{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T11:59:48Z","timestamp":1790164788219,"version":"4.1.0"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Aging"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Blood-based biomarkers are emerging as scalable tools for the diagnosis and monitoring of neurodegenerative diseases, but markers enabling differential diagnosis across major dementias remain limited. Here we show that large-scale plasma proteomics identifies disease-associated signatures across Alzheimer\u2019s disease, dementia with Lewy bodies and frontotemporal dementia. We analyzed 1,318 plasma samples from well-characterized international cohorts and identified more than 200 dysregulated proteins across disease groups. Glial fibrillary acidic protein showed the strongest increase along the Alzheimer\u2019s disease continuum, whereas integrin alpha-V and integrin alpha-M were consistently reduced in Lewy body disorders, including autopsy-confirmed cases. Elevated neurofilament light chain and lower glial fibrillary acidic protein were associated with frontotemporal dementia. We translated these findings into a 21-protein quantitative multiplex panel and validated it in an independent multicenter cohort (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009805). These findings support plasma proteomics as an approach for biomarker-based differential diagnosis and disease staging across major neurodegenerative dementias.\n                  <\/jats:p>","DOI":"10.1038\/s43587-026-01162-7","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:02:33Z","timestamp":1784538153000},"page":"1717-1732","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Plasma proteome profiling identified biomarkers for the differential diagnosis and molecular staging of neurodegenerative dementias"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0456-5650","authenticated-orcid":false,"given":"Giovanni","family":"Bellomo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7420-6384","authenticated-orcid":false,"given":"Lisa","family":"Vermunt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3680-8437","authenticated-orcid":false,"given":"Sjors","family":"in \u2018t Veld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2863-0293","authenticated-orcid":false,"given":"James D.","family":"Doecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9713-116X","authenticated-orcid":false,"given":"Yanaika S.","family":"Hok-A-Hin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5845-1854","authenticated-orcid":false,"given":"Kate\u0159ina","family":"Veverov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel M.","family":"Houtkamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3819-3245","authenticated-orcid":false,"given":"Daniel","family":"Alcolea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8711-5702","authenticated-orcid":false,"given":"Steffen","family":"Halbgebauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7234-5268","authenticated-orcid":false,"given":"Carlos","family":"Quesada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8885-7724","authenticated-orcid":false,"given":"Niklas","family":"Mattsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9036-2595","authenticated-orcid":false,"given":"Minerva","family":"Martinez-Castillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jos\u00e9","family":"L\u00f3pez-Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9320-6566","authenticated-orcid":false,"given":"Alberto","family":"R\u00e1bano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn","family":"Boonkamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Fowler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1340-638X","authenticated-orcid":false,"given":"Juan","family":"Fortea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3967-8954","authenticated-orcid":false,"given":"Lorenzo","family":"Gaetani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9500-7632","authenticated-orcid":false,"given":"Andrea","family":"Toja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolande","family":"Pijnenburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afina","family":"Lemstra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiesje M.","family":"van der