The Ancestral ApoE4 Gene: Friend or Foe?

By Ram Rao, Ph.D., Principal Research Scientist for Apollo Health

Apolipoprotein E (ApoE) is a protein that helps carry cholesterol around the body. ApoE comes in mainly three forms-ε2, ε3 and ε4. We all inherit a copy of some form of ApoE from each parent. The ApoE3 variant is thought to have occurred through a mutation around 220,000 years ago and is the dominant version. The ApoE2 variant is thought to have appeared around 70,000 years ago. The ApoE4 variant is the oldest, evolutionarily speaking, and having one or two copies of the ApoE4 variant increases the risk of developing Alzheimer’s disease (AD). About 25 percent of people carry one copy of ApoE4 and develop the disease by age 85. The risk for AD rises to 55 percent for the 2 to 3% of people that carry two copies of ApoE4. In addition to raising risk, the ApoE4 variant may tend to make symptoms appear at a younger age than usual.

Interestingly, there appears to be a close connection between the ancestral ApoE4, inflammation, and walking upright on two legs which is the trait that defines the hominid lineage. When our ancestors-the hominids-descended from the trees and started walking on the savanna, they had to survive injuries to the feet and serious wounds during long hunts. Furthermore, they had to overcome infections from bodily injuries, poor hygiene, or eating raw meat. They very likely went long periods without eating and physically labored as hunter-gatherers to find food. They would have been awakened by the sunrise and slept with the sunset and would have been least exposed to modern aspects of living (stress, pollution, processed and/or fast foods or food on demand, autos, electronic devices, poor sleeping habits, etc.). In these situations and more, they would have survived thanks to a robust and protective inflammatory response triggered by ApoE4 together with other inflammatory genes.

However, in a process called antagonistic pleiotrophy, in which a gene promotes wellness and fitness early in life at the expense of longevity, the same ApoE4 now turns out to be the adversary of modern man, whose lifespan increased from 25+ to 65+ years. Increased lifespan, together with better comforts and a modern lifestyle, brought with it the negative aspect of ApoE4 in the form of ApoE4-triggered inflammation, which is now linked to AD. Thus, in today’s world, it is more likely that people who inherit one or two copies of ApoE4 will develop the inflammatory subtype of AD. In people that carry two copies of ApoE4, AD symptoms may begin very early (40+ years of age). Inflammatory AD is accompanied by increased levels of several inflammatory molecules like C-reactive protein, tumor necrosis factor, and IL6. In addition to promoting inflammation, ApoE4 increases the amounts of misfolded Aβ and Tau in the brain. ApoE4 slows the degradation and elimination of misfolded Aβ aggregates and exacerbates the cellular damage caused by misfolded Tau tangles. Research studies also point to ApoE4’s role in blocking the microglial response to Aβ accumulation, suppressing autophagy, and inhibiting the disposal of damaged mitochondria, thereby perturbing cellular energy metabolism. Furthermore, ApoE4 damages blood vessels in the brain and makes them leaky, slowing down cerebral blood flow.

Thus, in the present modern and industrialized world, ApoE4 is considered a purely deleterious allele, increasing inflammation and lipid levels and escalating the risk of inflammatory-associated diseases. However, inheriting one or both copies of the ApoE4 allele does not mean that a person will definitely develop AD. Some people with the ApoE4 allele never get the disease, and others who develop AD do not have the ApoE4 allele. Thus, it appears that not all of ApoE4 is Mr. Hyde, as it also has a friendlier Dr. Jekyll’s face.

It appears that in a high-pathogen, insufficient food, and an energy-limited environment, carrying an ApoE4 allele may actually be beneficial. Most of the benefits associated with ApoE4 come from studies on indigenous tribes that live in remote, tropical rainforests. One such tribe is the Tsimane of lowland Bolivia. This is an indigenous forager-farmer population living in small, mobile, hunter-gathering groups without access to sanitation or clean water, with high infectious morbidity, inflammation, and shortened life expectancy. A preliminary study of genetic markers in the Tsimane suggests some notable differences in ApoE allele frequencies relative to other populations. For example, ApoE4 and not ApoE2 is the predominant gene in this relatively large sample of Tsimane subjects, which is consistent with studies of other Amazonian tribes, Mayans of Mexico, and Australian aborigines.

Contrary to observations in industrial populations, E4 carriers with a high parasite burden either maintained or showed improvements in cognitive performance, whereas non-E4 carriers with a high parasite burden showed reduced cognitive performance. Similarly, adults with high eosinophil counts (indicative of parasitic infection or a severe allergic reaction) and who carried at least one copy of the E4 allele showed better cognitive performance than did non-carriers indicating a protective effect of ApoE4 on cognition when exposed to environmental insults. Other studies have found evidence of protective interactions between ApoE4 alleles, testosterone, and estrogen. In all these cases, free testosterone, estrogen, and physical exercise enhanced memory performance in ApoE4 carriers.  Considered together, the evidence suggests that the impact of the ApoE4 allele is not always deleterious and may be adaptive and beneficial in some populations with a high infectious burden. In a subgroup analysis of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) study, ApoE4 carriers had a better and faster improvement in terms of cognitive benefits from a multipronged intervention compared to non-ApoE4 carriers. This is good news for people who worry that having an ApoE4 gene may hinder healthy lifestyle changes’ potential benefits. While ApoE4 carriers have higher lipid levels, these may be beneficial for immune response and survival and unlikely to increase cardiovascular risk without other cardio-metabolic risk factors.

Thus, despite being present in an industrialized, hyper-competitive, and stressful environment, ApoE4 carriers could still reap the benefits associated with their forest-dwelling ancestors. At Apollo health, we have the ReCODE Program™ which is based largely on diet, physical and mental exercise, sleep, detox, stress management, and supplementation. The program is very congruent with the ancestral lifestyle, including an emphasis on whole, low-glycemic index foods, lots of vegetables (preferably organic), clean protein, and a minimum of a 12-hour fast and physical exercise. Honoring the still primitive gene and following ancestral patterns to a greater extent will hopefully continue to reveal more of the friendlier face of the ApoE4 gene.