Last month this column considered current and future progress in Alzheimer Disease (AD) diagnosis, management, and treatment. Because AD is a terrible brain disease with an increasing rate of prevalence with age, and because it represents one of – if not the – worst conditions that can afflict a person with cryopreservation arrangements, I would like to continue our consideration of this well-known and widely-feared neurodegenerative disease. Specifically, our focus will be on apolipoprotein E (apoE) and research regarding its role in the modulation of physiological responses to certain viral infections.

ApoE protein is primarily synthesized peripherally in the liver and mediates cholesterol metabolism systemically, but it is also made in the central nervous system by astroglia and microglia (non-neuronal cell types) where it transports cholesterol to neurons. In the CNS, neurons express receptors for apoE that are part of the low density lipoprotein receptor gene family. Historically, apoE has been recognized for its role in lipoprotein metabolism and its importance in cardiovascular disease. Of course, apoE carrier status is also widely known as the major factor determining one’s risk of developing late-onset Alzheimer disease (AD). But more recent research has indicated that the various isoforms of apoE may also have significant immunological impact by conferring different susceptibilities to other diseases, as well.

The human apoE gene is located on chromosome 19 and is composed of 79 individual single nucleotide polymorphisms (SNPs). The three major alleles of apoE, named Epsilon-2 (Ɛ2), Epsilon-3 (Ɛ3), and Epsilon-4 (Ɛ4), are determined by differences in SNPs s429358 and rs7412. The products of these alleles are the protein isoforms apoE2, apoE3, and apoE4, which differ only by a single amino acid at two residues (amino acid 112 and amino acid 158). These amino acid substitutions affect noncovalent “salt bridge” formation within the proteins, which ultimately impacts on lipoprotein preference, stability of the protein, and receptor binding activities of the isoforms (see Table 1).

Table 1. ApoE isoform amino acid differences and resulting chemical and physiological changes.

There are also two minor alleles, Epsilon-1 (Ɛ1) and Epsilon-5 (Ɛ5), which are present in less than 0.1% of the population. The three major alleles are responsible for three homozygous (Ɛ2/Ɛ2, Ɛ3/Ɛ3, Ɛ4/Ɛ4) and three heterozygous (Ɛ2/Ɛ3, Ɛ2/Ɛ4, Ɛ3/Ɛ4) genotypes. [I will pause to mention here that it is now quite easy to determine one’s genotype through services such as 23andme.com.]

An interesting document in the field is the literature review by Inga Kuhlman, et al. (Lipids in Health and Disease 2010, 9:8) which assesses hepatitis C, HIV and herpes simplex disease risk by ApoE genotype. An important finding is that the Ɛ4 allele is found less frequently in populations as they age (e.g., 14% of the general German population vs. 5% in centenarians), indicating that Ɛ4 is a major mortality factor in the elderly. This is assumed to be a result of the Ɛ4 allele’s well-known predisposition to Alzheimer and cardiovascular diseases.

The authors explain that “apoE4 carriers have a tendency for 5-10% higher fasting total cholesterol, LDL-cholesterol and triglyceride levels relative to homozygote Ɛ3/Ɛ3” and that this tendency towards higher lipid levels is probably responsible for the 40-50% greater cardiovascular disease risk in Ɛ4 carriers. They also point out that “although the molecular basis of the pathology is poorly understood, and likely to be in part due to apoE genotype associated differences in brain lipid metabolism, an apoE4 genotype has been highly consistently associated with the risk of an age-related loss of cognitive function, in an allele dose fashion.” This means, of course, that Ɛ4/Ɛ4 carriers are at greatest risk for cognitive dysfunction with increasing age.

In the field of immune regulation, a growing number of studies point to apoE’s interaction with many immunological processes. In their article, Kuhlman, et al., summarize the impact of the Ɛ4 allele on the susceptibility to specific infectious viral disease. The authors review a number of studies of the effects of apoE4 genotype on hepatitis C (HCV), human immunodeficiency virus (HIV), and herpes simplex (HSV) infection and outcome in humans.

In general, apoE4 was found to be protective against hepatitis C infection vs. (Ɛ3/Ɛ3) controls. Though the exact mechanisms of apoE genotype-specific effects on HCV life cycle remain uncertain, apoE seems to be involved because “available data indicate that the outcome of chronic HCV infection is better among Ɛ4 carriers due to slower fibrosis progression.”

Concerning the possible influence of apoE genotype on HIV infection and HIV-associated dementia, the authors call attention to the fact that “cholesterol is a crucial component of the HIV envelope and essential for viral entry and assembly.” Given that apoE is essential for cholesterol transport, they hypothesize that apoE genotype influences HIV-induced effects on neurological function. Subsequent review of available research suggests that the 4 allele is associated with higher steady-state viral load and faster disease progression due to accelerated virus entry in 4 carriers, but a correlation between apoE4 and HIV-associated dementia “remains controversial and needs to be clarified by further studies.”

Lastly, a review of the literature regarding the effects of apoE4 genotype on herpes simplex virus (HSV)-1 infection and outcome in humans indicates that apoE4 enhances the susceptibility for HSV-1 “as well as the neuroinvasiveness of HSV-1 compared to other apoE variants” (i.e., HSV-1 is found in more frequently in the CNS of 4 carriers). Importantly, the authors also note that “the combination of apoE4 and HSV-1 may lead to a higher risk of Alzheimer disease (AD) than either factor in isolation.”

Due to its generally being associated with higher risk of cardiovascular disease, dementia, and increased susceptibility to and/or accelerated progression of various viral infections, one may wonder why the 4 allele has not been eliminated by evolutionary selection. This may be explained, in part, by the protective and beneficial effects it exhibits in certain harmful infectious diseases, as demonstrated for hepatitis C.

The exact mechanisms of apoE influence on susceptibility to and course of viral infection remain shrouded. Because the mechanisms of HCV, HIV, and HSV infection are quite similar (i.e., all three viruses compete with apoE for cell attachment and receptor binding), it is interesting to find differences in receptor binding among them.

Involvement or interaction between the immune system, cognition, and brain diseases such as AD is an as-yet widely untouched field of inquiry. Further elucidation of the mechanisms by which apoE may influence the pathogenesis of infectious viral diseases can lead to new developments in the treatment of disease based on an individual’s apoE genotype.

Aside from the role that ApoE plays in susceptibility and progression of infectious disease, there is growing interest in the role that infection or a compromised immune system plays in the development of dementia. For example, despite the successful management of HIV with antiretroviral drugs, some patients are showing signs of memory impairment and dementia at a relatively young age. Interestingly, these people seem to show accelerated aging, too, which raises important questions about the relationship between the immune system, immunosenescence, and aging.

Originally published as an article (in the Cooler Minds Prevail series) in Cryonics magazine, May, 2013