{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T21:22:32Z","timestamp":1791148952571,"version":"4.1.0"},"reference-count":79,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":37,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/100000049","name":"U.S. Department of Health & Human Services | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["R01 AG065541"],"award-info":[{"award-number":["R01 AG065541"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"U.S. Department of Health & Human Services | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["R01 AG071465"],"award-info":[{"award-number":["R01 AG071465"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-21-1-0642"],"award-info":[{"award-number":["W81XWH-21-1-0642"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001167","name":"Larry L. Hillblom Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001167","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Bruce Ford & Anne Smith Bundy Foundation"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Biol"],"DOI":"10.1038\/s42003-026-09759-9","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T03:32:31Z","timestamp":1772508751000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["RNA isoform diversity, splicing variants and switching in single cells of the Alzheimer\u2019s disease brain"],"prefix":"10.1038","volume":"9","author":[{"given":"Anis","family":"Shahnaee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1239-4612","authenticated-orcid":false,"given":"Christine S.","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6779-2546","authenticated-orcid":false,"given":"Tony","family":"Ngo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carter R.","family":"Palmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3532-5819","authenticated-orcid":false,"given":"Derya","family":"Ziomek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7308-1601","authenticated-orcid":false,"given":"Valerie P.","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3673-0429","authenticated-orcid":false,"given":"Natalia L.","family":"Jimenez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3964-0921","authenticated-orcid":false,"given":"Jerold","family":"Chun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"9759_CR1","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/s41392-024-01911-3","volume":"9","author":"J Zhang","year":"2024","unstructured":"Zhang, J. et al. Recent advances in Alzheimer\u2019s disease: mechanisms, clinical trials and new drug development strategies. Signal Transduct. Target Ther. 9, 211 (2024).","journal-title":"Signal Transduct. Target Ther."},{"key":"9759_CR2","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1002\/alz.12694","volume":"19","author":"A Gustavsson","year":"2023","unstructured":"Gustavsson, A. et al. Global estimates on the number of persons across the Alzheimer\u2019s disease continuum. Alzheimers Dement. 19, 658\u2013670 (2023).","journal-title":"Alzheimers Dement."},{"key":"9759_CR3","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.semcdb.2022.05.028","volume":"139","author":"J Griffiths","year":"2023","unstructured":"Griffiths, J. & Grant, S. G. N. Synapse pathology in Alzheimer\u2019s disease. Semin. Cell Dev. Biol. 139, 13\u201323 (2023).","journal-title":"Semin. Cell Dev. Biol."},{"key":"9759_CR4","doi-asserted-by":"publisher","first-page":"a006189","DOI":"10.1101\/cshperspect.a006189","volume":"1","author":"A Serrano-Pozo","year":"2011","unstructured":"Serrano-Pozo, A., Frosch, M. P., Masliah, E. & Hyman, B. T. Neuropathological alterations in Alzheimer\u2019s disease. Cold Spring Harb. Perspect. Med. 1, a006189 (2011).","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"9759_CR5","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.cell.2022.12.032","volume":"186","author":"DM Wilson","year":"2023","unstructured":"Wilson, D. M. et al. Hallmarks of neurodegenerative diseases. Cell 186, 693\u2013714 (2023).","journal-title":"Cell"},{"key":"9759_CR6","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22399-3","volume":"12","author":"AM Crist","year":"2021","unstructured":"Crist, A. M. et al. Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer\u2019s disease. Nat. Commun. 12, 2311 (2021).","journal-title":"Nat. Commun."},{"key":"9759_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-83872-z","volume":"11","author":"B Guennewig","year":"2021","unstructured":"Guennewig, B. et al. Defining early changes in Alzheimer\u2019s disease from RNA sequencing of brain regions differentially affected by pathology. Sci. Rep. 11, 4865 (2021).","journal-title":"Sci. Rep."},{"key":"9759_CR8","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70025","volume":"21","author":"B Aguzzoli Heberle","year":"2025","unstructured":"Aguzzoli Heberle, B. et al. Systematic review and meta-analysis of bulk RNAseq studies in human Alzheimer\u2019s disease brain tissue. Alzheimer's Dement. 21, e70025 (2025).","journal-title":"Alzheimer's Dement."},{"key":"9759_CR9","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1126\/science.aaf1204","volume":"352","author":"BB Lake","year":"2016","unstructured":"Lake, B. B. et al. Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain. Science 352, 1586\u20131590 (2016).","journal-title":"Science"},{"key":"9759_CR10","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/nbt.4038","volume":"36","author":"BB Lake","year":"2018","unstructured":"Lake, B. B. et al. Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain. Nat. Biotechnol. 36, 70\u201380 (2018).","journal-title":"Nat. Biotechnol."},{"key":"9759_CR11","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1038\/s41586-024-07606-7","volume":"632","author":"H Mathys","year":"2024","unstructured":"Mathys, H. et al. Single-cell multiregion dissection of Alzheimer\u2019s disease. Nature 632, 858\u2013868 (2024).","journal-title":"Nature"},{"key":"9759_CR12","doi-asserted-by":"publisher","first-page":"4365","DOI":"10.1016\/j.cell.2023.08.039","volume":"186","author":"H Mathys","year":"2023","unstructured":"Mathys, H. et al. Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer\u2019s disease pathology. Cell 186, 4365\u20134385.e4327 (2023).","journal-title":"Cell"},{"key":"9759_CR13","doi-asserted-by":"publisher","first-page":"4438","DOI":"10.1016\/j.cell.2023.08.005","volume":"186","author":"V Gazestani","year":"2023","unstructured":"Gazestani, V. et al. Early Alzheimer\u2019s disease pathology in human cortex involves transient cell states. Cell 186, 4438\u20134453.e4423 (2023).","journal-title":"Cell"},{"key":"9759_CR14","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-022-01136-5","volume":"14","author":"T Luquez","year":"2022","unstructured":"Luquez, T. et al. Cell type-specific changes identified by single-cell transcriptomics in Alzheimer\u2019s disease. Genome Med. 14, 136 (2022).","journal-title":"Genome Med."},{"key":"9759_CR15","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1038\/s41392-024-01734-2","volume":"9","author":"Y Tao","year":"2024","unstructured":"Tao, Y., Zhang, Q., Wang, H., Yang, X. & Mu, H. Alternative splicing and related RNA binding proteins in human health and disease. Signal Transduct. Target. Ther. 9, 26 (2024).","journal-title":"Signal Transduct. Target. Ther."},{"key":"9759_CR16","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.tree.2021.11.010","volume":"37","author":"JP Verta","year":"2022","unstructured":"Verta, J. P. & Jacobs, A. The role of alternative splicing in adaptation and evolution. Trends Ecol. Evol. 37, 299\u2013308 (2022).","journal-title":"Trends Ecol. Evol."