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APOE4 and Alzheimer's Disease



Alzheimer’s disease is a progressive disease of memory loss that interferes with daily life. The risk of Alzheimer’s increases with age, with symptoms typically starting after 60. Approximately 10% of Americans over 65 have Alzheimer’s – about 5.8 million Americans living with this disease. With world populations growing older, there is an increased demand for treatments and preventative measures to combat Alzheimer’s. Meeting this demand requires understanding the root causes of this disease.

One genetic factor that is far and away the largest predictor of developing Alzheimer’s – the E4 allele of the human apolipoprotein E gene (APOE4). Carrying one copy of the E4 allele is associated with a 47% lifetime risk of developing Alzheimer’s, while carrying two copies increases lifetime risk to 91%. For comparison, non-carriers have a 20% lifetime risk of developing Alzheimer’s. While E4 is not the most common variant, it makes up approximately 13.7% of the global variation, with greater frequencies in the tropics. There are two other common apoE variants, E2 (8.4%) and E3 (77.9%).

The strong link between a debilitating disease like Alzheimer’s and a relatively common genetic variant is a bit of an evolutionary quandary. Why hasn’t natural selection eliminated the E4 allele from global populations? Let’s examine two different evolutionary hypotheses for the persistence of the E4 allele.

Antagonistic pleiotropy

The first hypothesis has a lot to do with timing. When a genetic variant provides benefits early in life but costs later in life, it is an example of antagonistic pleiotropy. Antagonistic pleiotropy is a special type of trade-off that often enables traits that are maladaptive later in life to become more common in a population because of the associated benefits that occurred earlier in life.  

Alzheimer’s disease is certainly a cost that occurs later in life, with onset typically occurring after reproductive years. Because natural selection acts on how many surviving offspring one has, diseases that manifest after reproductive ages are often said to be in a “selection shadow.” The negative health effects are hidden from natural selection. This is only half of the story, though. For E4 to fit antagonistic pleiotropy, there would also need to be an early life benefit.

As it turns out, it seems that E4 may provide early life benefits. The E4 allele provides added protection against parasitic infections compared to the E2 and E3 alleles. Some of the evidence for this comes from research with a population of malnourished children in Brazil, where parasitic infections are common. Compared to non-carriers of the E4 allele, children carrying the E4 allele experienced fewer diarrheal episodes, had greater weight-per-height, and scored higher on cognitive tests on average (Oriá et al. 2010; Oriá et al. 2005). A possible causal link exists between these outcomes and the functional role of APOE allele. APOE plays an important role with the absorption of dietary cholesterol, and the E4 allele is particularly effective in this role. While adding on extra cholesterol may be problematic in Westernized environments where dietary cholesterol is plentiful and parasitic infections are rare, higher levels of cholesterol are beneficial when dietary fat is rare and parasitic infections are common. In fact, higher levels of cholesterol can help clear infections faster. In turn, this can help offset metabolic costs and divert more energy to brain growth and development.


When considering evolutionary hypotheses, it is critical to consider that most data come from Westernized populations, where environments and lifestyles are vastly different from those experienced throughout most of human evolution. This is the case when it comes to the association between APOE and Alzheimer’s. An important question to ask, then, is whether the association between APOE4 and Alzheimer’s is novel to Westernized environments. Put another way, do E4 carriers with more evolutionarily relevant lifestyles and environments have the same risk for developing Alzheimer’s as carriers in Westernized settings? This is an evolutionary mismatch perspective. This perspective emphasizes the importance of recent and rapid environmental changes and how environmental novelties may result in health patterns that stem from a disequilibrium between our own biology and the environmental novelties.

