The physiological effects of <scp> <i>APOE</i> </scp> genotype in healthy young/middle‐aged individuals

The apolipoprotein E ε4 (APOE4) allele is a risk factor for cardiovascular disease and for multiple neurodegenerative diseases, most notably Alzheimer's disease (AD). However, in healthy infants to adults, the encoded apolipoprotein E protein plays a role in many physiological functions, in both the periphery and in the brain, which can help us understand the biological contribution of this protein to disease. This review aims to describe the role of APOE genotype in a wide range of human physiological processes in healthy young/middle-aged individuals, including reproduction, cardiovascular health, inflammation, lipid metabolism, cognition, and brain structure/function, as well as how APOE genotype mediates the effects of external factors in these individuals, such as traumatic brain injury, pollution, lifestyle factors, and viral infections. The research covered in this review demonstrates that a person's APOE genotype affects a wide array of human physiological processes, from infancy to adulthood, with important differences observed in male and female study participants. We also discuss the evolutionary involvement and the 'antagonistic pleiotropy' hypothesis of APOE4. Understanding the biology and the mechanisms that are affected by APOE genotype in healthy young/middle-aged individuals is vital for understanding how this common allele contributes to the development of cardiovascular and neurodegenerative diseases, and how these diseases can be prevented.