APOE and Alzheimer disease: There is also evidence that APOE4 reduces weight and fat mass (Ando et al., 2022), alters the relationship between plasma metabolites and AD biomarkers (Arnold et al., 2020), and reduces resting energy expenditure (Farmer et al., 2021) in a sex-dependent manner, supporting a role for APOE in modulating whole-body metabolism and sex as a modifying factor.