High-dose DHA supplementation in APOE4 carriers before the onset of AD dementia can be a promising approach to decrease the incidence of AD. Given the safety profile, availability, and affordability of DHA supplements, refining an ω-3 intervention in APOE4 carriers is warranted.

The APOE 4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE protein aggregation plays a central role in AD pathology, including the accumulation of ␤-amyloid (A␤). Lipid-poor ApoE4 protein is prone to aggregate and lipidating ApoE4 protects it from aggregation. The mechanisms regulating ApoE4 aggregation in vivo are surprisingly not known. ApoE lipidation is controlled by the activity of the ATP binding cassette A1 (ABCA1). ABCA1 recycling and degradation is regulated by ADP-ribosylation factor 6 (ARF6). We found that ApoE4 promoted greater expression of ARF6 compared with ApoE3, trapping ABCA1 in late-endosomes and impairing its recycling to the cell membrane. This was associated with lower ABCA1-mediated cholesterol efflux activity, a greater percentage of lipid-free ApoE particles, and lower A␤ degradation capacity. Human CSF from APOE 4/4 carriers showed a lower ability to induce ABCA1-mediated cholesterol efflux activity and greater percentage of aggregated ApoE protein compared with CSF from APOE 3/3 carriers. Enhancing ABCA1 activity rescued impaired A␤ degradation in ApoE4-treated cells and reduced both ApoE and ABCA1 aggregation in the hippocampus of male ApoE4-targeted replacement mice. Together, our data demonstrate that aggregated and lipidpoor ApoE4 increases ABCA1 aggregation and decreases ABCA1 cell membrane recycling. Enhancing ABCA1 activity to reduce ApoE and ABCA1 aggregation is a potential therapeutic strategy for the prevention of ApoE4 aggregation-driven pathology.

These data suggest that exercise alone is an effective nonpharmacological treatment strategy for insulin resistance, metabolic syndrome, and cardiovascular disease risk factors in older obese adults.

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.