{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T12:12:10Z","timestamp":1783771930607,"version":"3.55.0"},"posted":{"date-parts":[[2026,6,3]]},"group-title":"Neuroscience","reference-count":86,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"the FTF Foundation"},{"name":"Massachusetts Alzheimer Disease Research Center","award":["NIH\/NIA P30AG062421"],"award-info":[{"award-number":["NIH\/NIA P30AG062421"]}]},{"name":"Dreyfoos Fund for Alzheimer Research"},{"name":"APOE Biology in Alzheimer\u2019s Grant","award":["ABA-25-1373553"],"award-info":[{"award-number":["ABA-25-1373553"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Apolipoprotein E (\n                  <jats:italic>APOE<\/jats:italic>\n                  ) associates with amyloid plaques (A\u03b2) in Alzheimer disease (AD). The \u03b54 allele of apolipoprotein E (\n                  <jats:italic>APOE<\/jats:italic>\n                  \u03b54) is the strongest genetic risk factor for sporadic AD and exacerbates A\u03b2 plaque burden relative to\n                  <jats:italic>APOE<\/jats:italic>\n                  \u03b53 and\n                  <jats:italic>APOE<\/jats:italic>\n                  \u03b52. The majority of ApoE associates with multiple lipid classes to form lipoproteins both in the brain and the periphery. However, the lipidation status of A\u03b2 plaque-associated ApoE is not yet fully defined. Here, we use fluorescence lifetime imaging microscopy coupled with F\u00f6rster resonance energy transfer (FLIM-FRET) to determine the lipidation status of ApoE in plaques, as well as the nanoscale spatial proximity of ApoE and A\u03b2 to anionic lipids and cholesterol within human AD brain tissue. We demonstrate that lipids are in close nanoscale proximity to ApoE and A\u03b2 within A\u03b2 plaques. Our results reveal that lipidated ApoE complexes enriched in anionic lipids and cholesterol are core constituents of AD plaques\n                  <jats:italic>in-situ<\/jats:italic>\n                  . We propose a pathological mechanism in which the surface presentation of anionic lipids on ApoE lipoproteins facilitates initial interaction with and subsequent aggregation of A\u03b2.\n                <\/jats:p>","DOI":"10.64898\/2026.05.30.729004","type":"posted-content","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T13:20:14Z","timestamp":1780492814000},"source":"Crossref","is-referenced-by-count":0,"title":["Lipidated ApoE is found in nanoscale proximity to A\u03b2 aggregates in human Alzheimer brains"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3735-1093","authenticated-orcid":false,"given":"Desmond","family":"Owusu Kwarteng","sequence":"first","affiliation":[{"name":"Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemary J.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuneo","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Altig","sequence":"additional","affiliation":[{"name":"Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA"},{"name":"Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Massachusetts Alzheimer\u2019s Disease Research Center (MADRC), Charlestown, MA 02129, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Melloni","sequence":"additional","affiliation":[{"name":"Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA"},{"name":"Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Massachusetts Alzheimer\u2019s Disease Research Center (MADRC), Charlestown, MA 02129, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek","family":"Oakley","sequence":"additional","affiliation":[{"name":"Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA"},{"name":"Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Massachusetts Alzheimer\u2019s Disease Research Center (MADRC), Charlestown, MA 02129, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0899-7530","authenticated-orcid":false,"given":"Alberto","family":"Serrano-Pozo","sequence":"additional","affiliation":[{"name":"Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Massachusetts Alzheimer\u2019s Disease Research Center (MADRC), Charlestown, MA 02129, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1970-2462","authenticated-orcid":false,"given":"Masato","family":"Maesako","sequence":"additional","affiliation":[{"name":"Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7959-9401","authenticated-orcid":false,"given":"Bradley T.","family":"Hyman","sequence":"additional","affiliation":[{"name":"Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Massachusetts Alzheimer\u2019s Disease Research Center (MADRC), Charlestown, MA 02129, USA"},{"name":"Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026071104201415000_2026.05.30.729004v1.1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.12.4245"},{"key":"2026071104201415000_2026.05.30.729004v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.09.001"},{"key":"2026071104201415000_2026.05.30.729004v1.3","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-022-00574-4"},{"key":"2026071104201415000_2026.05.30.729004v1.4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.5.1977"},{"key":"2026071104201415000_2026.05.30.729004v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/ng0694-180"},{"key":"2026071104201415000_2026.05.30.729004v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0228-7"},{"key":"2026071104201415000_2026.05.30.729004v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/ng1197-263"},{"key":"2026071104201415000_2026.05.30.729004v1.8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.26.15233"},{"key":"2026071104201415000_2026.05.30.729004v1.