Inheritance of a single copy of the apolipoprotein E (APOE) ε4 allele increases the risk of Alzheimer’s disease (AD) by three–fourfold, with homozygosity associated with a 12–16-fold increase in risk, relative to ε3 allele homozygosity. There is a decreased risk associated with the APOE ε2 allele. The pathological consequence of APOE genotype has led to intense efforts to understand the mechanistic basis of the interplay between APOE status and loss of synapses. Numerous ε4 allele-related associations have been reported, with the potential relevance of these associations to the pathogenesis of AD unknown at this time. In primarily young subjects, we have reviewed a representative body of literature on ε4 allele associations related to the following: cardiovascular responses, impacts on reproduction and fetal development, comorbidities, resistance to infectious disease, responses to head injury, biochemical differences possibly related to neural stress, and brain structure-function differences. In addition, the literature on the association between the ε4 apolipoprotein and cognitive performance has been reviewed comprehensively. The weight-of-the-evidence supports the hypothesis that possession of the ancestral ε4 allele in youth is associated with improved fitness during fetal development, infancy, and youth relative to the more recently appearing ε3 allele, at the expense of decreased fitness in old age, which is substantially improved by the ε3 allele. However, possession of the ε4 allele is also associated with higher levels of synaptic macromolecular turnover, which likely stresses basic cellular neuroplasticity mechanisms. Clinical trials of potential AD therapeutics should consider apolipoprotein status as an enrollment criterion.