},{"key":"9759_CR17","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1016\/j.cell.2004.08.021","volume":"118","author":"WM Wojtowicz","year":"2004","unstructured":"Wojtowicz, W. M., Flanagan, J. J., Millard, S. S., Zipursky, S. L. & Clemens, J. C. Alternative splicing of Drosophila Dscam generates axon guidance receptors that exhibit isoform-specific homophilic binding. Cell 118, 619\u2013633 (2004).","journal-title":"Cell"},{"key":"9759_CR18","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.cell.2005.07.028","volume":"123","author":"BR Graveley","year":"2005","unstructured":"Graveley, B. R. Mutually exclusive splicing of the insect Dscam pre-mRNA directed by competing intronic RNA secondary structures. Cell 123, 65\u201373 (2005).","journal-title":"Cell"},{"key":"9759_CR19","doi-asserted-by":"publisher","first-page":"1601","DOI":"10.1016\/j.cell.2011.11.028","volume":"147","author":"T Iijima","year":"2011","unstructured":"Iijima, T. et al. SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1. Cell 147, 1601\u20131614 (2011).","journal-title":"Cell"},{"key":"9759_CR20","doi-asserted-by":"publisher","first-page":"E1291","DOI":"10.1073\/pnas.1403244111","volume":"111","author":"B Treutlein","year":"2014","unstructured":"Treutlein, B., Gokce, O., Quake, S. R. & Sudhof, T. C. Cartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing. Proc. Natl. Acad. Sci. USA 111, E1291\u2013E1299 (2014).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"9759_CR21","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1016\/j.neuron.2014.09.011","volume":"84","author":"D Schreiner","year":"2014","unstructured":"Schreiner, D. et al. Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins. Neuron 84, 386\u2013398 (2014).","journal-title":"Neuron"},{"key":"9759_CR22","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s40035-021-00240-7","volume":"10","author":"D Li","year":"2021","unstructured":"Li, D., McIntosh, C. S., Mastaglia, F. L., Wilton, S. D. & Aung-Htut, M. T. Neurodegenerative diseases: a hotbed for splicing defects and the potential therapies. Transl. Neurodegener. 10, 16 (2021).","journal-title":"Transl. Neurodegener."},{"key":"9759_CR23","doi-asserted-by":"publisher","first-page":"1573","DOI":"10.1016\/j.ajhg.2024.06.001","volume":"111","author":"JL Hervoso","year":"2024","unstructured":"Hervoso, J. L. et al. Splicing-specific transcriptome-wide association uncovers genetic mechanisms for schizophrenia. Am. J. Hum. Genet. 111, 1573\u20131587 (2024).","journal-title":"Am. J. Hum. Genet."},{"key":"9759_CR24","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2023.102529","volume":"231","author":"V Verdile","year":"2023","unstructured":"Verdile, V. et al. Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis. Prog. Neurobiol. 231, 102529 (2023).","journal-title":"Prog. Neurobiol."},{"key":"9759_CR25","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1038\/s41586-018-0718-6","volume":"563","author":"MH Lee","year":"2018","unstructured":"Lee, M. H. et al. Somatic APP gene recombination in Alzheimer\u2019s disease and normal neurons. Nature 563, 639\u2013645 (2018).","journal-title":"Nature"},{"key":"9759_CR26","doi-asserted-by":"publisher","first-page":"E29","DOI":"10.1038\/s41586-020-2523-2","volume":"584","author":"MH Lee","year":"2020","unstructured":"Lee, M. H. et al. Reply to: APP gene copy number changes reflect exogenous contamination. Nature 584, E29\u2013E33 (2020).","journal-title":"Nature"},{"key":"9759_CR27","doi-asserted-by":"crossref","unstructured":"Nicodemus, J. et al. Sequence diversity and encoded enzymatic differences of monocistronic L1 ORF2 mRNA variants in the aged normal and Alzheimer\u2019s disease brain. J. Neurosci. (2025).","DOI":"10.1523\/JNEUROSCI.2298-24.2025"},{"key":"9759_CR28","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-48993-7","volume":"13","author":"S Mitsunaga","year":"2023","unstructured":"Mitsunaga, S. et al. Detection of APP gene recombinant in human blood plasma. Sci. Rep. 13, 21703 (2023).","journal-title":"Sci. Rep."