AP4E1 encodes the epsilon-1 subunit of adaptor protein complex 4 (AP-4), a non-clathrin-associated vesicle coat component that mediates protein trafficking from the trans-Golgi network (TGN) to endosomal-lysosomal compartments and controls cargo sorting to basolateral membranes in epithelial cells and somatodendritic regions in neurons 1. AP-4 recognizes tyrosine-based sorting signals and other cargo determinants to coordinate selective protein transport 1. Bi-allelic AP4E1 mutations cause spastic paraplegia 51 (SPG51), characterized by early-onset developmental delay, intellectual disability, spastic diplegia progressing to tetraplegia, postnatal microcephaly (83%), epilepsy (66%), and white-matter abnormalities 1. The C-terminal region of AP4E1 is critical for maintaining AP-4 complex integrity 2. Notably, AP-4 deficiency also increases susceptibility to mycobacterial infections, suggesting roles in immune function 2. Genome-wide association studies identify AP4E1 variants associated with Alzheimer's disease genetics 3, and single-cell analysis highlights AP4E1 as a key regulator in type 2 diabetes-migraine comorbidity, implicating vesicle transport and lipid metabolism pathways 4. Knockout mouse studies suggest potential roles in ciliary biology 5. Monoallelic AP4E1 mutations are also linked to familial persistent stuttering 6.