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.050004797"},{"key":"2026071104201415000_2026.05.30.729004v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.01.045"},{"key":"2026071104201415000_2026.05.30.729004v1.11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1207022109"},{"key":"2026071104201415000_2026.05.30.729004v1.12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.17.8098"},{"key":"2026071104201415000_2026.05.30.729004v1.13","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abd7522"},{"key":"2026071104201415000_2026.05.30.729004v1.14","doi-asserted-by":"publisher","DOI":"10.1172\/JCI96429"},{"key":"2026071104201415000_2026.05.30.729004v1.15","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202212636"},{"key":"2026071104201415000_2026.05.30.729004v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.10.027"},{"key":"2026071104201415000_2026.05.30.729004v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110435"},{"key":"2026071104201415000_2026.05.30.729004v1.18","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.4c05636"},{"key":"2026071104201415000_2026.05.30.729004v1.19","doi-asserted-by":"publisher","DOI":"10.1023\/A:1007509608440"},{"key":"2026071104201415000_2026.05.30.729004v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23762-0"},{"key":"2026071104201415000_2026.05.30.729004v1.21","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.42.30001"},{"key":"2026071104201415000_2026.05.30.729004v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-49028-z"},{"key":"2026071104201415000_2026.05.30.729004v1.23","doi-asserted-by":"publisher","DOI":"10.1101\/2025.11.19.685371"},{"key":"2026071104201415000_2026.05.30.729004v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.09.014"},{"key":"2026071104201415000_2026.05.30.729004v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2011.03.005"},{"key":"2026071104201415000_2026.05.30.729004v1.26","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-011-0910-3"},{"key":"2026071104201415000_2026.05.30.729004v1.27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0014586"},{"key":"2026071104201415000_2026.05.30.729004v1.28","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-012-1065-6"},{"key":"2026071104201415000_2026.05.30.729004v1.29","doi-asserted-by":"publisher","DOI":"10.1117\/1.1584444"},{"key":"2026071104201415000_2026.05.30.729004v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-025-01749-z"},{"key":"2026071104201415000_2026.05.30.729004v1.31","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201505298"},{"key":"2026071104201415000_2026.05.30.729004v1.32","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.116.307023"},{"key":"2026071104201415000_2026.05.30.729004v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2021.183692"},{"key":"2026071104201415000_2026.05.30.729004v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpc.2023.107005"},{"key":"2026071104201415000_2026.05.30.729004v1.35","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.1997.6710"},{"key":"2026071104201415000_2026.05.30.729004v1.36","doi-asserted-by":"publisher","DOI":"10.1002\/ca.980080612"},{"key":"2026071104201415000_2026.05.30.729004v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07185-7"},{"key":"2026071104201415000_2026.05.30.729004v1.38","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202305003"},{"key":"2026071104201415000_2026.05.30.729004v1.39","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M207712200"},{"key":"2026071104201415000_2026.05.30.729004v1.40","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002201"},{"key":"2026071104201415000_2026.05.30.729004v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2012.09.017"},{"key":"2026071104201415000_2026.05.30.729004v1.42","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/60.8.778"},{"key":"2026071104201415000_2026.05.30.729004v1.43","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M001859"},{"key":"2026071104201415000_2026.05.30.729004v1.44","doi-asserted-by":"publisher","DOI":"10.1039\/c3an00295k"},{"key":"2026071104201415000_2026.05.30.729004v1.45","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2019.00212"},{"key":"2026071104201415000_2026.05.30.729004v1.46","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.308856"},{"key":"2026071104201415000_2026.05.30.729004v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3710"},{"key":"2026071104201415000_2026.05.30.729004v1.48","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