APOE4 and INPP5D converge on membrane mechanics to regulate endocytosis in human astrocytes.

Disrupted endocytosis is an early feature of Alzheimer's disease (AD), but how genetic risk factors functionally impact this pathway remains unclear. Using isogenic human iPSC-derived astrocytes, we show that the AD risk variant, APOE4, impairs clathrin-mediated membrane curvature, clathrin-mediated endocytosis, and alters plasma membrane lipid saturation and tension. Compared to APOE3 astrocytes, APOE4 cells display an accumulation of flat clathrin structures, reduced maturation of clathrin-coated pits, decreased early endosomes, and reduced endocytic uptake. We then identify the AD risk gene INPP5D as a modifier that restores early endocytosis in APOE4 astrocytes by promoting clathrin curvature and maturation through a mechanism distinct from membrane tension regulation. Beyond effects on trafficking, INPP5D overexpression also reduces lipid droplet accumulation and attenuates inflammatory signaling, linking membrane dynamics to disease-associated astrocytic phenotypes. Together, these findings establish altered membrane mechanics as a proximal consequence of the APOE4 variant and identify endocytosis as a common node linking AD risk genes.