By Grace Turek and Aaron Goldman
The APOE ε4 allele has been associated with detrimental health outcomes such as increased risk for Alzheimer’s disease (AD), cardiovascular disease, and overall mortality. Despite its deleterious effects, an estimated 15% of our world population carries this allele, and this frequency is much higher in some populations – for example, this allele is found in approximately 27% of Africans. The high prevalence of the APOE ε4 allele in the human population begs the question as to how this ‘harmful’ allele was maintained throughout human evolution; i.e., if the allele is so harmful, what’s keeping it in the gene pool? One hypothesis for this is that the ε4 allele may have once played a beneficial role in populations with high pathogen exposure.
A recent study has found that the ε4 allele has a protective effect against cognitive decline in environments with a heavy pathogen burden, which is contrary to what has been observed in industrial populations. This study showed that in a population of Amazonian forager-horticulturalists with a high parasite burden, older individuals that carry the ε4 allele actually maintained or showed improvements in cognitive performance, whereas non-ε4 carriers with a high parasite burden showed reduced cognitive performance. This suggests that there are actually advantages associated with the ε4 allele under certain environmental conditions.
By applying Darwin’s theory of Natural Selection, if the ε4 helped individuals to survive, or reproduce, this variation would be more likely passed onto the next generation, thus encouraging the maintenance of this allele. However, as infections decreased and lifespans increased throughout history, the protective effects of this allele became less important and its harmful effects on aging were unveiled. Also, given that the impact of the ε4 allele on Alzheimer’s disease risk is related to late-onset AD which affects individuals much later in life as fat plaques build up in the brain over the course of a long lifetime, there is relatively little selection pressure to remove it from the gene pool in younger individuals that are reproducing and passing it on.
Moreover, the APOE ε4 allele has been suggested as the original APOE variant and divergence of the ε2 and ε3 alleles did not occur until well after human lifespan was already increasing. Therefore, how did lifespan successfully increase despite most of our ancestors being homozygous for APOE ε4? Some studies have suggested that increase in exercise may have mediated some of the allele’s harmful effects on the aging population.
Approximately 1.8 million years ago, hunting and food gathering increased causing our ancestors to live much less sedentary lifestyles and become more physically active. It is hypothesized that this shift to a more active lifestyle may have dampened its harmful effect on human health and lifespan. This idea has been confirmed in many studies that show a reduced risk of cognitive decline and cardiovascular disease in APOE ε4 carriers who engage in regular physical activity. These results are hopeful; as they suggest that lifestyle changes can reduce the risk of adverse health outcomes in those with the APOE ε4 allele.
Raichlen, D. A., & Alexander, G. E. (2014). Exercise, APOE genotype, and the evolution of the human lifespan. Trends in Neurosciences, 37(5), 247–255.
van Exel, E., Koopman, J. J. E., et al. (2017). Effect of APOE ε4 allele on survival and fertility in an adverse environment. PLOS ONE, 12(7), e0179497.
Trumble, B. C., Stieglitz, J., et al. (2017). Apolipoprotein E4 is associated with improved cognitive function in Amazonian forager-horticulturalists with a high parasite burden. FASEB J., 31(4), 1508–1515.
Aaron Goldman, PhD
Chief Science Officer