, Volume 17, Issue 5–6, pp 893–905 | Cite as

Protective role of the apolipoprotein E2 allele in age-related disease traits and survival: evidence from the Long Life Family Study

  • Alexander M. KulminskiEmail author
  • Nalini Raghavachari
  • Konstantin G. Arbeev
  • Irina Culminskaya
  • Liubov Arbeeva
  • Deqing Wu
  • Svetlana V. Ukraintseva
  • Kaare Christensen
  • Anatoliy I. Yashin
Research Article


The apolipoprotein E (apoE) is a classic example of a gene exhibiting pleiotropism. We examine potential pleiotropic associations of the apoE2 allele in three biodemographic cohorts of long-living individuals, offspring, and spouses from the Long Life Family Study, and intermediate mechanisms, which can link this allele with age-related phenotypes. We focused on age-related macular degeneration, bronchitis, asthma, pneumonia, stroke, creatinine, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, diseases of heart (HD), cancer, and survival. Our analysis detected favorable associations of the ε2 allele with lower LDL-C levels, lower risks of HD, and better survival. The ε2 allele was associated with LDL-C in each gender and biodemographic cohort, including long-living individuals, offspring, and spouses, resulting in highly significant association in the entire sample (β = −7.1, p = 6.6 × 10−44). This allele was significantly associated with HD in long-living individuals and offspring (relative risk [RR] = 0.60, p = 3.1 × 10−6) but this association was not mediated by LDL-C. The protective effect on survival was specific for long-living women but it was not explained by LDL-C and HD in the adjusted model (RR = 0.70, p = 2.1 × 10−2). These results show that ε2 allele may favorably influence LDL-C, HD, and survival through three mechanisms. Two of them (HD- and survival-related) are pronounced in the long-living parents and their offspring; the survival-related mechanism is also sensitive to gender. The LDL-C-related mechanism appears to be independent of these factors. Insights into mechanisms linking ε2 allele with age-related phenotypes given biodemographic structure of the population studied may benefit translation of genetic discoveries to health care and personalized medicine.


ApoE Health span Life span 



The Long Life Family Study is funded by U01AG023749, U01AG023744 and U01AG023712 from the National Institute on Aging. This work was supported by the National Institute on Aging (Grant Numbers U01 AG023712, P01 AG043352, R01 AG047310).

Compliance with ethical standards

Conflict of interests

No conflict of interests exist.

Supplementary material

10522_2016_9659_MOESM1_ESM.doc (184 kb)
Supplementary material 1 (DOC 184 kb)


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Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Alexander M. Kulminski
    • 1
    Email author
  • Nalini Raghavachari
    • 2
  • Konstantin G. Arbeev
    • 1
  • Irina Culminskaya
    • 1
  • Liubov Arbeeva
    • 1
  • Deqing Wu
    • 1
  • Svetlana V. Ukraintseva
    • 1
  • Kaare Christensen
    • 3
    • 4
  • Anatoliy I. Yashin
    • 1
  1. 1.Biodemography of Aging Research Unit, Social Science Research InstituteDuke UniversityDurhamUSA
  2. 2.National Institute on AgingBethesdaUSA
  3. 3.The Danish Aging Research CenterUniversity of Southern DenmarkOdense CDenmark
  4. 4.Department of Clinical Genetics and Department of Clinical Biochemistry and PharmacologyOdense University HospitalOdense CDenmark

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