APOE genotypes differentially remodel the astrocytic lipid droplet-associated proteome to shape lipid droplet dynamics.

The lipids and proteins that comprise lipid droplets regulate several cellular functions including lipid storage, stress responses, and inflammation. Glial lipid droplets have been implicated in the pathogenesis and progression of Alzheimer's disease (AD), yet the mechanisms linking genetic risk to lipid droplet biology remain unclear. Here we examined how APOE, the strongest genetic modulator of late-onset AD, impacts lipid droplet composition and dynamics. We defined the lipid droplet-associated proteome and lipidome in human induced pluripotent stem cell-derived astrocytes harboring the three common APOE genotypes: APOE2 (protective), APOE3 (neutral), and APOE4 (risk). Each APOE variant displays distinct lipid droplet-associated proteins and lipids. These molecular changes yield differences in lipophagy; lipid droplets in APOE2 astrocytes undergo autophagic turnover, whereas those in APOE4 astrocytes are resistant to degradation. These findings suggest that impaired lipid droplet clearance, rather than accumulation, distinguishes APOE4-associated AD risk, and may present a new metabolic node for modulating risk.