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Two detrimental waves of neuroinflammation have been proposed, the first during early A\u03b2 accumulation, and the second during widespread tau deposition. However, the neuroinflammatory signatures associated with each phase remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We studied 63 individuals who underwent A\u03b2 and tau positron emission tomography imaging along with cerebrospinal fluid profiling of 368 inflammation\u2010related proteins. Protein contrasts between cognitively unimpaired A\u03b2\u2010negative and A\u03b2\u2010positive individuals defined the signature of the A\u03b2 phase, while comparisons between cognitively impaired A\u03b2\u2010positive individuals with early versus late tau pathology characterized the tau phase. Gene Ontology enrichment identified biological processes associated with differentially expressed proteins.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      During the A\u03b2 phase, 34 proteins were downregulated and mapped to 157 biological processes, including Toll\u2010like receptor signaling, nuclear factor kappa beta activation, and cytokine production. The tau phase showed upregulation of 23 proteins associated with 82 biological processes enriched in adaptive immune responses. A set of 48 biological processes and three proteins including interleukin 4 receptor, cystosolic phospholipidase A\n                      <jats:sub>2<\/jats:sub>\n                      , and secretoglobin family 3A member 2 showed opposite regulation patterns, being downregulated in the A\u03b2 phase and upregulated in the tau phase.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Our results revealed distinct neuroinflammatory signatures and biological processes associated with A\u03b2\u2010 and tau\u2010dominant stages of AD. The reversal in protein expression patterns across these stages underscores the need for stage\u2010specific neuroimmune therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.70275","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:01:24Z","timestamp":1781841684000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A\u03b2\u2010 and tau\u2010associated neuroinflammatory signatures in Alzheimer's disease"],"prefix":"10.1002","volume":"12","author":[{"given":"Bruna","family":"Bellaver","sequence":"first","affiliation":[{"name":"Department of Psychiatry University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilherme","family":"Povala","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco Ant\u00f4nio","family":"De Bastiani","sequence":"additional","affiliation":[{"name":"Graduate Program in Biological Sciences: Biochemistry Universidade Federal do Rio Grande do Sul  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Pola","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry The Sahlgrenska Academy at the University of Gothenburg  M\u00f6lndal Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela C. L.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilherme","family":"Bauer\u2010Negrini","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o Pedro","family":"Ferrari\u2010Souza","sequence":"additional","affiliation":[{"name":"Graduate Program in Biological Sciences: Biochemistry Universidade Federal do Rio Grande do Sul  Porto Alegre Brazil"},{"name":"Neuroscience Unit, Hospital Moinhos de Vento  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas T.","family":"Leffa","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Firoza Z.","family":"Lussier","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Therriault","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux (CIUSSS) de l'Ouest\u2010de\u2010l'\u00cele\u2010de\u2010Montr\u00e9al; Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nesrine","family":"Rahmouni","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux (CIUSSS) de l'Ouest\u2010de\u2010l'\u00cele\u2010de\u2010Montr\u00e9al; Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna","family":"Stevenson","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux (CIUSSS) de l'Ouest\u2010de\u2010l'\u00cele\u2010de\u2010Montr\u00e9al; Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stijn","family":"Servaes","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux (CIUSSS) de l'Ouest\u2010de\u2010l'\u00cele\u2010de\u2010Montr\u00e9al; Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riddhi","family":"Patira","sequence":"additional","affiliation":[{"name":"Department of Neurology, School of Medicine University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Gauthier","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux (CIUSSS) de l'Ouest\u2010de\u2010l'\u00cele\u2010de\u2010Montr\u00e9al; Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana L.","family":"Tudorascu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Biostatistics, School of Medicine University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas K.","family":"Karikari","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Ashton","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry The Sahlgrenska Academy at the University of Gothenburg  M\u00f6lndal Sweden"},{"name":"Banner Alzheimer's Institute and University of Arizona  Phoenix Arizona USA"},{"name":"Banner Sun Health Research Institute  Sun City Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry The Sahlgrenska Academy at the University of Gothenburg  M\u00f6lndal Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry The Sahlgrenska Academy at the University of Gothenburg  M\u00f6lndal Sweden"},{"name":"Department of Neurodegenerative Disease UCL Institute of Neurology, University College London, UK; UK Dementia Research Institute at UCL  London UK"},{"name":"Department of Pathology and Laboratory Medicine University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Wisconsin Alzheimer's Disease Research Center University of Wisconsin School of Medicine and Public Health, University of Wisconsin\u2010Madison  Madison Wisconsin USA"},{"name":"Centre for Brain Research Indian Institute of Science  Bangalore India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo R.","family":"Zimmer","sequence":"additional","affiliation":[{"name":"Graduate Program in Biological Sciences: Biochemistry Universidade Federal do Rio Grande do Sul  Porto Alegre Brazil"},{"name":"Neuroscience Unit, Hospital Moinhos de Vento  Porto Alegre Brazil"},{"name":"Department of Pharmacology Universidade Federal do Rio Grande do Sul  Porto Alegre Rio Grande do Sul Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea L.","family":"Benedet","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry The Sahlgrenska Academy at the University of Gothenburg  M\u00f6lndal Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Rosa\u2010Neto","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre int\u00e9gr\u00e9 universitaire de sant\u00e9 et de services sociaux (CIUSSS) de l'Ouest\u2010de\u2010l'\u00cele\u2010de\u2010Montr\u00e9al; 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