mechanisms of ageing

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Apolipoprotein E alleles in nonagenarian subjects in the Belfast Elderly Longitudinal Free-living Ageing Study (BELFAST)

M. Rea a,*, Ian Mc Dowell b,c, Dorothy McMaster Mike Smye b, Robert Stout a, Alun Evans d,

a Department of Geriatric Medicine, The Queen’s Uni(cid:1)ersity, Belfast BT7 1NN, UK b Department of Medicine, The Queen’s Uni(cid:1)ersity, Belfast, UK c Belfast MONICA Project, Cardio(cid:1)ascular Sciences Research Group, Uni(cid:1)ersity of Wales, UK d Department of Epidemiology and Public Health, The Queen’s Uni(cid:1)ersity, Belfast, UK

Received 25 September 2000; accepted 30 October 2000

Abstract

The ApoE gene has three alleles coding for the proteins apoE2, apoE3 and apoE4. E4 has been reported to be associated with hypercholesteraemia, ischaemic heart disease, age-related cognitive decline and Alzheimer’s disease. Conversely, the E2 allele has been associated with longevity in French centenarians and their siblings. In this study, we have assessed any shift in the ApoE genotypes in nonagenarian subjects from Belfast where there is a high intrinsic incidence of cardiovascular disease. ApoE phenotypes were determined by electrofocusing  and immunoblotting in 114 Senieur-approximated subjects 90 years old and compared with 2071 subjects, 30–65 years of age, recruited from the same geographical area by the MONItoring of CArdiovascular trends study group in Belfast (MONICA). The E4 allele was reduced in the nonagenarian group (X2=11.1; P=0.0006), the E3 unchanged and E2 frequency was increased (X2=4.0; P=0.047). These results suggest that longevity is negatively associated with the E4 allele and may be associated with carriage of E2. © 2001 Elsevier Science Ireland Ltd. All rights reserved.

ApoE alleles; Longevity; Nonagenarians

0047-6374/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0047-6374(01)00278-0

1. Introduction

Many studies have demonstrated the importance of the ApoE gene in cholesterol metabolism (Utermann, 1987; Xhignesse et al., 1991). The three main alleles of the gene E2, E3 and E4, which differ on the basis of two amino acids, appear to have different thresholds for solubility and association characteristics for their ligands, the ApoE and the low density lipoprotein receptors on liver cell plasma membranes. ApoE2 has markedly lower binding affinity to receptors compared with apoE3 and E4 isoforms and this may be the basis for the finding that E4 phenotypes tend to have higher cholesterol and for apoE-related disease associations (Utermann, 1987; Smith, 2000). Many studies have shown an association between ApoE genotype and ischaemic heart disease, with carriage of the E4 allele being associated with higher cholesterol and cardiovascular risk, compared with E3 and E2 alleles (Nassar et al., 1999; Alafuzoff et al., 2000). However, this is not invariably so since the Sudanese population have not only the highest allelic frequency of E4 (29%), described in any population group, but coronary heart disease is almost unkonwn (Hallman et al., 1991). Similarly, there has been a flurry of studies not only demonstrating a clear relationship between apoE4 and Alzheimer’s disease (Farrer et al., 1997) but with age-related cognitive decline (Henderson et al., 1999; Haan et al., 1999; O’Hara et al., 1998). These findings suggest that carriage of apoE alleles, particularly E4, may

Since, elderly people are survivors of their peer groups and seem likely to have been protected from premature vascular disease and its associated mortality, it might be predicted that there would be an under-representation of the E4 alleles in healthy very elderly people. In keeping with this hypothesis, several studies have demonstrated a decline in the E4 allele in very elderly subjects in Caucasian population groups (Eggertsen et al., 1993; Louhija et al., 1994; Rulu et al., 1995; Kervinen et al., 1994; Galinsky et al., 1997; Jian-Gang et al., 1998) though some studies did not (Bladbjerg et al., 1999). An interesting report by Schachter et al., 1994 not only substantiated this hypothesis but in addition demonstrated an association between the E2 allele and longevity in French centenarians and their siblings. In addition, reports also suggested that apoE2 might be protective against Alzheimers disease (Corder et al., 1994). We were interested to carry out a similar study in Northern Ireland, which has not only one of the highest incidences of heart disease in the world (Tunstall-Pedoe et al., 1994), but a relatively stable Caucasian gene pool which could enhance the possibility of identifying important ‘survivor’ or longevity genes.

2. Materials and methods

Subjects

Subjects in the 25–64 year age group were enlisted from the Greater Belfast area (target population 250 000) with the help of General Practitioners. This group has been earlier described (Tunstall-Pedoe et al., 1994) and formed part of the World

Health Organisation’s Belfast project, MONItoring of trends and determinants in CArdiovascular disease project (MONICA).

Nonagenarian subjects. As part of the Belfast Elderly Longitudinal Free-living >s Ageing STudy (BELFAST) ongoing study in ageing, subjects 90 years of age were invited to take part in the study with the help of General Practitioners as previously described (Rea et al., 2000). Briefly, 114 nonagenarians who lived within the same geographical area as MONICA subjects, were self-reporting as well, free-living in the community and mentally competant by Folstein (Folstein et al.,  1975) assessment ( 28/30) and who approximated SENIEUR status (Ligthart et al., 1984), were enlisted to the study. Ethical permission was obtained from the Queen’s University of Belfast.

2.2. Methods