APOEAlleles and Diet in Brain Aging and Alzheimer's Disease

TheAPOEgene 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 ofAPOEisoforms and diet, we analyze how cellular trafficking of apoE proteins affects energy metabolism, the immune system, and reproduction. The age-acceleratingAPOE4allele alters the endosomal trafficking of cell surface receptors that mediate lipid and glucose metabolism. TheAPOE4allele is the ancestral human allele, joined byAPOE3and thenAPOE2in the human species. Under conditions of high infection, uncertain food, and shorter life expectancy,APOE4may be adaptive for reducing mortality. As humans transitioned into modern less-infectious environments and longer life spans,APOE4increased risks of aging-related diseases, particularly impacting arteries and the brain. The association ofAPOE4with glucose dysregulation and body weight promotes many aging-associated diseases. Additionally, theAPOEgene 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 byAPOEgenotype in both animal and human studies and identify gaps. Much remains obscure in howAPOEalleles modify nutritional factors in human aging. Identifying risk variant haplotypes in theAPOEgene complex will clarify homeostatic adaptive responses to environmental conditions.