Flier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascual","family":"S\u00e1nchez-Juan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakub","family":"Hort","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4273-4267","authenticated-orcid":false,"given":"Markus","family":"Otto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Anderl-Staub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Sieben","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1924-2029","authenticated-orcid":false,"given":"Bart","family":"de Viel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0304-9785","authenticated-orcid":false,"given":"Sebastiaan","family":"Engelborghs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8467-7286","authenticated-orcid":false,"given":"Oskar","family":"Hansson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Masters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2568-5478","authenticated-orcid":false,"given":"Alberto","family":"Lle\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5722-3967","authenticated-orcid":false,"given":"Lucilla","family":"Parnetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4061-0837","authenticated-orcid":false,"given":"Charlotte E.","family":"Teunissen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2808-3699","authenticated-orcid":false,"given":"Marta","family":"del Campo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"1162_CR1","doi-asserted-by":"publisher","first-page":"2557","DOI":"10.1093\/brain\/awad059","volume":"146","author":"JL Robinson","year":"2023","unstructured":"Robinson, J. L. et al. Pathological combinations in neurodegenerative disease are heterogeneous and disease-associated. Brain 146, 2557\u20132569 (2023).","journal-title":"Brain"},{"key":"1162_CR2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14573","volume":"21","author":"JD Doecke","year":"2025","unstructured":"Doecke, J. D. et al. Diagnostic performance of plasma A\u03b242\/40 ratio, p-tau181, GFAP, and NfL along the continuum of Alzheimer\u2019s disease and non-AD dementias: an international multi-center study. Alzheimers Dement. 21, e14573 (2025).","journal-title":"Alzheimers Dement."},{"key":"1162_CR3","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0333-5","volume":"14","author":"MA DeTure","year":"2019","unstructured":"DeTure, M. A. & Dickson, D. W. The neuropathological diagnosis of Alzheimer\u2019s disease. Mol. Neurodegener. 14, 32 (2019).","journal-title":"Mol. Neurodegener."},{"key":"1162_CR4","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1002\/mds.27867","volume":"35","author":"DG Coughlin","year":"2020","unstructured":"Coughlin, D. G., Hurtig, H. I. & Irwin, D. J. Pathological influences on clinical heterogeneity in Lewy body diseases. Mov. Disord. 35, 5\u201319 (2020).","journal-title":"Mov. Disord."},{"key":"1162_CR5","doi-asserted-by":"publisher","DOI":"10.1016\/j.tjpad.2025.100224","volume":"12","author":"C Bermudez","year":"2025","unstructured":"Bermudez, C. et al. Impact of cardiovascular risk factors on plasma biomarkers in prediction of Alzheimer\u2019s and cerebrovascular neuropathology. J. Prev. Alzheimers Dis. 12, 100224 (2025).","journal-title":"J. Prev. Alzheimers Dis."},{"key":"1162_CR6","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1001\/jamaneurol.2023.0199","volume":"80","author":"S Janelidze","year":"2023","unstructured":"Janelidze, S., Barth\u00e9lemy, N. R., He, Y., Bateman, R. J. & Hansson, O. Mitigating the associations of kidney dysfunction with blood biomarkers of Alzheimer disease by using phosphorylated tau to total tau ratios. JAMA Neurol. 80, 516\u2013522 (2023).","journal-title":"JAMA Neurol."},{"key":"1162_CR7","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70765","volume":"21","author":"T Jacobs","year":"2025","unstructured":"Jacobs, T. et al. Body mass index and blood volume influence plasma biomarkers and positron emission tomography classification in preclinical Alzheimer\u2019s disease. Alzheimers Dement. 21, e70765 (2025).","journal-title":"Alzheimers Dement."},{"key":"1162_CR8","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1007\/s00401-024-02706-0","volume":"147","author":"J Rutledge","year":"2024","unstructured":"Rutledge, J. et al. Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson\u2019s disease. Acta Neuropathol. 147, 52 (2024).","journal-title":"Acta Neuropathol."},{"key":"1162_CR9","doi-asserted-by":"publisher","first-page":"2444","DOI":"10.1002\/alz.13658","volume":"20","author":"G Bellomo","year":"2024","unstructured":"Bellomo, G. et al. Investigating alpha-synuclein co-pathology in Alzheimer\u2019s disease by means of cerebrospinal fluid alpha-synuclein seed amplification assay. Alzheimers Dement. 