The Evolutionary Biology of the Apolipoprotein E Allele System with Special Reference to Alzheimer's Disease

Jessica Anne Garver

MA Thesis 2003

This thesis explores both the proximate and the evolutionary biology of the ApoE allele system as they relate to Alzheimer's disease (AD). One particular ApoE allele predisposes AD and the question naturally arises as to why selection has not eliminated this allele. In order to approach this question I begin by detailing the biology of AD itself, in terms of its cognitive and neuropathological manifestations. Then I introduce the ApoE alleles, explaining both their structural and functional (metabolic) differences as they relate to the etiology of AD. Finally these differences will be viewed in an evolutionary context. This evolutionary approach involves a consideration of neurological and cognitive changes in aged non-human primates, a review of relevant aspect of life-history theory and reproductive schedules, and a consideration of the effects of gonadal steroids (estrogen in particular) on the AD process. Reproductive schedules and hence the timing of various senescent processes, including AD-like changes, have been altered over the last 5 million years of human evolution. But the most relevant facts regarding the persistence of an AD-predisposing ApoE allele concern the relatively recent transition to domesticated foods and the concomitant shifts in nutrient availability, especially lipids. These shifts have probably altered selective regimes such that a long-favored ApoE allele has recently become disadvantageous. The human ApoE locus can carry any diploid combination of three common alleles, labeled APoE 2, 3 and 4. These alleles differ both slightly in terms of their DNA base sequence and their protein products. Their various gene products are active in both plasma lipoprotein metabolism and in lipid transport, as well as cholestrol homeostasis in the brain (Hass et al.;1998; Weisgraber, Ross and Strittmatter, 1994). The ApoE locus is of considerable medical interest because certain geneotypes are predisposing, and others protective, with respect to two major disorders, coronary artery disease (CAD) and Alzheimer's disease (AD) (Davignon, Gregg and Sing;1998; Strittmatter et al;, 1993). The same geneotypes predispose both disorders, so there is no counterbalanceing natural selection in relation to the two disease risks. Nor does there appear to be any heterozygote superiority (Roses, 1995). Thus, the central question of this Master's paper is, why has selection not eliminated the disease-prone allele?