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journal homepage: www.elsevier.com/locate/neuaging

Apolipoprotein E and familial longevity

Schupf a,*, Sandra Barral a , Thomas Perls b , Anne Newman c , Kaare Christensen g h i a Thyagarajan , Michael Province , Winifred K. Rossi , Richard Mayeux

aTaub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA bGeriatrics Section, Boston University Medical Center, Boston, MA, USA cDepartment of Epidemiology, Graduate School of Public Health, Pittsburgh, PA, USA dThe Danish Aging Research Center, University of Southern Denmark, Odense, Denmark eDepartment of Clinical Genetics, Odense University Hospital, Odense, Denmark fDepartment of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark gDepartment of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA hDivision of Statistical Genomics, Data Management Coordinating Center, Washington University School of Medicine, St. Louis, MO, USA iNational Institute on Aging, Bethesda, MD, USA



Exceptional longevity is associated with substantial heritability. The ε4 allele in apolipoprotein E and the linked G allele in rs2075650 of TOMM40 have been associated with increased mortality and the ε2 allele with decreased mortality, although inconsistently. Offspring from long-lived families and spouse controls were recruited at 3 sites in the United States and Denmark. We used generalized estimating equations to compare the likelihood of carrying risk alleles in offspring (n ¼ 2307) and spouse controls (n ¼ 764), adjusting for age, sex, level of education, and family membership. The likelihood of carrying an APOE ε4 allele or a G allele in rs2075650 was lower (odds ratio [OR], 0.75; p ¼ 0.005 and OR, 0.70; p ¼ 0.002) and the likelihood of carrying an APOE ε2 allele was higher (OR,1.5; p ¼ 0.007) among family members in the offspring generation than among their spouse controls. Our findings support the hypothesis that both reduction in the frequency of the ε4 allele and increase in the frequency of the ε2 allele contribute to longevity.

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consistently emerged as a determinant of longevity (Deelen et al., 2011; Nebel et al., 2011, Sebastiani, et al., 2012). APOE has 3 common alleles, ε2, ε3, and ε4. The ε4 allele of APOE has been associated with early mortality and a decreased frequency of the allele in the oldest old (McKay et al., 2011; Schachter et al., 1994; Soerensen et al., 2012; Tan et al., 2004). However, the association of the ε4 allele with mortality risk is inconsistent and varies by pop- ulation (Bader et al., 1998; Galinsky et al., 1997; Lee et al., 2001). Some studies (Ewbank, 2002, 2007) reported that the effect of the ε4 allele on mortality risk diminishes with increasing age, but a recent study in the Danish 1905 cohort showed an increased effect of carrying the ε4 alleles with increasing age (Jacobsen et al., 2010). Recent studies have also identified a variant inTOMM40, marked by the single nucleotide polymorphism (SNP) rs2075650, which is associated with longevity, but is close to and in linkage disequi- librium with rs429358, the marker for the APOE ε4 allele (Deelen et al., 2011; Nebel et al., 2011; Sebastiani et al., 2012).

1. Introduction

Human exceptional longevity is the outcome of a complex interplay between genetic and environmental influences (Finch and Tanzi, 1997; McGue et al., 1993). Exceptional longevity has been noted to cluster in families and is associated with moderate heri- tability (De Benedictis et al., 2001; Herskind et al., 1996; Mitchell et al., 2001). In a study of centenarians and their siblings, male and female siblings of centenarians were 17 and 8 times more likely, respectively, to survive to 100 years compared with males and females in their birth cohort (Perls et al., 2002). First degree rela- tives of individuals who lived beyond 95 years were twice as likely to survive to the same age as were relatives of married-in controls (Gudmundsson et al., 2000; Kerber et al., 2001).

Several candidate genes have been investigated to determine their effects on life span and apolipoprotein E (APOE) has

* Corresponding author at: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, P&S Box Unit 16, 630 West 168th Street, New York, NY 10032, USA. Tel.: þ1 212 305 2381; fax: þ1 212 305 2426. E-mail address: ns24@columbia.edu (N. Schupf).

Because longevity is heritable, a family-based study design might serve well to address the question of the relation of APOE to longevity. Mortality associated with the presence of a risk allele

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might lead to reduced frequencies of risk alleles in the parental generation. Thus, it might be more informative to examine if there is a reduced frequency of risk alleles in offspring of people achieving exceptional longevity, where mortality is unlikely to confound the association between genetic risk factors and longevity. We exam- ined the likelihood of carrying an APOE ε4 or ε2 allele and distri- bution of the TOMM40 SNP rs2075650 in the offspring generation of the Long Life Family Study (LLFS). We hypothesized that offspring of LLFS members would have a decreased frequency of the APOE ε4 allele, a decreased frequency of the G allele in TOMM40 rs2075650 and an increased frequency of the APOE ε2 allele compared with similarly aged peers not selected for familial longevity.