},{"key":"9759_CR29","doi-asserted-by":"crossref","unstructured":"Palmer, C. R., Liu, C. S., Romanow, W. J., Lee, M. H. & Chun, J. Altered cell and RNA isoform diversity in aging Down syndrome brains. Proc. Natl. Acad. Sci. USA 118, (2021).","DOI":"10.1073\/pnas.2114326118"},{"key":"9759_CR30","doi-asserted-by":"publisher","first-page":"12786","DOI":"10.1074\/jbc.REV120.009192","volume":"295","author":"G Kaeser","year":"2020","unstructured":"Kaeser, G. & Chun, J. Brain cell somatic gene recombination and its phylogenetic foundations. J. Biol. Chem. 295, 12786\u201312795 (2020).","journal-title":"J. Biol. Chem."},{"key":"9759_CR31","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-021-02464-2","volume":"22","author":"M Sun","year":"2021","unstructured":"Sun, M. et al. Systematic functional interrogation of human pseudogenes using CRISPRi. Genome Biol. 22, 240 (2021).","journal-title":"Genome Biol."},{"key":"9759_CR32","doi-asserted-by":"publisher","first-page":"2374","DOI":"10.1093\/nar\/gki531","volume":"33","author":"PM Harrison","year":"2005","unstructured":"Harrison, P. M., Zheng, D., Zhang, Z., Carriero, N. & Gerstein, M. Transcribed processed pseudogenes in the human genome: an intermediate form of expressed retrosequence lacking protein-coding ability. Nucleic Acids Res. 33, 2374\u20132383 (2005).","journal-title":"Nucleic Acids Res."},{"key":"9759_CR33","doi-asserted-by":"publisher","first-page":"2541","DOI":"10.1101\/gr.1429003","volume":"13","author":"Z Zhang","year":"2003","unstructured":"Zhang, Z., Harrison, P. M., Liu, Y. & Gerstein, M. Millions of years of evolution preserved: a comprehensive catalog of the processed pseudogenes in the human genome. Genome Res. 13, 2541\u20132558 (2003).","journal-title":"Genome Res."},{"key":"9759_CR34","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1146\/annurev.ge.19.120185.001345","volume":"19","author":"EF Vanin","year":"1985","unstructured":"Vanin, E. F. Processed pseudogenes: characteristics and evolution. Annu. Rev. Genet. 19, 253\u2013272 (1985).","journal-title":"Annu. Rev. Genet."},{"key":"9759_CR35","doi-asserted-by":"crossref","unstructured":"Monz\u00f3, C., Liu, T. & Conesa, A. Transcriptomics in the era of long-read sequencing. Nat. Rev. Genet. 26, 681\u2013701 (2025).","DOI":"10.1038\/s41576-025-00828-z"},{"key":"9759_CR36","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1038\/s41587-024-02245-9","volume":"43","author":"B Aguzzoli Heberle","year":"2025","unstructured":"Aguzzoli Heberle, B. et al. Mapping medically relevant RNA isoform diversity in the aged human frontal cortex with deep long-read RNA-seq. Nat. Biotechnol. 43, 635\u2013646 (2025).","journal-title":"Nat. Biotechnol."},{"key":"9759_CR37","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110022","volume":"37","author":"SK Leung","year":"2021","unstructured":"Leung, S. K. et al. Full-length transcript sequencing of human and mouse cerebral cortex identifies widespread isoform diversity and alternative splicing. Cell Rep. 37, 110022 (2021).","journal-title":"Cell Rep."},{"key":"9759_CR38","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114061","volume":"43","author":"LS Ransom","year":"2024","unstructured":"Ransom, L. S. et al. Human brain small extracellular vesicles contain selectively packaged, full-length mRNA. Cell Rep. 43, 114061 (2024).","journal-title":"Cell Rep."