A test of these hypotheses:

Trumble et al. tested antagonistic pleiotropy and mismatch hypotheses of E4 by examining the relationship between APOE and Alzheimer’s in a hunter-forager population in Bolivia – the Tsimané. The Tsimané are modern hunter foragers. While their lifestyle is not a perfect representation of the evolutionary past, it is much closer than the lifestyles of populations represented in medical literature. In particular, Tsimané diets, exposure to parasites, and activity levels tend to Thus, the relationship between the E4 allele and cognitive decline among Tsimané can provide evolutionary insight into this enigmatic allele.

In this study, the researchers investigated the relationship between lifetime parasitic burden, APOE genotype, and cognitive decline. As previously mentioned, the E4 allele appears to buffer against parasites, a common ailment amongst the Tsimané. Their results would support the antagonistic pleiotropy hypothesis if all carriers of the E4 allele experienced positive benefits early in life, but greater cognitive decline later in life. Their results would support the mismatch hypothesis if the E4 allele was not associated with increased cognitive decline later in life, specifically for individuals who experienced higher rates of past infections.

Among individuals with high lifetime parasitic burdens, the E4 allele was associated with lower levels of cognitive decline. However, individuals with lower parasite burdens showed the same association between E4 and cognitive decline. These results support the mismatch hypothesis. This means that the strong association between the E4 allele and Alzheimer’s disease may have emerged recently in human history, perhaps since public health measures and modern medicine provided a means to lower parasitic burdens.

Principles this example illustrates:

Reproductive success - Antagonistic Pleiotropy:

Students can be asked to predict whether natural selection is likely to act on Alzheimer’s disease. Make sure students consider Alzheimer’s Disease decreases reproductive fitness given that its onset occurs later in life. This is an opportune time to have students consider inclusive fitness – that is, the fitness derived from helping direct relatives survive and reproduce. For example, even if Alzheimer’s Disease does not reduce the number of surviving children one has, could it reduce the number of surviving grandchildren one has? Students should also consider the survival benefits of the E4 allele, and their timing.

The instructor can then present the class with data about early health effects of the APOE4 allele in certain contexts. Students can analyze these results and determine whether there is any support of an early life benefit to the APOE4 allele. In doing so, students may want to explore the actual role of the APOE gene, the global frequency, and so on.


Students should appreciate that drawing evolutionary conclusions based on data from Westernized contexts is not ideal. While carrying the E4 allele is a major risk for developing Alzheimer’s in Westernized populations, this association may not be observed in all populations.

The data from the Tsimané help us understand one way that evolutionary mismatch can alter disease risk. In this case, the environment moderates the association between the E4 allele and Alzheimer’s risk. That is, when parasitic burdens are high, E4 is associated with less cognitive decline, but when parasitic burdens are low, it is associated with greater cognitive decline. Students can be asked to contrast how mismatch is operationalized in this case with other examples where mismatch more simply leads to new disease risks (e.g. increased risks of autoimmune diseases associated with hygienic environments). As moderating effects can be complex to understand, students may be tasked with drawing a graph to represent the relationship between parasite burden, the E4 allele, and cognitive decline.

There are other directions one might want students to take. For example, students may be asked how this research might inform potential therapies or preventative measures when it comes to Alzheimer’s Disease. Students may also be asked to brainstorm other examples of diseases where understanding may be advanced by study in non-Westernized contexts.

Additional resources:





Journal articles

  1. Oria, R. B., Patrick, P. D., Oriá, M. O. B., Lorntz, B., Thompson, M. R., Azevedo, O. G. R., ... & Lima, A. A. M. (2010). ApoE polymorphisms and diarrheal outcomes in Brazilian shanty town children. Brazilian Journal of Medical and Biological Research43(3), 249-256.

  2. Oria, R. B., Patrick, P. D., Zhang, H., Lorntz, B., de Castro Costa, C. M., Brito, G. A., ... & Guerrant, R. L. (2005). APOE4 protects the cognitive development in children with heavy diarrhea burdens in Northeast Brazil. Pediatric Research57(2), 310-316.

  3. 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 Journal31(4), 1508-1515.

Teaching materials:

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