Mechanisms of Ageing and Development. www.elsevier.com/locate/mechagedev. Apolipoprotein E alleles in nonagenarian subjects in the Belfast Elderly Longitudinal Free-living Ageing Study (BELFAST). M. Rea*, Ian McDowell, Dorothy McMaster, Mike Smye, Robert Stout, Alun Evans, Department of Geriatric Medicine, The Queen's University, Belfast BT7 1NN, UK; Department of Medicine, The Queen's University, Belfast, UK; Belfast MONICA Project, Cardiovascular Sciences Research Group, University of Wales, UK; Department of Epidemiology and Public Health, The Queen's University, 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 hypercholesterolemia, ischemic 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.

Keywords: ApoE alleles; Longevity; Nonagenarians.

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 ischemic 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 has not only the highest allelic frequency of E4 (29%), described in any population group but coronary heart disease is almost unknown (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; OHara et al., 1998). These findings suggest that carriage of apoE alleles, particularly E4, may be associated with atherosclerosis and/or Alzheimer's disease, thus reducing the chance of survival to very old age by about 50%.

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).