},{"key":"9759_CR39","doi-asserted-by":"crossref","unstructured":"Liu, C. S. et al. RNA isoform diversity in human neurodegenerative diseases. eNeuro 11, ENEURO.0296-24.2024 (2024).","DOI":"10.1523\/ENEURO.0296-24.2024"},{"key":"9759_CR40","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1101\/gr.276405.121","volume":"32","author":"A Mikheenko","year":"2022","unstructured":"Mikheenko, A., Prjibelski, A. D., Joglekar, A. & Tilgner, H. U. Sequencing of individual barcoded cDNAs using Pacific Biosciences and Oxford Nanopore Technologies reveals platform-specific error patterns. Genome Res. 32, 726\u2013737 (2022).","journal-title":"Genome Res."},{"key":"9759_CR41","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1038\/s41587-023-01815-7","volume":"42","author":"AM Al\u2019Khafaji","year":"2024","unstructured":"Al\u2019Khafaji, A. M. et al. High-throughput RNA isoform sequencing using programmed cDNA concatenation. Nat. Biotechnol. 42, 582\u2013586 (2024).","journal-title":"Nat. Biotechnol."},{"key":"9759_CR42","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1002\/ana.410270502","volume":"27","author":"ST DeKosky","year":"1990","unstructured":"DeKosky, S. T. & Scheff, S. W. Synapse loss in frontal cortex biopsies in Alzheimer\u2019s disease: correlation with cognitive severity. Ann. Neurol. 27, 457\u2013464 (1990).","journal-title":"Ann. Neurol."},{"key":"9759_CR43","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1001\/archneur.56.3.338","volume":"56","author":"DH Salat","year":"1999","unstructured":"Salat, D. H., Kaye, J. A. & Janowsky, J. S. Prefrontal gray and white matter volumes in healthy aging and Alzheimer\u2019s disease. Arch. Neurol. 56, 338\u2013344 (1999).","journal-title":"Arch. Neurol."},{"key":"9759_CR44","doi-asserted-by":"publisher","first-page":"4720","DOI":"10.1093\/bioinformatics\/btac582","volume":"38","author":"B Phipson","year":"2022","unstructured":"Phipson, B. et al. propeller: testing for differences in cell type proportions in single cell data. Bioinformatics 38, 4720\u20134726 (2022).","journal-title":"Bioinformatics"},{"key":"9759_CR45","doi-asserted-by":"publisher","first-page":"W415","DOI":"10.1093\/nar\/gkae456","volume":"52","author":"JM Elizarraras","year":"2024","unstructured":"Elizarraras, J. M. et al. WebGestalt 2024: faster gene set analysis and new support for metabolomics and multi-omics. Nucleic Acids Res. 52, W415\u2013w421 (2024).","journal-title":"Nucleic Acids Res."},{"key":"9759_CR46","doi-asserted-by":"publisher","first-page":"25800","DOI":"10.1073\/pnas.2008762117","volume":"117","author":"SF Lau","year":"2020","unstructured":"Lau, S. F., Cao, H., Fu, A. K. Y. & Ip, N. Y. Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer\u2019s disease. Proc. Natl. Acad. Sci. USA 117, 25800\u201325809 (2020).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"9759_CR47","doi-asserted-by":"publisher","first-page":"578031","DOI":"10.1016\/j.jneuroim.2023.578031","volume":"375","author":"DC Shippy","year":"2023","unstructured":"Shippy, D. C. & Ulland, T. K. Genome-wide identification of murine interferon genes in microglial-mediated neuroinflammation in Alzheimer\u2019s disease. J. Neuroimmunol. 375, 578031 (2023).","journal-title":"J. Neuroimmunol."},{"key":"9759_CR48","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/s13024-024-00759-z","volume":"19","author":"A Ishii","year":"2024","unstructured":"Ishii, A. et al. Contribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer\u2019s disease. Mol. Neurodegener. 19, 83 (2024).","journal-title":"Mol. Neurodegener."},{"key":"9759_CR49","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1038\/s41593-024-01730-3","volume":"27","author":"AO Sasmita","year":"2024","unstructured":"Sasmita, A. O. et al. Oligodendrocytes produce amyloid-\u03b2 and contribute to plaque formation alongside neurons in Alzheimer\u2019s disease model mice. Nat. Neurosci. 