20, 2444\u20132452 (2024).","journal-title":"Alzheimers Dement."},{"key":"1162_CR10","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-52299-1","volume":"15","author":"LE Collij","year":"2024","unstructured":"Collij, L. E. et al. Lewy body pathology exacerbates brain hypometabolism and cognitive decline in Alzheimer\u2019s disease. Nat. Commun. 15, 8061 (2024).","journal-title":"Nat. Commun."},{"key":"1162_CR11","doi-asserted-by":"publisher","first-page":"4495","DOI":"10.1093\/brain\/awad213","volume":"146","author":"EL van der Ende","year":"2023","unstructured":"van der Ende, E. L. et al. CSF proteomics in autosomal dominant Alzheimer\u2019s disease highlights parallels with sporadic disease. Brain 146, 4495\u20134507 (2023).","journal-title":"Brain"},{"key":"1162_CR12","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1002\/alz.12369","volume":"18","author":"Y Jiang","year":"2022","unstructured":"Jiang, Y. et al. Large-scale plasma proteomic profiling identifies a high-performance biomarker panel for Alzheimer\u2019s disease screening and staging. Alzheimers Dement. 18, 88\u2013102 (2022).","journal-title":"Alzheimers Dement."},{"key":"1162_CR13","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1038\/s43587-025-00872-8","volume":"5","author":"G Heo","year":"2025","unstructured":"Heo, G. et al. Large-scale plasma proteomic profiling unveils diagnostic biomarkers and pathways for Alzheimer\u2019s disease. Nat. Aging 5, 1114\u20131131 (2025).","journal-title":"Nat. Aging"},{"key":"1162_CR14","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1186\/s13195-022-01113-5","volume":"14","author":"EB Dammer","year":"2022","unstructured":"Dammer, E. B. et al. Multi-platform proteomic analysis of Alzheimer\u2019s disease cerebrospinal fluid and plasma reveals network biomarkers associated with proteostasis and the matrisome. Alzheimers Res. Ther. 14, 174 (2022).","journal-title":"Alzheimers Res. Ther."},{"key":"1162_CR15","doi-asserted-by":"publisher","first-page":"2567","DOI":"10.1038\/s41591-025-03833-1","volume":"31","author":"M Ali","year":"2025","unstructured":"Ali, M. et al. Shared and disease-specific pathways in frontotemporal dementia and Alzheimer\u2019s and Parkinson\u2019s diseases. Nat. Med. 31, 2567\u20132577 (2025).","journal-title":"Nat. Med."},{"key":"1162_CR16","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.cell.2024.10.045","volume":"188","author":"Y-T Deng","year":"2025","unstructured":"Deng, Y.-T. et al. Atlas of the plasma proteome in health and disease in 53,026 adults. Cell 188, 253\u2013271 (2025).","journal-title":"Cell"},{"key":"1162_CR17","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1186\/s13195-024-01578-6","volume":"16","author":"L Meng","year":"2024","unstructured":"Meng, L. et al. Multi-omics analysis reveals the key factors involved in the severity of the Alzheimer\u2019s disease. Alzheimers Res. Ther. 16, 213 (2024).","journal-title":"Alzheimers Res. Ther."},{"key":"1162_CR18","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2019103649","volume":"39","author":"TM Nthiga","year":"2020","unstructured":"Nthiga, T. M. et al. CALCOCO1 acts with VAMP-associated proteins to mediate ER-phagy. EMBO J. 39, e103649 (2020).","journal-title":"EMBO J."},{"key":"1162_CR19","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1002\/jnr.25225","volume":"101","author":"MA Hill","year":"2023","unstructured":"Hill, M. A., Sykes, A. M. & Mellick, G. D. ER-phagy in neurodegeneration. J. Neurosci. Res. 101, 1611\u20131623 (2023).","journal-title":"J. Neurosci. Res."},{"key":"1162_CR20","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.54083","volume":"9","author":"L Sebastian Monasor","year":"2020","unstructured":"Sebastian Monasor, L. et al. Fibrillar A\u03b2 triggers microglial proteome alterations and dysfunction in Alzheimer mouse models. eLife 9, e54083 (2020).","journal-title":"eLife"},{"key":"1162_CR21","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2023.106356","volume":"189","author":"AL Wojda\u0142a","year":"2023","unstructured":"Wojda\u0142a, A. L. et al. Trajectories of CSF and plasma biomarkers across Alzheimer\u2019s disease continuum: disease staging by NF-L, p-tau181, and GFAP. Neurobiol. Dis. 189, 106356 (2023).","journal-title":"Neurobiol. Dis."},{"key":"1162_CR22","doi-asserted-by":"publisher","first-page":"1775","DOI":"10.1038\/s41591-023-02380-x","volume":"29","author":"B Bellaver","year":"2023","unstructured":"Bellaver, B. et al. Astrocyte reactivity influences amyloid-\u03b2 effects on tau pathology in preclinical Alzheimer\u2019s disease. Nat. Med. 29, 1775\u20131781 (2023).","journal-title":"Nat. Med."