.3) 18 (0.8) GA 176 (23.6) 432 (19.0) AA 553 (74.1) 1824 (80.2) One or more TOMM40 G allelesb 193 (25.9) 450 (19.8) Stroke (n, %) 16 (2.1) 33 (1.4) Heart Disease (n, %) 27 (3.5) 65 (2.8) Hypertension (n, %)c 258 (33.9) 676 (29.4) Diabetes (n, %) 42 (5.5) 123 (5.4) Parkinson’s disease 2 (0.3) 6 (0.3)

Key: APOE, apolipoprotein. a p < 0.01. b p < 0.001. c p < 0.05.

Fig. 1. Linkage disequilibrium patterns for single nucleotide polymorphisms in APOE and TOMM40. Abbreviation: APOE, apolipoprotein.

to examine a wide range of populations of differing ethnicity and ancestry. Additionally, there is some selection bias among the older generation of the LLFS for cognitively intact subjects because of the inclusion criteria.

Table 3

Likelihood of carrying the rs2075650 G allele in TOMM40 by relative group and among those with the APOE ε3/ε3 genotype

Likelihood of the G allele At risk, G allele Odds ratio, Odds ratio, n (n, %) model Aa model Bb All participants Offspring generation 2274 450 (19.8) 0.7 (0.6e0.9) 0.7 (0.6e0.9) Spouse controls 746 193 (25.9) 1.0 (reference) 1.0 (reference) Participants with the APOE ε3/ε3 genotype Offspring generation 1439 86 (6.0) 0.7 (0.5e1.05) 0.7 (0.5e1.08) Spouse controls 467 39 (8.4) 1.0 (reference) 1.0 (reference)

4.1. Conclusions

Our findings support the hypothesis that reduction in the frequency of the ε4 allele, and an increase in the frequency of the ε2 allele contribute to longevity. The decreased allelic frequency of the ε4 allele, increased frequency of the ε2 allele, and decreased frequency of the rs2075650 G allele in TOMM40 in LLFS family members compared with controls, and similarities or discrepancies in these associations in other studies suggests the need for follow- up functional studies to better understand the role of these genetic factors and their interactions with other genetic and environmental factors in survival to extreme old age.

a Model A adjusted for age, sex, level of education, and family membership. b Model B adjusted for age, sex, level of education, family membership, history of myocardial infarction, hypertension, stroke, diabetes, and Parkinson’s disease.

age-related, potentially confounding conditions, including stroke, heart disease, hypertension, diabetes, and Parkinson’s disease did not change the pattern of results.

Previous studies have reported lower APOE ε4 allele frequencies in older compared with younger cohorts (Davignon et al., 1988; Kervinen et al.,1994; Rebeck et al.,1994; Schachter et al., 1994; van Bockxmeer, 1994), suggesting that the ε4 allele increases risk for mortality. In this study, we found a lower APOE ε4 allele frequency in a relatively young cohort of offspring of long-lived individuals, before substantial mortality has occurred: thus the reduced frequency of the ε4 allele in the oldest old might not be due to early mortality but to a heritable lower frequency of the risk allele, reducing risk for APOE-related disease. Previous studies have sug- gested that the APOE ε2 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 ε2 allele in offspring of long-lived individuals, consistent with an association of the ε2 allele and longevity in the parent genera- tion. 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 ε2 allele was similar in the older and younger cohorts, and the frequency of the ε4 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

Disclosure statement

All procedures were done in accord with the ethical standards of the Committee on Human Experimentation and have been approved by the Institutional Review Boards of Columbia University Medical Center and the Institutional Review Board of all partici- pating sites.

Acknowledgements

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.

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