2010.07017.x"},{"key":"2026071104201415000_2026.05.30.729004v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/J.JLR.2021.100084"},{"key":"2026071104201415000_2026.05.30.729004v1.50","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00028.2012"},{"key":"2026071104201415000_2026.05.30.729004v1.51","doi-asserted-by":"publisher","DOI":"10.1039\/c3ay41308j"},{"key":"2026071104201415000_2026.05.30.729004v1.52","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2016.081"},{"key":"2026071104201415000_2026.05.30.729004v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(93)90070-8"},{"key":"2026071104201415000_2026.05.30.729004v1.54","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2760(94)00232-N"},{"key":"2026071104201415000_2026.05.30.729004v1.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2023.12.018"},{"key":"2026071104201415000_2026.05.30.729004v1.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemphyslip.2013.11.004"},{"key":"2026071104201415000_2026.05.30.729004v1.57","doi-asserted-by":"publisher","DOI":"10.1117\/1.2837169"},{"key":"2026071104201415000_2026.05.30.729004v1.58","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2019.04.010"},{"key":"2026071104201415000_2026.05.30.729004v1.59","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2022.12.003"},{"key":"2026071104201415000_2026.05.30.729004v1.60","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1220484110"},{"key":"2026071104201415000_2026.05.30.729004v1.61","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-9-2"},{"key":"2026071104201415000_2026.05.30.729004v1.62","doi-asserted-by":"publisher","DOI":"10.1021\/bi5008172"},{"key":"2026071104201415000_2026.05.30.729004v1.63","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1542-12.2012"},{"key":"2026071104201415000_2026.05.30.729004v1.64","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.001388"},{"key":"2026071104201415000_2026.05.30.729004v1.65","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-021-00851-3"},{"key":"2026071104201415000_2026.05.30.729004v1.66","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M407963200"},{"key":"2026071104201415000_2026.05.30.729004v1.67","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-009-8092-x"},{"key":"2026071104201415000_2026.05.30.729004v1.68","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2022.101894"},{"key":"2026071104201415000_2026.05.30.729004v1.69","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1987.tb05619.x"},{"key":"2026071104201415000_2026.05.30.729004v1.70","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2100"},{"key":"2026071104201415000_2026.05.30.729004v1.71","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0604954103"},{"key":"2026071104201415000_2026.05.30.729004v1.72","doi-asserted-by":"publisher","DOI":"10.1039\/C7SC00215G"},{"key":"2026071104201415000_2026.05.30.729004v1.73","doi-asserted-by":"publisher","DOI":"10.1021\/jp905889z"},{"key":"2026071104201415000_2026.05.30.729004v1.74","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.1c00140"},{"key":"2026071104201415000_2026.05.30.729004v1.75","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M609737200"},{"key":"2026071104201415000_2026.05.30.729004v1.76","doi-asserted-by":"publisher","DOI":"10.1021\/bi702097s"},{"key":"2026071104201415000_2026.05.30.729004v1.77","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2004.11.005"},{"key":"2026071104201415000_2026.05.30.729004v1.78","doi-asserted-by":"crossref","unstructured":"Ladutl MJ , Faldutonll MT , Manellill AM , Reardons CA , Getz8 GS, Frail7 DE. Isoform-Specific Binding of Apolipoprotein E to p-Amyloid*. Vol 269. 1994.","DOI":"10.1016\/S0021-9258(17)31529-6"},{"key":"2026071104201415000_2026.05.30.729004v1.79","doi-asserted-by":"publisher","DOI":"10.1038\/srep13489"},{"key":"2026071104201415000_2026.05.30.729004v1.80","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1605104113"},{"key":"2026071104201415000_2026.05.30.729004v1.81","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.13428"},{"key":"2026071104201415000_2026.05.30.729004v1.82","doi-asserted-by":"publisher","DOI":"10.1042\/bj3480359"},{"key":"2026071104201415000_2026.05.30.729004v1.83","doi-asserted-by":"publisher","DOI":"10.1021\/bi971843e"},{"key":"2026071104201415000_2026.05.30.729004v1.84","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25126401"},{"key":"2026071104201415000_2026.05.30.729004v1.85","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-43822-x"},{"key":"2026071104201415000_2026.05.30.729004v1.86","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16738"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.30.729004","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T11:20:23Z","timestamp":1783768823000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.05.30.729004"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,3]]},"references-count":86,"URL":"https:\/\/doi.org\/10.64898\/2026.05.30.729004","relation":{},"subject":[],"published":{"date-parts":[[2026,6,3]]},"subtype":"preprint"}}