},{"key":"1162_CR23","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-024-00750-8","volume":"19","author":"T Guo","year":"2024","unstructured":"Guo, T. et al. Astrocyte reactivity is associated with tau tangle load and cortical thinning in Alzheimer\u2019s disease. Mol. Neurodegener. 19, 58 (2024).","journal-title":"Mol. Neurodegener."},{"key":"1162_CR24","doi-asserted-by":"publisher","first-page":"828","DOI":"10.14283\/jpad.2023.83","volume":"10","author":"A Feizpour","year":"2023","unstructured":"Feizpour, A. et al. Two-year prognostic utility of plasma p217+tau across the Alzheimer\u2019s continuum. J. Prev. Alzheimers Dis. 10, 828\u2013836 (2023).","journal-title":"J. Prev. Alzheimers Dis."},{"key":"1162_CR25","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1038\/s43587-024-00599-y","volume":"4","author":"G Salvad\u00f3","year":"2024","unstructured":"Salvad\u00f3, G. et al. Disease staging of Alzheimer\u2019s disease using a CSF-based biomarker model. Nat. Aging 4, 694\u2013708 (2024).","journal-title":"Nat. Aging"},{"key":"1162_CR26","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-024-00749-1","volume":"19","author":"A Shantaraman","year":"2024","unstructured":"Shantaraman, A. et al. Network proteomics of the Lewy body dementia brain reveals presynaptic signatures distinct from Alzheimer\u2019s disease. Mol. Neurodegener. 19, 60 (2024).","journal-title":"Mol. Neurodegener."},{"key":"1162_CR27","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2022.101771","volume":"83","author":"A Tsamourgelis","year":"2023","unstructured":"Tsamourgelis, A., Swann, P., Chouliaras, L. & O\u2019Brien, J. T. From protein biomarkers to proteomics in dementia with Lewy Bodies. Ageing Res. Rev. 83, 101771 (2023).","journal-title":"Ageing Res. Rev."},{"key":"1162_CR28","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1002\/gps.4274","volume":"30","author":"I Suzuki","year":"2015","unstructured":"Suzuki, I. et al. Serum peptides as candidate biomarkers for dementia with Lewy bodies. Int. J. Geriatr. Psychiatry 30, 1195\u20131206 (2015).","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"1162_CR29","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1038\/s43587-025-00818-0","volume":"5","author":"Y-H Gan","year":"2025","unstructured":"Gan, Y.-H. et al. Large-scale proteomic analyses of incident Parkinson\u2019s disease reveal new pathophysiological insights and potential biomarkers. Nat. Aging 5, 642\u2013657 (2025).","journal-title":"Nat. Aging"},{"key":"1162_CR30","doi-asserted-by":"publisher","first-page":"31388","DOI":"10.1074\/jbc.M110.113878","volume":"285","author":"K Ieguchi","year":"2010","unstructured":"Ieguchi, K. et al. Direct binding of the EGF-like domain of neuregulin-1 to integrins (\u03b1v\u03b23 and \u03b16\u03b24) is involved in neuregulin-1\/ErbB signaling. J. Biol. Chem. 285, 31388\u201331398 (2010).","journal-title":"J. Biol. Chem."},{"key":"1162_CR31","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.neulet.2014.12.024","volume":"587","author":"Y Hama","year":"2015","unstructured":"Hama, Y. et al. Level of plasma neuregulin-1 SMDF is reduced in patients with idiopathic Parkinson\u2019s disease. Neurosci. Lett. 587, 17\u201321 (2015).","journal-title":"Neurosci. Lett."},{"key":"1162_CR32","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1111\/j.1471-4159.2011.07284.x","volume":"117","author":"T Carlsson","year":"2011","unstructured":"Carlsson, T. et al. Systemic administration of neuregulin-1\u03b21 protects dopaminergic neurons in a mouse model of Parkinson\u2019s disease. J. Neurochem. 117, 1066\u20131074 (2011).","journal-title":"J. Neurochem."},{"key":"1162_CR33","doi-asserted-by":"publisher","DOI":"10.1038\/srep42111","volume":"7","author":"Y Izumi","year":"2017","unstructured":"Izumi, Y. et al. Integrin \u03b15\u03b21 expression on dopaminergic neurons is involved in dopaminergic neurite outgrowth on striatal neurons. Sci. Rep. 7, 42111 (2017).","journal-title":"Sci. Rep."},{"key":"1162_CR34","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaf284","volume":"7","author":"D Urso","year":"2025","unstructured":"Urso, D. et al. Striatal dopaminergic patterns and clinical features in frontotemporal dementia. Brain Commun. 7, fcaf284 (2025).","journal-title":"Brain Commun."