{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T12:23:03Z","timestamp":1789129383577,"version":"build-2803163510"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":245,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Airalzh-Grants-for-Young-Researchers","award":["AGYR 2025"],"award-info":[{"award-number":["AGYR 2025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Recent studies show that serum glial fibrillary acidic protein (GFAP) is highest in healthy infancy and early childhood and then declines steadily with age, while plasma tau protein phosphorylated at position 217 is strikingly elevated in healthy newborns and can exceed values observed in Alzheimer\u2019s disease (AD). Additional evidence indicates that soluble phosphorylated tau forms are not specific to AD, as increased tau protein phosphorylated-217 has been reported in MAPT R406W carriers without amyloid pathology and in Niemann-Pick disease type C, where plasma tau protein phosphorylated-217 is associated with disease progression and lysosomal enlargement. These observations invite a broader review of biomarker biology across development, physiological remodelling and neurodegeneration. We hypothesize that, at least in part, increases of GFAP, tau protein phosphorylated-217 and related biomarkers in AD reflect a chronic attempt of the ageing brain to reactivate multicellular programmes that are physiologically engaged during development, repair and circuit refinement. In this framework, biomarker elevation does not necessarily indicate that the reactive programme is intrinsically toxic. Rather, persistent elevation may index the duration and intensity of unresolved metabolic, inflammatory, vascular, proteostatic, mitochondrial or infectious stressors that keep repair and homeostatic systems engaged until their compensatory capacity is exceeded. Protein precipitation is therefore positioned as a downstream consequence of persistent stress, chronic compensatory activation, increased protein turnover, secretion or processing and impaired clearance or proteostasis. This Review summarizes the developmental biomarker evidence, examines alternative interpretations and discusses therapeutic implications focused on upstream stressors and failed resolution rather than biomarker lowering alone.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag337","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T07:19:10Z","timestamp":1788419950000},"source":"Crossref","is-referenced-by-count":0,"title":["Developmental brain programmes and biomarker activation in Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"8","author":[{"given":"Lorenzo","family":"Pini","sequence":"first","affiliation":[{"name":"Department of Neuroscience, University of Padova , Padova 35122 ,","place":["Italy"]},{"name":"Padova Neuroscience Center, University of Padova , Padova 35122 ,","place":["Italy"]},{"name":"Veneto Institute of Molecular Medicine (VIMM) , Padova 35122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Margoni","sequence":"additional","affiliation":[{"name":"Neurology Unit, IRCCS San Raffaele Scientific Institute , Milan 20132 ,","place":["Italy"]},{"name":"Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute , Milan 20132 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5485-0479","authenticated-orcid":false,"given":"Massimo","family":"Filippi","sequence":"additional","affiliation":[{"name":"Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute , Milan 20132 ,","place":["Italy"]},{"name":"Center for Alzheimer\u2019s and Related Diseases (CARD), Neurology Unit, IRCCS San Raffaele Scientific Institute , Milan 20132 ,","place":["Italy"]},{"name":"Vita-Salute San Raffaele University , Milan 20132 ,","place":["Italy"]},{"name":"Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute , Milan 20132 ,","place":["Italy"]},{"name":"Neurotech Hub, Vita-Salute San Raffaele University , Milan 20132 ,","place":["Italy"]},{"name":"Neurophysiology Service, IRCCS San Raffaele Scientific Institute , Milan 20132 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0327-7262","authenticated-orcid":false,"given":"Bruno Pietro","family":"Imbimbo","sequence":"additional","affiliation":[{"name":"Department of Research and Development, Chiesi Farmaceutici , Parma 43122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"2026091107171119700_fcag337-B1","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1038\/s43587-023-00523-w","article-title":"TANGO: A placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer\u2019s disease","volume":"3","author":"Shulman","year":"2023","journal-title":"Nat Aging."},{"key":"2026091107171119700_fcag337-B2","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.conb.2021.03.003","article-title":"A current view on Tau protein phosphorylation in Alzheimer\u2019s disease","volume":"69","author":"Wegmann","year":"2021","journal-title":"Curr Opin Neurobiol."},{"key":"2026091107171119700_fcag337-B3","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1002\/acn3.51435","article-title":"MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology","volume":"8","author":"Sato","year":"2021","journal-title":"Ann Clin Transl Neurol."