APOE ε4 raises LDL and total cholesterol across lifestyles but other effects vary by environment

# What the study asked The authors tested whether the biological consequences of APOE genotypes depend on the environment. APOE ε4 raises Alzheimer's and cardiometabolic risk in industrialized settings, yet the allele remains common worldwide. One hypothesis is that its costs and benefits shift between non-industrial and industrialized environments. The study directly tests genotype-by-environment (GxE) interactions for cholesterol, immune, and reproductive traits.

# Who was studied

# Main findings

• Cholesterol: Across lifestyles and both populations, more APOE ε4 alleles correlated with higher total cholesterol and higher LDL cholesterol, and with lower HDL cholesterol. These genotype–cholesterol relationships were robust across environments.

• Innate immune biomarkers: The relationship between APOE genotype and innate immune markers depended on lifestyle for the Orang Asli. Specifically, genotype effects on systemic innate immune biomarkers varied between non-industrial and urban Orang Asli participants. Comparable lifestyle-dependent immune effects were not observed among the Turkana in this study.

• Reproduction: Having more APOE ε4 alleles showed an association with a longer reproductive lifespan in some analyses. That association was relatively weak, inconsistent across the two populations, and did not translate into higher overall reproductive output.

# What the results mean The results separate two types of APOE effects. The impact on cholesterol measures appears consistent regardless of lifestyle, suggesting a stable biological role for APOE in lipid biology across environments. Other APOE-linked traits, especially innate immune markers, are sensitive to local environment and vary by population. Reproductive effects exist but are small and inconsistent.

# Practical implications

• Risk assessment: APOE ε4 remains a useful indicator of higher LDL and total cholesterol independent of lifestyle context, so genotype-aware lipid monitoring may be relevant across populations.

• Evolutionary questions: The persistence of APOE ε4 cannot be explained by a single universal benefit in non-industrial contexts. Local environmental variation shapes whether APOE variants confer advantages or disadvantages.

# Data and transparency The authors provide code and reference repositories for analyses and lifestyle measures. Individual-level data are stored in a controlled-access repository consistent with data governance practices described by the study.

# Bottom line APOE ε4 reliably alters cholesterol across environments, but its effects on immune markers and reproduction depend on local lifestyle and population. The allele's persistence reflects complex, context-dependent tradeoffs rather than a single consistent advantage.