Impact of apoE genotype on oxidative stress, inflammation and disease risk

Abstract

Although in developing countries an apolipoprotein E4 (apoE4) genotype may offer an evolutionary advantage, as it has been shown to offer protection against certain infectious disease, in Westernised societies it is associated with increased morbidity and mortality, and represents a significant risk factor for cardiovascular disease, late-onset Alzheimer's disease and other chronic disorders. ApoE is an important modulator of many stages of lipoprotein metabolism and traditionally the increased risk was attributed to higher lipid levels in E4 carriers. However, more recent evidence demonstrates the multifunctional nature of the apoE protein and the fact that the impact of genotype on disease risk may be in large part due to an impact on oxidative status or the immunomodulatory/anti-inflammatory properties of apoE. An increasing number of studies in cell lines, targeted replacement rodents and human volunteers indicate higher oxidative stress and a more pro-inflammatory state associated with the epsilon4 allele. The impact of genotype on the antioxidant and immunomodulatory/anti-inflammatory properties of apoE is the focus of the current review. Furthermore, current information on the impact of environment (diet, exercise, smoking status, alcohol) on apoE genotype-phenotype associations are discussed with a view to identifying particular lifestyle strategies that could be adapted to counteract the 'at-risk' E4 genotype.

Decreased plasma C‐reactive protein levels in APOE ε4 allele carriers

“…CRP is an important regulator of immune responses and it is commonly used as a biomarker for systemic inflammation. The presence of the APOE ε 4 allele has been suggested to promote a pro‐inflammatory state in comparison to other APOE alleles 3, 4, 5. Thus, it is surprising that lower hs‐CRP levels, indicating lower levels of inflammation, are repeatedly detected among the individuals with the risk‐conferring APOE ε 4 allele.…”

“…The presence of the APOE ε 4 allele considerably increases the risk and lowers the age of onset of AD, while the APOE ε 2 allele significantly decreases the AD risk 1. ApoE is a multifunctional protein that has an important role in modulating plasma lipid and lipoprotein levels as well as inflammatory responses in the brain and periphery 3, 4, 5. Binding of ApoE to low‐density lipoprotein (LDL) receptors in the liver mediates the clearance of chylomicrons and LDL from the bloodstream.…”

“…For example, the affinity of ApoE2 to the LDL receptors is markedly reduced compared to ApoE3 and E4 6. Carriers of the APOE ɛ 4 allele have higher total cholesterol levels as compared to those without the APOE ɛ 4 allele 4, 5. In addition, the presence of the APOE ɛ 4 allele has been suggested to augment pathophysiological states, such as oxidative stress and neuroinflammation.…”

Mitochondrial DNA and traumatic brain injury

“…For those who lack APOE ε4, haplogroup K appears to have no impact on outcome. The low ROS production associated with haplogroup K might be expected to mitigate the low efficiency of the antioxidant activity of APOE ε4 ,35 and this would seem to be an attractive possible mechanism of interaction for further study.…”

Long-chain omega3 polyunsaturated fatty acids and cognition in older people: interaction with APOE genotype

“…In particular, ApoE can coordinate the mobilization of cholesterol for maintenance and repair of neuron membranes (Poirier, 2003). In addition to its role in lipid metabolism, ApoE exerts multiple functions (Jofre-Monseny et al, 2008). Indeed, ApoE has antioxidant properties depending on its isoforms, with a protective effect of ApoE2 while ApoE4 is associated with increased oxidative stress.…”