},{"key":"1162_CR35","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-025-00882-5","volume":"20","author":"YS Hok-A-Hin","year":"2025","unstructured":"Hok-A-Hin, Y. S. et al. Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia. Mol. Neurodegener. 20, 93 (2025).","journal-title":"Mol. Neurodegener."},{"key":"1162_CR36","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23620-z","volume":"12","author":"NJ Ashton","year":"2021","unstructured":"Ashton, N. J. et al. A multicentre validation study of the diagnostic value of plasma neurofilament light. Nat. Commun. 12, 3400 (2021).","journal-title":"Nat. Commun."},{"key":"1162_CR37","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.jpsychires.2019.03.019","volume":"113","author":"MR Al Shweiki","year":"2019","unstructured":"Al Shweiki, M. R. et al. Neurofilament light chain as a blood biomarker to differentiate psychiatric disorders from behavioural variant frontotemporal dementia. J. Psychiatr. Res. 113, 137\u2013140 (2019).","journal-title":"J. Psychiatr. Res."},{"key":"1162_CR38","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-021-00275-w","volume":"10","author":"N Zhu","year":"2021","unstructured":"Zhu, N. et al. Plasma glial fibrillary acidic protein and neurofilament light chain for the diagnostic and prognostic evaluation of frontotemporal dementia. Transl. Neurodegener. 10, 50 (2021).","journal-title":"Transl. Neurodegener."},{"key":"1162_CR39","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1136\/jnnp-2019-321954","volume":"91","author":"C Heller","year":"2020","unstructured":"Heller, C. et al. Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia. J. Neurol. Neurosurg. Psychiatry 91, 263\u2013270 (2020).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"1162_CR40","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1001\/jamaneurol.2022.3265","volume":"79","author":"KAQ Cousins","year":"2022","unstructured":"Cousins, K. A. Q. et al. Distinguishing frontotemporal lobar degeneration tau from TDP-43 using plasma biomarkers. JAMA Neurol. 79, 1155\u20131164 (2022).","journal-title":"JAMA Neurol."},{"key":"1162_CR41","doi-asserted-by":"publisher","first-page":"2513","DOI":"10.4103\/1673-5374.391309","volume":"19","author":"W Chen","year":"2024","unstructured":"Chen, W., Jiang, S., Li, S., Li, C. & Xu, R. OSMR is a potential driver of inflammation in amyotrophic lateral sclerosis. Neural Regen. Res. 19, 2513\u20132521 (2024).","journal-title":"Neural Regen. Res."},{"key":"1162_CR42","doi-asserted-by":"publisher","first-page":"56","DOI":"10.3389\/fncel.2016.00056","volume":"10","author":"RJ Turner","year":"2016","unstructured":"Turner, R. J. & Sharp, F. R. Implications of MMP9 for blood brain barrier disruption and hemorrhagic transformation following ischemic stroke. Front. Cell Neurosci. 10, 56 (2016).","journal-title":"Front. Cell Neurosci."},{"key":"1162_CR43","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.3233\/JAD-170850","volume":"62","author":"WM van der Flier","year":"2018","unstructured":"van der Flier, W. M. & Scheltens, P. Amsterdam Dementia Cohort: performing research to optimize care. J. Alzheimers Dis. 62, 1091\u20131111 (2018).","journal-title":"J. Alzheimers Dis."},{"key":"1162_CR44","first-page":"597","volume":"5","author":"D Alcolea","year":"2019","unstructured":"Alcolea, D. et al. The Sant Pau Initiative on Neurodegeneration (SPIN) cohort: a data set for biomarker discovery and validation in neurodegenerative disorders. Alzheimers Dement. 5, 597\u2013609 (2019).","journal-title":"Alzheimers Dement."},{"key":"1162_CR45","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1021\/acs.jproteome.9b00824","volume":"19","author":"P Oeckl","year":"2020","unstructured":"Oeckl, P. et al. Targeted mass spectrometry suggests beta-synuclein as synaptic blood marker in Alzheimer\u2019s disease. J. Proteome Res. 19, 1310\u20131318 (2020).","journal-title":"J. Proteome Res."},{"key":"1162_CR46","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10918","volume":"7","author":"N Mattsson","year":"2016","unstructured":"Mattsson, N. et al. Increased amyloidogenic APP processing in APOE \u025b4-negative individuals with cerebral \u03b2-amyloidosis. Nat. Commun. 7, 10918 (2016).","journal-title":"Nat. Commun."},{"key":"1162_CR47","doi-asserted-by":"publisher","first-page":"443","DOI":"10.3233\/ADR-210005","volume":"5","author":"C Fowler","year":"2021","unstructured":"Fowler, C. et al. Fifteen years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study: progress and observations from 2,359 older adults spanning the spectrum from cognitive normality to Alzheimer\u2019s disease. J. Alzheimers Dis. Rep. 5, 443\u2013468 (2021).","journal-title":"J. Alzheimers Dis. Rep."