},{"key":"2026091107171119700_fcag337-B4","doi-asserted-by":"crossref","DOI":"10.1093\/braincomms\/fcae375","article-title":"Plasma phosphorylated-tau217 is increased in Niemann\u2013Pick disease type C","volume":"6","author":"Gonzalez-Ortiz","year":"2024","journal-title":"Brain Commun."},{"key":"2026091107171119700_fcag337-B5","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/B978-0-323-85538-9.00009-2","article-title":"Models of precision medicine for neurodegeneration","volume":"192","author":"Espay","year":"2023","journal-title":"Handb Clin Neurol."},{"key":"2026091107171119700_fcag337-B6","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/B978-0-323-85555-6.00001-1","article-title":"The shift to a proteinopenia paradigm in neurodegeneration","volume":"193","author":"Ezzat","year":"2023","journal-title":"Handb Clin Neurol."},{"key":"2026091107171119700_fcag337-B7","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1111\/j.1749-6632.1984.tb13859.x","article-title":"Functional staging of dementia of the Alzheimer type","volume":"435","author":"Reisberg","year":"1984","journal-title":"Ann N Y Acad Sci."},{"key":"2026091107171119700_fcag337-B8","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1093\/cercor\/bhp118","article-title":"Brain maturation in adolescence and young adulthood: Regional age-related changes in cortical thickness and white matter volume and microstructure","volume":"20","author":"Tamnes","year":"2010","journal-title":"Cereb Cortex"},{"key":"2026091107171119700_fcag337-B9","doi-asserted-by":"crossref","DOI":"10.1093\/braincomms\/fcaf321","article-title":"Does p-tau217 play a physiological reparative role in neonates and neurodegenerative diseases?","volume":"7","author":"Daly","year":"2025","journal-title":"Brain Commun."},{"key":"2026091107171119700_fcag337-B10","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/s41586-023-05964-2","article-title":"A somato-cognitive action network alternates with effector regions in motor cortex","volume":"617","author":"Gordon E","year":"2023","journal-title":"Nature"},{"key":"2026091107171119700_fcag337-B11","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1038\/s41586-025-10059-1","article-title":"Parkinson\u2019s disease as a somato-cognitive action network disorder","volume":"651","author":"Ren","year":"2026","journal-title":"Nature"},{"key":"2026091107171119700_fcag337-B12","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.neures.2009.11.012","article-title":"Converging molecular pathways in human neural development and degeneration","volume":"66","author":"Mattsson","year":"2010","journal-title":"Neurosci Res."},{"key":"2026091107171119700_fcag337-B13","doi-asserted-by":"crossref","DOI":"10.1093\/braincomms\/fcaf221","article-title":"The potential dual role of tau phosphorylation: Plasma phosphorylated-tau217 in newborns and Alzheimer\u2019s disease","volume":"7","author":"Gonzalez-Ortiz","year":"2025","journal-title":"Brain Commun."},{"key":"2026091107171119700_fcag337-B14","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1515\/cclm-2023-0280","article-title":"Serum GFAP \u2013 Pediatric reference interval in a cohort of Danish children","volume":"61","author":"Tybirk","year":"2023","journal-title":"Clin Chem Lab Med."},{"key":"2026091107171119700_fcag337-B15","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1515\/cclm-2023-0660","article-title":"Pediatric reference intervals for serum neurofilament light and glial fibrillary acidic protein using the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort","volume":"62","author":"Stukas","year":"2024","journal-title":"Clin Chem Lab Med."},{"key":"2026091107171119700_fcag337-B16","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1001\/jama.2020.12134","article-title":"Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders","volume":"324","author":"Palmqvist","year":"2020","journal-title":"JAMA"},{"key":"2026091107171119700_fcag337-B17","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1038\/s41467-020-15436-0","article-title":"Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer\u2019s disease","volume":"11","author":"Janelidze","year":"2020","journal-title":"Nat Commun."},{"key":"2026091107171119700_fcag337-B18","doi-asserted-by":"crossref","DOI":"10.1016\/j.neulet.2024.137674","article-title":"GFAP-expressing cells in the adult hypothalamus can generate multiple neural cell lineages in vitro","volume":"824","author":"Butruille","year":"2024","journal-title":"Neurosci Lett."},{"key":"2026091107171119700_fcag337-B19","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/j.stemcr.2014.04.008","article-title":"Primitive neural stem cells in the adult mammalian brain give rise to GFAP-expressing neural stem cells","volume":"2","author":"Sachewsky","year":"2014","journal-title":"Stem Cell Reports"},{"key":"2026091107171119700_fcag337-B20","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1016\/j.bbamcr.2014.04.018","article-title":"Temporal oligodendrocyte lineage progression: In vitro models of proliferation, differentiation and myelination","volume":"1843","author":"Barateiro","year":"2014","journal-title":"Biochim Biophys Acta."},{"key":"2026091107171119700_fcag337-B21","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aag1767","article-title":"Early changes in CSF sTREM2 in dominantly inherited Alzheimer\u2019s disease occur after amyloid deposition and neuronal injury","volume":"8","author":"Su\u00e1rez-Calvet","year":"2016","journal-title":"Sci Transl Med."