APOE and Alzheimer disease: In particular, the APOE ε4 allele (APOE4) has been shown to increase the risk of AD through multiple pathways, such as reduced β-amyloid clearance, increased microglial proinflammatory activation, disrupted glucose and lipid metabolism, synaptic dysfunction, and increased blood–brain barrier (BBB) permeability (Yamazaki et al., 2019; Serrano-Pozo et al., 2021).