The gene alleles modify human aging and the response to the diet at many levels with diverse pleotropic effects from gut to brain. To understand the interactions of isoforms and diet, we analyze how cellular trafficking of apoE proteins affects energy metabolism, the immune system, and reproduction. The age-accelerating allele alters the endosomal trafficking of cell surface receptors that mediate lipid and glucose metabolism. The allele is the ancestral human allele, joined by and then in the human species. Under conditions of high infection, uncertain food, and shorter life expectancy, may be adaptive for reducing mortality. As humans transitioned into modern less-infectious environments and longer life spans, increased risks of aging-related diseases, particularly impacting arteries and the brain. The association of with glucose dysregulation and body weight promotes many aging-associated diseases. Additionally, the gene locus interacts with adjacent genes on chromosome 19 in haplotypes that modify neurodegeneration and metabolism, for which we anticipate complex gene-environment interactions. We summarize how diet and Alzheimer's disease (AD) risk are altered by genotype in both animal and human studies and identify gaps. Much remains obscure in how alleles modify nutritional factors in human aging. Identifying risk variant haplotypes in the gene complex will clarify homeostatic adaptive responses to environmental conditions.