APOE4 - does it cause Alzheimer's?
The human apolipoprotein E gene (APOE) is known for its association with both Alzheimer’s and coronary heart disease. Three common allelic isomorphs of APOE are found worldwide - E2, E3, and E4. The E4 allelic is significantly associated with both coronary heart disease and Alzheimer’s Disease.
A meta-analysis of 48 different studies that examined the association between APOE genotypes and coronary heart disease found that carriers of the E4 allele had a 42% higher risk of coronary heart disease compared to individuals who were homozygous for E3 (Song et al 2004). Meanwhile, non-carriers of the E4 allele have a 20% lifetime risk of Alzheimer’s, individuals with one copy of E4 have a 47% lifetime risk of Alzheimer’s, while individuals homozygous for E4 carry a 91% lifetime risk of Alzheimer’s. E4 also results in an earlier age of onset for Alzheimer’s is gets lower the more copies of E4 an individual has – ranging from 84 years old for non-carriers to 68 years for homozygous individuals (Corder et al).
Despite these associated health risks, the E4 allele maintains a global allelic frequency of around 13.9%. In the US, around 23% of individuals carry one copy of E4 while around 2% of individuals are homozygous (Singh et al). Why would an allele that carries such high risks of debilitating diseases be so common?
1) Antagonistic pleiotropy: The E4 allele provides fitness benefits early in life that counteract the costs associated with the increased health risks that emerge later in life.
The onset of Alzheimer’s Disease and coronary heart disease typically occurs after reproductive years, meaning these diseases are unlikely to negatively impact reproduction. Put another way – the fact that someone experiences cognitive decline at 75 or has a heart attack at 60 does not prevent them from having 5 children between the ages of 18 and 50 (though it may impede their ability to help their children or grandchildren). This is the idea of a selection shadow; the strength of selection weakens for traits that manifest at ages past one’s reproductive prime. The late onset of E4’s associated morbidities means that it is unlikely to be facing strong negative selection.
The second part antagonistic pleiotropy is for there to exist some positive impact on reproductive fitness that occurs earlier in life. Evidence for this happens to exist - but these benefits may depend on the environment where someone lives. Research on children living in urban slums in Brazil, where malnutrition and diarrhea caused by parasitic infection are endemic, found that those that carried the E4 allele had fewer diarrheal episodes on average, greater weight-per-height, and scored higher on cognitive tests compared to non-carriers. E4 may help fight enteric parasitic infections and simultaneously aid brain development in the face of these infections through its role in cholesterol transport.
2) Mismatch: The negative associations between E4 and various morbidities are only seen in modern environments, and more evolutionary relevant environments do not result in the same costs.
This second hypothesis suggests that the links between E4 and morbidities like coronary heart disease and Alzheimer’s Disease are an example of evolutionary mismatch. In this case, aspects of our modern environments, that are novel in an evolutionary sense, interact with E4 in a way that results in morbidities that would not be seen in more evolutionarily relevant environments. Carriers of the E4 allele living in environments that more closely reflect past evolutionary conditions may not experience the associated risks of coronary heart disease or Alzheimer’s that we see in Westernized environments.
A test of these hypotheses:
Researchers with the Tsimane Health Initiative set out to better understand the evolutionary picture of the E4 allele. These researchers were particularly interested in whether the negative health associations observed in Westernized contexts would hold in a population with a higher parasitic load, a more physically active lifestyle, and hunter-forager diet. They were particularly interested in the role of parasite burden, because the E4 allele is more common in tropical regions, where the burden of infectious disease is greater.
The researchers took a number of measures, including cognitive performance, height and weight, looked at markers of past infection, and of course, genotyped participants for APOE.
If the first hypothesis was supported (antagonistic pleiotropy), they expected the E4 allele to be associated with positive benefits early in life and costs in the form of cognitive decline later in life. If the second hypothesis was supported, they expected to see no negative impacts of E4 later in life, specifically for individuals who experienced higher rates of past infections.
Their results supported the mismatch hypothesis. Amongst elderly Tsimane who had experienced higher parasite and pathogen loads, individuals with the E4 allele showed improved cognitive performance compared to those without the E4 allele. This not only suggests that the negative health impacts of E4 late in life do not exist in populations with high parasite loads, but that it may actually provide a late in life benefit.
Mismatch and plasticity
The APOE study performed with the Tsimane population is a great reminder that any evolutionary perspective on genetic links to disease should consider whether the associated disease risks of genetic variants are environment specific. In the medical community, E4 is painted as entirely negative. However, once the E4 allele was studied in a population whose lifestyle is closer to evolutionarily relevance, the negative associations with this allele were completely reversed. This reversal is an excellent example of plasticity, where changes to a developmental environment can result in completely different phenotypic outcomes.
Discussing evolution and APOE provides an opportunity to think about potential trade-offs, particularly those that involve antagonistic pleiotropy. One of the main hypotheses for why the E4 allele may persist at high frequencies is that it provides an early life benefit that outweighs the late in life costs. In this regard, APOE provides an example of a pleiotropic gene, a potential example of antagonistic pleiotropy, and an opportunity to think about selection shadows.
Embedded videos here
Song, Y., Stampfer, M. J., & Liu, S. (2004). Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Annals of internal medicine, 141(2), 137.
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G., ... & Pericak-Vance, M. A. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science, 261(5123), 921-923.
Singh, P. P., Singh, M., & Mastana, S. S. (2006). APOE distribution in world populations with new data from India and the UK. Annals of human biology, 33(3), 279-308.
Trumble, B. C., Stieglitz, J., Blackwell, A. D., Allayee, H., Beheim, B., Finch, C. E., ... & Kaplan, H. (2016). Apolipoprotein E4 is associated with improved cognitive function in Amazonian forager-horticulturalists with a high parasite burden. The FASEB Journal, 31(4), 1508-1515.
Vasunilashorn, S., Finch, C. E., Crimmins, E. M., Vikman, S. A., Stieglitz, J., Gurven, M., ... & Allayee, H. (2011). Inflammatory gene variants in the Tsimane, an indigenous Bolivian population with a high infectious load. Biodemography and social biology, 57(1), 33-52.