In post-industrial settings, apolipoprotein E4 (APOE4) is associated with increased cardiovascular and neurological disease risk. However, the majority of human evolutionary history occurred in environments with higher pathogenic diversity and low cardiovascular risk. We hypothesize that in high-pathogen and energy-limited contexts, the APOE4 allele confers benefits by reducing innate inflammation when uninfected, while maintaining higher lipid levels that buffer costs of immune activation during infection. Among Tsimane forager-farmers of Bolivia (N = 1266, 50% female), APOE4 is associated with 30% lower C-reactive protein, and higher total cholesterol and oxidized LDL. Blood lipids were either not associated, or negatively associated with inflammatory biomarkers, except for associations of oxidized LDL and inflammation which were limited to obese adults. Further, APOE4 carriers maintain higher levels of total and LDL cholesterol at low body mass indices (BMIs). These results suggest that the relationship between APOE4 and lipids may be beneficial for pathogen-driven immune responses and unlikely to increase cardiovascular risk in an active subsistence population.
Keywords: APOE; Alzheimer's disease; cardiovascular disease; cholesterol; dementia; evolutionary biology; human; inflammation; medicine.
Genes contain the instructions needed for a cell to make molecules called proteins, which perform various roles in the body. Different variants of a gene can affect how the protein works, and in some cases, can increase a person’s risk to develop certain diseases. For example, people who carry a version of the apolipoprotein E gene called APOE4 have a greater risk of developing Alzheimer’s disease or heart disease. Individuals with two copies of this genetic variant have a 45% higher risk of heart disease and 12 times higher risk of Alzheimer’s disease. Studies in industrialized countries suggest this increased risk may be the result of higher cholesterol and inflammation in people with APOE4. But if APOE4 is harmful, why does it continue to be so common worldwide? One potential explanation is that APOE4, which has been around since before modern humans, may be beneficial in some contexts. Cholesterol is essential for many vital tasks in the body. In physically demanding environments where parasitic infections are common – conditions similar to those experienced by early humans – APOE4 might be beneficial. Under those circumstances, having more cholesterol might help fuel metabolic activities, fight infections, or reduce inflammation caused by infections. Garcia et al. investigated the link between the APOE4 genetic variant, cholesterol and inflammation in 1,266 Indigenous Tsimane people from 80 villages in Bolivia. Tsimane people live an active lifestyle foraging and farming for food. Parasite infections are a common problem in their communities, but obesity rates are very low. Garcia et al. found that Tsimane people with at least one copy of the APOE4 have lower levels of inflammation and higher levels of cholesterol than those who have two copies of the APOE3 version of the gene. Very lean people with APOE4 had especially high levels of the so called “bad” low density lipoprotein (LDL) cholesterol compared to people with APOE3 only. However, in this situation, storing a little extra cholesterol may not be so bad. The findings contradict other studies that have linked obesity to higher LDL levels and APOE4 to higher levels of inflammation. For the majority of human history, humans lived in more physically strenuous and calorically restrictive environments, with less access to clean water. Garcia et al. suggest that the harmful effects of APOE4 seen in studies in more industrialized societies – where people tend to be more sedentary and have less exposure to pathogens – may reflect a mismatch between a person’s environment and their genes. More studies that capture the diversity of environmental conditions under which people live will help clarify the role of APOE4 health and disease.
© 2021, Garcia et al.