27, 1668\u20131674 (2024).","journal-title":"Nat. Neurosci."},{"key":"9759_CR50","doi-asserted-by":"crossref","unstructured":"Liu, C. S. & Chun, J. isoSeQL: comparing long-read isoforms across multiple datasets. Bioinformatics 42, btaf680 (2026).","DOI":"10.1093\/bioinformatics\/btaf680"},{"key":"9759_CR51","doi-asserted-by":"crossref","unstructured":"Costantino, I., Nicodemus, J. & Chun, J. Genomic mosaicism formed by somatic variation in the aging and diseased brain. Genes 12, 1071(2021).","DOI":"10.3390\/genes12071071"},{"key":"9759_CR52","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11000-7","volume":"10","author":"JS Park","year":"2019","unstructured":"Park, J. S. et al. Brain somatic mutations observed in Alzheimer\u2019s disease associated with aging and dysregulation of tau phosphorylation. Nat. Commun. 10, 3090 (2019).","journal-title":"Nat. Commun."},{"key":"9759_CR53","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2021.695808","volume":"13","author":"X Xiao","year":"2021","unstructured":"Xiao, X. et al. APP, PSEN1, and PSEN2 variants in Alzheimer\u2019s disease: systematic re-evaluation according to ACMG guidelines. Front. Aging Neurosci. 13, 695808 (2021).","journal-title":"Front. Aging Neurosci."},{"key":"9759_CR54","doi-asserted-by":"publisher","first-page":"e1002270","DOI":"10.1371\/journal.pmed.1002270","volume":"14","author":"HM Lanoisel\u00e9e","year":"2017","unstructured":"Lanoisel\u00e9e, H. M. et al. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: a genetic screening study of familial and sporadic cases. PLoS Med. 14, e1002270 (2017).","journal-title":"PLoS Med."},{"key":"9759_CR55","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09564-5","volume":"10","author":"N Franzmeier","year":"2019","unstructured":"Franzmeier, N., Rubinski, A., Neitzel, J. & Ewers, M. The BIN1 rs744373 SNP is associated with increased tau-PET levels and impaired memory. Nat. Commun. 10, 1766 (2019).","journal-title":"Nat. Commun."},{"key":"9759_CR56","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1038\/mp.2013.1","volume":"18","author":"J Chapuis","year":"2013","unstructured":"Chapuis, J. et al. Increased expression of BIN1 mediates Alzheimer\u2019s genetic risk by modulating tau pathology. Mol. Psychiatry 18, 1225\u20131234 (2013).","journal-title":"Mol. Psychiatry"},{"key":"9759_CR57","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/nrneurol.2012.263","volume":"9","author":"CC Liu","year":"2013","unstructured":"Liu, C. C., Liu, C. C., Kanekiyo, T., Xu, H. & Bu, G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9, 106\u2013118 (2013).","journal-title":"Nat. Rev. Neurol."},{"key":"9759_CR58","doi-asserted-by":"publisher","first-page":"e00018","DOI":"10.1097\/IN9.0000000000000018","volume":"5","author":"JJ Yen","year":"2023","unstructured":"Yen, J. J. & Yu, I. I. The role of ApoE-mediated microglial lipid metabolism in brain aging and disease. Immunometabolism 5, e00018 (2023).","journal-title":"Immunometabolism"},{"key":"9759_CR59","unstructured":"Biosciences, P. (2019)."},{"key":"9759_CR60","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1007\/s12035-022-03091-z","volume":"60","author":"P Guan","year":"2023","unstructured":"Guan, P., Zhu, D. & Wang, P. Meloxicam inhibits apoptosis in neurons by deactivating tumor necrosis factor receptor superfamily member 25, leading to the decreased cleavage of DNA fragmentation factor subunit \u03b1 in Alzheimer\u2019s disease. Mol. Neurobiol. 60, 395\u2013412 (2023).","journal-title":"Mol. Neurobiol."