},{"key":"2026091107171119700_fcag337-B22","doi-asserted-by":"crossref","first-page":"466","DOI":"10.15252\/emmm.201506123","article-title":"sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer\u2019s disease and associate with neuronal injury markers","volume":"8","author":"Su\u00e1rez-Calvet","year":"2016","journal-title":"EMBO Mol Med."},{"key":"2026091107171119700_fcag337-B23","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0014530","article-title":"The physiological link between metabolic rate depression and tau phosphorylation in mammalian hibernation","volume":"6","author":"Stieler","year":"2011","journal-title":"PLoS One"},{"key":"2026091107171119700_fcag337-B24","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1007\/s00401-025-02930-2","article-title":"Reversible tau hyperphosphorylation in hibernation: A blood biomarker and brain tissue study","volume":"150","author":"Brum","year":"2025","journal-title":"Acta Neuropathol."},{"key":"2026091107171119700_fcag337-B25","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/s41582-021-00616-3","article-title":"Blood GFAP as an emerging biomarker in brain and spinal cord disorders","volume":"18","author":"Abdelhak","year":"2022","journal-title":"Nat Rev Neurol."},{"key":"2026091107171119700_fcag337-B26","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1126\/science.aad8373","article-title":"Complement and microglia mediate early synapse loss in Alzheimer mouse models","volume":"352","author":"Hong","year":"2016","journal-title":"Science"},{"key":"2026091107171119700_fcag337-B27","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/s41591-019-0375-9","article-title":"Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer\u2019s disease","volume":"25","author":"Moreno-Jim\u00e9nez","year":"2019","journal-title":"Nat Med."},{"key":"2026091107171119700_fcag337-B28","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41591-019-0695-9","article-title":"Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer\u2019s disease","volume":"26","author":"Zhou","year":"2020","journal-title":"Nat Med."},{"key":"2026091107171119700_fcag337-B29","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2024.114574","article-title":"Neurofibrillary tangle-bearing neurons have reduced risk of cell death in mice with Alzheimer\u2019s pathology","volume":"43","author":"Zwang","year":"2024","journal-title":"Cell Rep."},{"key":"2026091107171119700_fcag337-B30","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/s41582-023-00822-1","article-title":"Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration","volume":"19","author":"Patani","year":"2023","journal-title":"Nat Rev Neurol."},{"key":"2026091107171119700_fcag337-B31","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1126\/science.abl5163","article-title":"Impact of neurodegenerative diseases on human adult hippocampal neurogenesis","volume":"374","author":"Terreros-Roncal","year":"2021","journal-title":"Science"},{"key":"2026091107171119700_fcag337-B32","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.stem.2019.06.001","article-title":"Is Alzheimer\u2019s disease a neurogenesis disorder?","volume":"25","author":"Choi","year":"2019","journal-title":"Cell Stem Cell"},{"key":"2026091107171119700_fcag337-B33","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1002\/ana.27180","article-title":"Subventricular zone microstructure in pediatric-onset multiple sclerosis","volume":"97","author":"Margoni","year":"2025","journal-title":"Ann Neurol."},{"key":"2026091107171119700_fcag337-B34","doi-asserted-by":"crossref","DOI":"10.15252\/emmm.201911170","article-title":"Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer\u2019s disease","volume":"11","author":"Palmqvist","year":"2019","journal-title":"EMBO Mol Med."},{"key":"2026091107171119700_fcag337-B35","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41586-018-0784-9","article-title":"L1 drives IFN in senescent cells and promotes age-associated inflammation","volume":"566","author":"De Cecco","year":"2019","journal-title":"Nature"},{"key":"2026091107171119700_fcag337-B36","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/s41583-021-00507-y","article-title":"Mechanisms governing activity-dependent synaptic pruning in the developing mammalian CNS","volume":"22","author":"Faust","year":"2021","journal-title":"Nat Rev Neurosci."}],"container-title":["Brain Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/braincomms\/advance-article-pdf\/doi\/10.1093\/braincomms\/fcag337\/70935083\/fcag337.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/8\/5\/fcag337\/70935083\/fcag337.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/8\/5\/fcag337\/70935083\/fcag337.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T11:17:25Z","timestamp":1789125445000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/braincomms\/article\/doi\/10.1093\/braincomms\/fcag337\/8780894"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":36,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,9,1]]}},"URL":"https:\/\/doi.org\/10.1093\/braincomms\/fcag337","relation":{},"ISSN":["2632-1297"],"issn-type":[{"value":"2632-1297","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026]]},"published":{"date-parts":[[2026]]},"article-number":"fcag337"}}