Linking ecological immunology and evolutionary medicine: the case for apolipoprotein E

P>1. Evolutionary medicine seeks to understand whether and to what extent aspects of human disease are adaptations for coping with infections or injuries, or the consequence of mismatches between modern and ancestral environments. Ecological immunology by comparison focuses largely on how organisms balance investments in immune defences against other traits (e.g., cognitive and reproductive functions) to maximize fitness. 2. Here we address the potential benefit of merging these two young disciplines by reviewing the biomedical literature involving variation at the human apolipoprotein epsilon (apoE) locus. Allelic variants at this locus are differentially susceptible to certain parasites [e.g. herpes-simplex virus-1 (HSV-1) and Chlamydia pneumoniae], as well as Alzheimer's and coronary artery disease, although susceptibility is impacted by environmental factors such as exercise and diet. ApoE variants also exhibit extensive physiological differences, particularly in immune and cognitive traits. 3. Considered altogether, we suggest that apoe-associated diseases are maladaptive plastic responses to conditions in modern environments, and predict that allelic variation at the apoE locus arose as both a consequence of genetic accommodation of historically adaptive environmental responses and because of the particular susceptibility of lipid transport molecules as infection pathways for certain parasites. 4. The goal of this paper is not to support unequivocally this hypothesis because relevant data remain scarce. We intend instead to provide a framework whereby existing hypotheses, which tend to emphasize faulty signalling via one allele (apoE4), can be evaluated through ecologically-informed experiments.