},{"key":"9759_CR61","doi-asserted-by":"publisher","first-page":"901","DOI":"10.3233\/JAD-140624","volume":"42","author":"A Antonell","year":"2014","unstructured":"Antonell, A. et al. Cerebrospinal fluid level of YKL-40 protein in preclinical and prodromal Alzheimer\u2019s disease. J. Alzheimer\u2019s Dis. 42, 901\u2013908 (2014).","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"9759_CR62","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1002\/alz.12612","volume":"19","author":"K Connolly","year":"2023","unstructured":"Connolly, K. et al. Potential role of chitinase-3-like protein 1 (CHI3L1\/YKL-40) in neurodegeneration and Alzheimer\u2019s disease. Alzheimer\u2019s Dement 19, 9\u201324 (2023).","journal-title":"Alzheimer\u2019s Dement"},{"key":"9759_CR63","doi-asserted-by":"publisher","first-page":"42051","DOI":"10.1074\/jbc.M111.300541","volume":"286","author":"L Abuhatzira","year":"2011","unstructured":"Abuhatzira, L., Shamir, A., Schones, D. E., Sch\u00e4ffer, A. A. & Bustin, M. The chromatin-binding protein HMGN1 regulates the expression of methyl CpG-binding protein 2 (MECP2) and affects the behavior of mice. J. Biol. Chem. 286, 42051\u201342062 (2011).","journal-title":"J. Biol. Chem."},{"key":"9759_CR64","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s13072-022-00471-6","volume":"15","author":"SJ Farley","year":"2022","unstructured":"Farley, S. J., Grishok, A. & Zeldich, E. Shaking up the silence: consequences of HMGN1 antagonizing PRC2 in the Down syndrome brain. Epigenet. Chromatin 15, 39 (2022).","journal-title":"Epigenet. Chromatin"},{"key":"9759_CR65","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-99309-6","volume":"11","author":"LN Manganas","year":"2021","unstructured":"Manganas, L. N. et al. Author Correction: BASP1 labels neural stem cells in the neurogenic niches of mammalian brain. Sci. Rep. 11, 20008 (2021).","journal-title":"Sci. Rep."},{"key":"9759_CR66","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s12014-020-09285-8","volume":"17","author":"M Zhou","year":"2020","unstructured":"Zhou, M. et al. Targeted mass spectrometry to quantify brain-derived cerebrospinal fluid biomarkers in Alzheimer\u2019s disease. Clin. Proteom. 17, 19 (2020).","journal-title":"Clin. Proteom."},{"key":"9759_CR67","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1016\/j.neuron.2007.01.019","volume":"53","author":"M Ihara","year":"2007","unstructured":"Ihara, M. et al. Sept4, a component of presynaptic scaffold and Lewy bodies, is required for the suppression of alpha-synuclein neurotoxicity. Neuron 53, 519\u2013533 (2007).","journal-title":"Neuron"},{"key":"9759_CR68","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1016\/S0002-9440(10)65743-4","volume":"153","author":"A Kinoshita","year":"1998","unstructured":"Kinoshita, A. et al. Identification of septins in neurofibrillary tangles in Alzheimer\u2019s disease. Am. J. Pathol. 153, 1551\u20131560 (1998).","journal-title":"Am. J. Pathol."},{"key":"9759_CR69","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1002\/mds.22306","volume":"24","author":"L Shehadeh","year":"2009","unstructured":"Shehadeh, L., Mitsi, G., Adi, N., Bishopric, N. & Papapetropoulos, S. Expression of Lewy body protein septin 4 in postmortem brain of Parkinson\u2019s disease and control subjects. Mov. Disord. 24, 204\u2013210 (2009).","journal-title":"Mov. Disord."},{"key":"9759_CR70","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1111\/jnc.15824","volume":"165","author":"F Li","year":"2023","unstructured":"Li, F., Liu, A., Zhao, M. & Luo, L. Astrocytic Chitinase-3-like protein 1 in neurological diseases: Potential roles and future perspectives. J. Neurochem. 165, 772\u2013790 (2023).","journal-title":"J. Neurochem."},{"key":"9759_CR71","doi-asserted-by":"publisher","first-page":"1340","DOI":"10.1038\/s42003-024-07043-2","volume":"7","author":"T Wang","year":"2024","unstructured":"Wang, T. et al. snPATHO-seq, a versatile FFPE single-nucleus RNA sequencing method to unlock pathology archives. Commun. Biol. 7, 1340 (2024).","journal-title":"Commun. Biol."