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Using isogenic human iPSC-derived astrocytes, we show that the AD risk variant,\n                  <jats:italic>APOE4,<\/jats:italic>\n                  impairs clathrin-mediated membrane curvature, clathrin-mediated endocytosis, and alters plasma membrane lipid saturation and tension. Compared to\n                  <jats:italic>APOE3<\/jats:italic>\n                  astrocytes,\n                  <jats:italic>APOE4<\/jats:italic>\n                  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\n                  <jats:italic>INPP5D<\/jats:italic>\n                  as a modifier that restores early endocytosis in\n                  <jats:italic>APOE4<\/jats:italic>\n                  astrocytes by promoting clathrin curvature and maturation through a mechanism distinct from membrane tension regulation. Beyond effects on trafficking,\n                  <jats:italic>INPP5D<\/jats:italic>\n                  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\n                  <jats:italic>APOE4<\/jats:italic>\n                  variant and identify endocytosis as a common node linking AD risk genes.\n                <\/jats:p>","DOI":"10.64898\/2026.05.22.726347","type":"posted-content","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T18:15:22Z","timestamp":1779732922000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>APOE4<\/i>\n                  and\n                  <i>INPP5D<\/i>\n                  converge on membrane mechanics to regulate endocytosis in human astrocytes"],"prefix":"10.64898","author":[{"given":"Artur S.","family":"Gevorgyan","sequence":"first","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lila M.","family":"Gordon","sequence":"additional","affiliation":[{"name":"Biochemistry and Biophysics Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4656-4840","authenticated-orcid":false,"given":"Christian A.","family":"Combs","sequence":"additional","affiliation":[{"name":"Light Microscopy Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0115-6077","authenticated-orcid":false,"given":"Adrian","family":"Lita","sequence":"additional","affiliation":[{"name":"Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1671-8792","authenticated-orcid":false,"given":"Linda G.","family":"Yang","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8804-8970","authenticated-orcid":false,"given":"Carla","family":"Cun\u00ed-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9150-9579","authenticated-orcid":false,"given":"Jessica T.","family":"Root","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7016-9587","authenticated-orcid":false,"given":"Mioara","family":"Larion","sequence":"additional","affiliation":[{"name":"Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5355-9535","authenticated-orcid":false,"given":"Justin W.","family":"Taraska","sequence":"additional","affiliation":[{"name":"Biochemistry and Biophysics Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9328-4959","authenticated-orcid":false,"given":"Priyanka S.","family":"Narayan","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD USA"},{"name":"National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD USA"},{"name":"Center for Alzheimer\u2019s and Related Dementias (CARD), National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026052715103310000_2026.05.22.726347v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2013.11.006"},{"key":"2026052715103310000_2026.05.22.726347v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2004.09.018"},{"key":"2026052715103310000_2026.05.22.726347v1.3","doi-asserted-by":"crossref","unstructured":"Bellenguez, C. , K\u00fc\u00e7\u00fckali, F. , Jansen, I.E. , Kleineidam, L. , Moreno-Grau, S. , Amin, N. , Naj, A.C. , Campos-Martin, R. , Grenier-Boley, B. , Andrade, V. , et al. 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