{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T17:29:50Z","timestamp":1793986190114,"version":"4.8.0"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Alzheimer\u2019s disease (AD) has long been associated with hallmark protein aggregates, yet increasing evidence suggests immune involvement may contribute to its progression. Prior studies have found increased T cell presence in AD brain tissue, raising the possibility of neuroimmune crosstalk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used single-nucleus RNA sequencing data from the Religious Orders Study and Memory and Aging Project (ROSMAP), the largest available postmortem AD cohort, to investigate T cell dynamics in prefrontal cortex (PFC) and hippocampus.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Contrary to prior findings, we observed no significant increase in T cell frequency in individuals with pathologically confirmed AD in either region. We replicated these findings in dorsolateral PFC (DLPFC) using the Seattle Alzheimer\u2019s Disease Brain Cell Atlas (SEA-AD). Notably, although we confirmed a prior finding of T cell expansion in middle temporal gyrus (MTG), the strength of this association was affected by donor age. Additionally, we detected no change in gene expression in T cells in the brain parenchyma from individuals with AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Impact<\/jats:title>\n                    <jats:p>These results suggest that T cell enrichment in AD may be regionally restricted and not as widespread as previously assumed. Our findings underscore the importance of brain region selection, analytical approach, and dataset composition in interpreting immune cell dynamics in neurodegenerative disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fncel.2025.1681881","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T06:27:06Z","timestamp":1765780026000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Single-nucleus RNA-seq reveals no increase in T cells in Alzheimer\u2019s disease prefrontal cortex or hippocampus"],"prefix":"10.3389","volume":"19","author":[{"given":"Jake D.","family":"Oxendine","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel W.","family":"Sirkis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Jonson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer S.","family":"Yokoyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"3708","DOI":"10.1002\/alz.13809","article-title":"2024 Alzheimer\u2019s disease facts and figures","volume":"20","year":"2024","journal-title":"Alzheimers Dement."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"S161","DOI":"10.3233\/jad-179939","article-title":"Religious orders study and rush memory and aging project","volume":"64","author":"Bennett","year":"2018","journal-title":"J Alzheimer's Dis"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1038\/s41582-021-00549-x","article-title":"Peripheral and central immune system crosstalk in Alzheimer disease \u2014 a research prospectus","volume":"17","author":"Bettcher","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1038\/s41586-023-05788-0","article-title":"Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy","volume":"615","author":"Chen","year":"2023","journal-title":"Nature"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1186\/s12974-022-02605-9","article-title":"The role of the adaptive immune system and T cell dysfunction in neurodegenerative diseases","volume":"19","author":"DeMaio","year":"2022","journal-title":"J. Neuroinflammation"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1007\/s00281-009-0177-0","article-title":"The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction","volume":"31","author":"Engelhardt","year":"2009","journal-title":"Semin. Immunopathol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"2366","DOI":"10.1038\/s41593-024-01774-5","article-title":"Integrated multimodal cell atlas of Alzheimer\u2019s disease","volume":"27","author":"Gabitto","year":"2024","journal-title":"Nat. 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Dis."},{"key":"ref17","author":"Pag\u00e8s","year":"2025"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"fcac109","DOI":"10.1093\/braincomms\/fcac109","article-title":"Structural progression of Alzheimer\u2019s disease over decades: the MRI staging scheme","volume":"4","author":"Planche","year":"2022","journal-title":"Brain Commun."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"3143","DOI":"10.1016\/j.neuron.2025.07.001","article-title":"Human brain vascular multi-omics elucidates disease-risk associations","volume":"113","author":"Reid","year":"2025","journal-title":"Neuron"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1016\/j.immuni.2022.03.018","article-title":"Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid \u03b2 plaques","volume":"55","author":"Roy","year":"2022","journal-title":"Immunity"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1038\/s41588-025-02148-8","article-title":"CHOIR improves significance-based detection of cell types and states from single-cell data","volume":"57","author":"Sant","year":"2025","journal-title":"Nat. Genet."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"2590","DOI":"10.1038\/s41591-025-03835-z","article-title":"APOE \u03b54 carriers share immune-related proteomic changes across neurodegenerative diseases","volume":"31","author":"Shvetcov","year":"2025","journal-title":"Nat. Med."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"5062","DOI":"10.1002\/alz.13892","article-title":"Expansion of highly interferon-responsive T cells in early-onset Alzheimer\u2019s disease","volume":"20","author":"Sirkis","year":"2024","journal-title":"Alzheimers Dement."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"4386","DOI":"10.1016\/j.cell.2023.08.037","article-title":"Human microglial state dynamics in Alzheimer\u2019s disease progression","volume":"186","author":"Sun","year":"2023","journal-title":"Cell"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/S0165-5728(01)00496-9","article-title":"Occurrence of T cells in the brain of Alzheimer\u2019s disease and other neurological diseases","volume":"124","author":"Togo","year":"2002","journal-title":"J. Neuroimmunol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"3292","DOI":"10.1038\/s41596-024-01020-z","article-title":"Using clusterProfiler to characterize multiomics data","volume":"19","author":"Xu","year":"2024","journal-title":"Nat. Protoc."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"308","DOI":"10.3390\/biomedicines12020308","article-title":"Cell states and interactions of CD8 T cells and disease-enriched microglia in human brains with Alzheimer\u2019s disease","volume":"12","author":"Yamakawa","year":"2024","journal-title":"Biomedicine"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1038\/s41586-021-04369-3","article-title":"A human brain vascular atlas reveals diverse mediators of Alzheimer\u2019s risk","volume":"603","author":"Yang","year":"2022","journal-title":"Nature"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1001\/jamaneurol.2016.0150","article-title":"Association between genetic traits for immune-mediated diseases and Alzheimer disease","volume":"73","author":"Yokoyama","year":"2016","journal-title":"JAMA Neurol."}],"container-title":["Frontiers in Cellular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2025.1681881\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T06:27:07Z","timestamp":1765780027000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2025.1681881\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,15]]},"references-count":29,"alternative-id":["10.3389\/fncel.2025.1681881"],"URL":"https:\/\/doi.org\/10.3389\/fncel.2025.1681881","relation":{},"ISSN":["1662-5102"],"issn-type":[{"value":"1662-5102","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,15]]},"article-number":"1681881"}}