},{"key":"9759_CR72","doi-asserted-by":"publisher","first-page":"19802","DOI":"10.1073\/pnas.1319700110","volume":"110","author":"RV Grindberg","year":"2013","unstructured":"Grindberg, R. V. et al. RNA-sequencing from single nuclei. Proc. Natl. Acad. Sci. USA 110, 19802\u201319807 (2013).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"9759_CR73","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/nprot.2016.015","volume":"11","author":"SR Krishnaswami","year":"2016","unstructured":"Krishnaswami, S. R. et al. Using single nuclei for RNA-seq to capture the transcriptome of postmortem neurons. Nat. Protoc. 11, 499\u2013524 (2016).","journal-title":"Nat. Protoc."},{"key":"9759_CR74","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1038\/s41587-022-01231-3","volume":"40","author":"SA Hardwick","year":"2022","unstructured":"Hardwick, S. A. et al. Single-nuclei isoform RNA sequencing unlocks barcoded exon connectivity in frozen brain tissue. Nat. Biotechnol. 40, 1082\u20131092 (2022).","journal-title":"Nat. Biotechnol."},{"key":"9759_CR75","first-page":"648","volume":"3","author":"J Chun","year":"2022","unstructured":"Chun, J. Somatic genomic mosaicism in the brain: Identified mutations provide challenges and opportunities for the clinic. Medicines 3, 648\u2013650 (2022).","journal-title":"Medicines"},{"key":"9759_CR76","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1002\/dneu.22626","volume":"78","author":"S Rohrback","year":"2018","unstructured":"Rohrback, S., Siddoway, B., Liu, C. S. & Chun, J. Genomic mosaicism in the developing and adult brain. Dev. Neurobiol. 78, 1026\u20131048 (2018).","journal-title":"Dev. Neurobiol."},{"key":"9759_CR77","doi-asserted-by":"publisher","first-page":"390","DOI":"10.3389\/fgene.2020.00390","volume":"11","author":"GE Kaeser","year":"2020","unstructured":"Kaeser, G. E. & Chun, J. Mosaic somatic gene recombination as a potentially unifying hypothesis for Alzheimer\u2019s disease. Front. Genet. 11, 390 (2020).","journal-title":"Front. Genet."},{"key":"9759_CR78","unstructured":"Aguzzoli Heberle, B. et al. Mapping medically relevant RNA isoform diversity in the aged human frontal cortex with deep long-read RNA-seq. Synapse. https:\/\/www.synapse.org\/#!Synapse:syn52047893 (2025)."},{"key":"9759_CR79","unstructured":"Leung, S. K. et al. Full-length transcript sequencing of human and mouse cerebral cortex identifies widespread isoform diversity and altnerative splicing. SRA. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA664117 (2021)."}],"container-title":["Communications Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-09759-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-09759-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-09759-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T14:04:58Z","timestamp":1775743498000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-09759-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,3]]},"references-count":79,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["9759"],"URL":"https:\/\/doi.org\/10.1038\/s42003-026-09759-9","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-7436496\/v1","asserted-by":"object"}]},"ISSN":["2399-3642"],"issn-type":[{"value":"2399-3642","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,3]]},"assertion":[{"value":"2 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"J.C. has an employment relationship with Neurocrine Biosciences, a company that may potentially benefit from the research results. J.C.\u2019s relationship with Neurocrine Biosciences has been reviewed and approved by Sanford Burnham Prebys Medical Discovery Institute in accordance with its conflict of interest policies. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"506"}}