APOE4is associated with elevated blood lipids and lower levels of innate immune biomarkers in a tropical Amerindian subsistence population

In post-industrial settings,APOE4is 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, theAPOE4allele confers benefits by reducing baseline 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),APOE4is 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,APOE4carriers maintain higher levels of total and LDL cholesterol at low BMIs. These results suggest the relationship betweenAPOE4and lipids is likely beneficial for pathogen-driven immune responses, and unlikely to increase cardiovascular risk in an active subsistence population.