{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:39:31Z","timestamp":1792643971240,"version":"4.5.0"},"reference-count":57,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["PID2022\u2010137384OA\u2010I00"],"award-info":[{"award-number":["PID2022\u2010137384OA\u2010I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["RYC2021\u2010031713\u2010I"],"award-info":[{"award-number":["RYC2021\u2010031713\u2010I"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["EUR2024\u2010153539"],"award-info":[{"award-number":["EUR2024\u2010153539"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["CNS2024\u2010154632"],"award-info":[{"award-number":["CNS2024\u2010154632"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["PID2025\u2010173801OB\u2010I00"],"award-info":[{"award-number":["PID2025\u2010173801OB\u2010I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008054","name":"Fundaci\u00f3n Ram\u00f3n Areces","doi-asserted-by":"publisher","award":["CIVP22A7609"],"award-info":[{"award-number":["CIVP22A7609"]}],"id":[{"id":"10.13039\/100008054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Eur J of Neuroscience"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Alzheimer's disease (AD) is a complex neurodegenerative disorder in which most risk variants are noncoding and are enriched at gene regulatory regions, implicating epigenetic mechanisms as central mediators of disease pathogenesis. For most of the history of AD epigenetics research, bulk tissue analysis has dominated, obscuring the fundamentally distinct epigenomic landscapes of individual brain cell types and masking cell\u2010type\u2010specific contributions to disease. Advances in single\u2010cell and single\u2010nucleus sequencing, fluorescence\u2010activated nuclei sorting and multiplexed epigenomic platforms have transformed this landscape, enabling cell\u2010type\u2010resolved profiling of chromatin accessibility, DNA methylation, histone modifications and transcription across the major neuronal, glial and neurovascular populations of the human brain. Here, we review these advances, structured around the argument that cell\u2010type resolution is not a methodological refinement but a conceptual necessity. We describe the distinct epigenomic programs disrupted in neurons, microglia, astrocytes, oligodendrocytes and neurovascular cells in AD, highlighting how each cell type responds to pathology. We discuss the discovery of epigenomic erosion, the progressive loss of cell\u2010type\u2010specific epigenomic identity across virtually all brain cell populations as AD advances, as a unifying disease mechanism linking chromatin dysregulation to cognitive decline. Finally, we identify critical gaps in current knowledge, including the near\u2010complete absence of cell\u2010type\u2010resolved histone modification and DNA methylation data for most brain cell types, the underrepresentation of rare populations in standard preparations and the untapped potential of metabolic acylation marks as indicators of the epigenome\u2013metabolism interface in neurodegeneration.<\/jats:p>","DOI":"10.1111\/ejn.70683","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T02:07:21Z","timestamp":1789006041000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond Bulk: Cell\u2010Type\u2010Resolved Epigenomics as the Path Forward in Alzheimer's Disease Research"],"prefix":"10.1111","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4060-5365","authenticated-orcid":false,"given":"Luc\u00eda","family":"Ca\u00f1izares\u2010Moscato","sequence":"first","affiliation":[{"name":"Molecular Neuropathology Unit, Physiological and Pathological Processes Program Centro de Biolog\u00eda Molecular Severo Ochoa, CSIC\u2010UAM  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3111-9805","authenticated-orcid":false,"given":"Jose","family":"Ruiz\u2010Iglesias","sequence":"additional","affiliation":[{"name":"Molecular Neuropathology Unit, Physiological and Pathological Processes Program Centro de Biolog\u00eda Molecular Severo Ochoa, CSIC\u2010UAM  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7400-9679","authenticated-orcid":false,"given":"Javier","family":"Isoler\u2010Alcaraz","sequence":"additional","affiliation":[{"name":"Molecular Neuropathology Unit, Physiological and Pathological Processes Program Centro de Biolog\u00eda Molecular Severo Ochoa, CSIC\u2010UAM  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8629-2443","authenticated-orcid":false,"given":"Ernest","family":"Palomer","sequence":"additional","affiliation":[{"name":"Molecular Neuropathology Unit, Physiological and Pathological Processes Program Centro de Biolog\u00eda Molecular Severo Ochoa, CSIC\u2010UAM  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2016.59"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09662-z"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-022-01535-4"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-00869-9"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01024-z"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-022-01166-7"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau0730"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaf452"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03149-4"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abg7216"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-021-00416-x"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-018-0089-8"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01149-1"},{"key":"e_1_2_13_15_1","article-title":"Postmortem Changes in Brain Cell Structure: A Review","volume":"4","author":"Krassner M. M.","year":"2023","journal-title":"Free Neuropathol"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13153"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2025-0214"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10101-7"},{"key":"e_1_2_13_19_1","article-title":"A Comparative Atlas of Single\u2010Cell Chromatin Accessibility in the Human Brain","volume":"2023","author":"Li Y. E.","year":"2023","journal-title":"Science"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.06.031"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.09.035"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0253-7"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07606-7"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1195-2"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2021.04.004"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2015.09.001"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01961-x"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00894-z"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2025.1716805"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.crmeth.2025.101032"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0101-9"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-0696-0"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay0793"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21823-y"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2022.02.013"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2016.05.003"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-023-00424-y"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-024-01650-w"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-023-01066-9"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2022.948456"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2025.07.001"},{"key":"e_1_2_13_42_1","doi-asserted-by":"crossref","unstructured":"Ruiz\u2010Iglesias J. E. R.Bovolenta L.Canizares\u2010Moscato et\u00a0al.2026. \u201cEpiFlow: Multidimensional Single\u2010Cell Epigenetic Profiling by Spectral Flow Cytometry.\u201dbioRxiv 2026.03.16.711606.","DOI":"10.64898\/2026.03.16.711606"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.03.008"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32205-4"},{"key":"e_1_2_13_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-024-01791-4"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33394-7"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-024-00760-8"},{"key":"e_1_2_13_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-023-01334-3"},{"key":"e_1_2_13_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.08.037"},{"key":"e_1_2_13_50_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adf5357"},{"key":"e_1_2_13_51_1","unstructured":"Xie Y. L.Chang G.Zhong et\u00a0al.2026. \u201cSingle\u2010Cell Atlas of Transcription and Chromatin States Reveals Regulatory Programs in the Human Brain.\u201dbioRxiv. 2026.02.02.703166."},{"key":"e_1_2_13_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.08.040"},{"key":"e_1_2_13_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04369-3"},{"key":"e_1_2_13_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.12.027"},{"key":"e_1_2_13_55_1","first-page":"1","article-title":"HMGCS2\u2010Dependent \u03b2\u2010OHB\/H3K9bhb Ameliorates Synaptic Plasticity and Cognition in Alzheimer's Disease","volume":"2026","author":"Yu H.","year":"2026","journal-title":"Experimental & Molecular Medicine"},{"key":"e_1_2_13_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05795-1"},{"key":"e_1_2_13_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-022-00719-6"},{"key":"e_1_2_13_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2025.10.001"}],"updated-by":[{"DOI":"10.1111\/ejn.70696","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000}}],"container-title":["European Journal of Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ejn.70683","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/ejn.70683","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ejn.70683","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T03:54:48Z","timestamp":1792641288000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/ejn.70683"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":57,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1111\/ejn.70683"],"URL":"https:\/\/doi.org\/10.1111\/ejn.70683","archive":["Portico"],"relation":{},"ISSN":["0953-816X","1460-9568"],"issn-type":[{"value":"0953-816X","type":"print"},{"value":"1460-9568","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9]]},"assertion":[{"value":"2026-04-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70683"}}