The Genetic Variability of APOE in Different Human Populations and Its Implications for Longevity

Abstract

Human longevity is a complex phenotype resulting from the combinations of context-dependent gene-environment interactions that require analysis as a dynamic process in a cohesive ecological and evolutionary framework. Genome-wide association (GWAS) and whole-genome sequencing (WGS) studies on centenarians pointed toward the inclusion of the apolipoprotein E (APOE) polymorphisms ε2 and ε4, as implicated in the attainment of extreme longevity, which refers to their effect in age-related Alzheimer's disease (AD) and cardiovascular disease (CVD). In this case, the available literature on APOE and its involvement in longevity is described according to an anthropological and population genetics perspective. This aims to highlight the evolutionary history of this gene, how its participation in several biological pathways relates to human longevity, and which evolutionary dynamics may have shaped the distribution of APOE haplotypes across the globe. Its potential adaptive role will be described along with implications for the study of longevity in different human groups. This review also presents an updated overview of the worldwide distribution of APOE alleles based on modern day data from public databases and ancient DNA samples retrieved from literature in the attempt to understand the spatial and temporal frame in which present-day patterns of APOE variation evolved.

Keywords: APOE; apolipoprotein E; genomics; longevity; populations.

Figure 1

Polymorphisms underlying the three main APOE variants in humans. (A) Chromosome location, gene structure, identity of the mutating sites in the gene, and the corresponding mutating residues in the context of the protein structure. In yellow, it is indicated as the receptor-binding region in helix 4 and, in green, it is the lipid-binding region in the C-terminal domain. Red and black dots indicate the genetic variants in APOE and their position in the genomic and protein sequences, respectively. (B) Table reporting the haplotypes and corresponding residue combination associated to each APOE allele.

Figure 2

Frequency distribution of APOE alleles in 82 countries. Data from the 1000 Genome Project have been integrated with those published in Singh et al. 2006. (A) Frequency distribution of the ε2 variant. (B) Frequency distribution of the ε3 variant. (C) Frequency distribution of the ε4 variant.

Figure 3

Distribution and approximate age of the analyzed ancient samples. Those coming from the same location and belonging to the same culture have been clustered together and share the same label. The number of grouped individuals is given in brackets.