PICALM is a cytoplasmic adapter protein essential for clathrin-mediated endocytosis, functioning primarily by recruiting AP-2 and attaching clathrin triskelions to the plasma membrane to assemble clathrin-coated vesicles 123. Beyond vesicle assembly, PICALM regulates clathrin-coated vesicle size and maturation by directly sensing and driving membrane curvature 4. PICALM mediates endocytosis of small R-SNAREs (including VAMP2-8) between plasma membranes and endosomes, which is required for autophagosome formation and maturation 5678. This autophagy function enables PICALM to modulate turnover of substrates such as tau and amyloid precursor protein 98. PICALM represents one of the most significant genetic susceptibility loci for late-onset Alzheimer's disease after APOE and BIN1 1011. A pathogenic PICALM allele (rs10792832) reduces transcription factor binding and expression, impairing microglial phagocytosis of amyloid-β and myelin debris while promoting lipid droplet accumulation 12. PICALM modulates AD risk through multiple mechanisms including Aβ production, transportation, clearance, and tau pathology 13, with microglial phagocytosis deficits representing a key pathogenic mechanism 14. Additionally, PICALM influences ROS-induced neuroprotective lipid droplet formation in glia 15.