APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease

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.

APOE and Alzheimer’s Disease: From Lipid Transport to Physiopathology and Therapeutics

“…Lipidation of apoE and lipid transport within the CNS are currently under investigation to clarify their roles in the development of LOAD. ApoE is unique among apolipoproteins with its minimal intracellular degradation ( Yassine and Finch, 2020 ). Internalized lipids are dissociated from apoE into late endosomal compartments after intracellular absorption of apoE-containing lipoprotein particles, followed by recycling of apoE into early endosomes and its re-secretion within or into HDL particles ( Yassine and Finch, 2020 ).…”

“…This property reduces the efflux of cholesterol and enriches the cell membrane with cholesterol ( Yassine and Finch, 2020 ). ApoE recycling controls the expression of several cell surface proteins, such as ABCA1 ( Rawat et al, 2019 ), the insulin receptor (IR), or LRP1 ( Yassine and Finch, 2020 ). The reduced apoE4 recycling traps ABCA1 in endosomes, away from the cell surface.…”

“…Reduced activity of ABCA1 hence contributes to lower efflux of cholesterol to HDL and redistributes cholesterol to cell membranes ( Rawat et al, 2019 ). Greater cell membrane cholesterol enhances TLR4 signaling in macrophages which in turn, activates NFkB and induces inflammatory genes response ( Singh et al, 2020 ; Yassine and Finch, 2020 ). Lower apoE4 recycling in the brain also traps insulin receptor (IR) away from cell surface in the endosome ( Zhao N. et al, 2017 ), hence modifying its preferences for cellular energy sources.…”

“…Moreover, apoE4 proteins secreted from primary astrocytes are poorly lipidated compared to apoE3. Increasing the activity of ABCA1 could therefore provide a therapeutic approach to promote the recycling of apoE4 from endosomes and restore its function at the membrane level ( Yassine and Finch, 2020 ). A greater distribution of cholesterol at the neuronal plasma membrane increases the expression of BACE1 and APP processing to generate more Aβ ( Cui et al, 2011 ).…”

“…Therefore, apoE4 lipid transport capabilities to supply neurons and astrocytes are probably decreased in late stages of life in APOE4 carriers. Hence, a young brain might have mechanisms in place to cope with inadequate lipid transport related to apoE4 protein structure ( Yassine and Finch, 2020 ). During aging, there is a potential loss of these alternative mechanisms while there is also a decreased production of cholesterol ( Boisvert et al, 2018 ), and both could lead to neuronal lipid deficits ( Fernandez et al, 2019 ).…”