Abstract
The APOE 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 APOE isoforms and diet, we analyze how cellular trafficking of apoE proteins affects energy metabolism, the immune system, and reproduction. The age-accelerating APOE4 allele alters the endosomal trafficking of cell surface receptors that mediate lipid and glucose metabolism. The APOE4 allele is the ancestral human allele, joined by APOE3 and then APOE2 in the human species. Under conditions of high infection, uncertain food, and shorter life expectancy, APOE4 may be adaptive for reducing mortality. As humans transitioned into modern less-infectious environments and longer life spans, APOE4 increased risks of aging-related diseases, particularly impacting arteries and the brain. The association of APOE4 with glucose dysregulation and body weight promotes many aging-associated diseases. Additionally, the APOE 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 APOE genotype in both animal and human studies and identify gaps. Much remains obscure in how APOE alleles modify nutritional factors in human aging. Identifying risk variant haplotypes in the APOE gene complex will clarify homeostatic adaptive responses to environmental conditions.
Highlights
Circulating lipoproteins have three major roles in lipid binding and transport, that are arguably interdependent and, to a large extent, based on the capacity to exchange lipids among cells and within different cellular compartments
APOE4 affects cellular preferences for energy during aging with preclinical and clinical evidence indicating a shift from glucose to PUFA fatty acids as a source of energy, increasing the susceptibility of the brain to disease when ω-3 intake is restricted
APOE genotype has a complex relationship with inflammation that differs by race and region
Summary
Circulating lipoproteins have three major roles in lipid binding and transport, that are arguably interdependent and, to a large extent, based on the capacity to exchange lipids among cells and within different cellular compartments. The underlying pathologic role of the APOE alleles may be understood in terms of its metabolic impact during aging, which has implications for optimizing our diet. These questions are approached by examining basic mechanisms of apoE cell biology relevant to energy metabolism with insights into how adaptive responses to infections could facilitate reproduction, but increase the risk of aging-associated diseases. VLDL is catabolized faster than HDL and has a higher affinity to surface apoE receptors These biochemical properties have a major impact on VLDL and HDL metabolism, and affect the distribution of lipids carried by these particles in different tissues, discussed below. The sialylation is at the C terminus and appears to differ by isoform (Flowers et al, 2020), much more work is TABLE 1 | Human APOE polymorphisms and differences by species
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