},{"key":"1162_CR48","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2019-030379","volume":"9","author":"K Sheardova","year":"2019","unstructured":"Sheardova, K. et al. Czech Brain Aging Study (CBAS): prospective multicentre cohort study on risk and protective factors for dementia in the Czech Republic. BMJ Open 9, e030379 (2019).","journal-title":"BMJ Open"},{"key":"1162_CR49","doi-asserted-by":"publisher","first-page":"4056","DOI":"10.1093\/brain\/awac013","volume":"145","author":"C Bridel","year":"2022","unstructured":"Bridel, C. et al. Associating Alzheimer\u2019s disease pathology with its cerebrospinal fluid biomarkers. Brain 145, 4056\u20134064 (2022).","journal-title":"Brain"},{"key":"1162_CR50","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1016\/j.jalz.2014.01.001","volume":"10","author":"F Jessen","year":"2014","unstructured":"Jessen, F. et al. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer\u2019s disease. Alzheimers Dement. 10, 844\u2013852 (2014).","journal-title":"Alzheimers Dement."},{"key":"1162_CR51","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.jalz.2011.03.008","volume":"7","author":"MS Albert","year":"2011","unstructured":"Albert, M. S. et al. The diagnosis of mild cognitive impairment due to Alzheimer\u2019s disease: recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease. Alzheimers Dement. 7, 270\u2013279 (2011).","journal-title":"Alzheimers Dement."},{"key":"1162_CR52","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1016\/S1474-4422(07)70178-3","volume":"6","author":"B Dubois","year":"2007","unstructured":"Dubois, B. et al. Research criteria for the diagnosis of Alzheimer\u2019s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 6, 734\u2013746 (2007).","journal-title":"Lancet Neurol."},{"key":"1162_CR53","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1212\/WNL.0000000000004058","volume":"89","author":"IG McKeith","year":"2017","unstructured":"McKeith, I. G. et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology 89, 88\u2013100 (2017).","journal-title":"Neurology"},{"key":"1162_CR54","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1212\/WNL.53.5.1158-b","volume":"53","author":"R Faber","year":"1999","unstructured":"Faber, R. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 53, 1159 (1999).","journal-title":"Neurology"},{"key":"1162_CR55","doi-asserted-by":"publisher","first-page":"2456","DOI":"10.1093\/brain\/awr179","volume":"134","author":"K Rascovsky","year":"2011","unstructured":"Rascovsky, K. et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134, 2456\u20132477 (2011).","journal-title":"Brain"},{"key":"1162_CR56","doi-asserted-by":"publisher","first-page":"1914","DOI":"10.1212\/WNL.0b013e3181c47cc2","volume":"73","author":"CE Teunissen","year":"2009","unstructured":"Teunissen, C. E. et al. A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking. Neurology 73, 1914\u20131922 (2009).","journal-title":"Neurology"},{"key":"1162_CR57","doi-asserted-by":"publisher","first-page":"1863","DOI":"10.1212\/01.wnl.0000187889.17253.b1","volume":"65","author":"IG McKeith","year":"2005","unstructured":"McKeith, I. G. et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65, 1863\u20131872 (2005).","journal-title":"Neurology"},{"key":"1162_CR58","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00401-011-0910-3","volume":"123","author":"TJ Montine","year":"2012","unstructured":"Montine, T. J. et al. National Institute on Aging-Alzheimer\u2019s Association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease: a practical approach. Acta Neuropathol. 123, 1\u201311 (2012).","journal-title":"Acta Neuropathol."},{"key":"1162_CR59","doi-asserted-by":"publisher","first-page":"337","DOI":"10.3233\/JAD-2010-101149","volume":"21","author":"P Mart\u00ednez-Mart\u00edn","year":"2010","unstructured":"Mart\u00ednez-Mart\u00edn, P., Avila, J. & AD Research Unit Investigators. Alzheimer Center Reina Sofia Foundation: fighting the disease and providing overall solutions. J. Alzheimers Dis. 21, 337\u2013348 (2010).","journal-title":"J. Alzheimers Dis."},{"key":"1162_CR60","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1093\/brain\/awae035","volume":"147","author":"P S\u00e1nchez-Juan","year":"2024","unstructured":"S\u00e1nchez-Juan, P. et al. Serum GFAP levels correlate with astrocyte reactivity, post-mortem brain atrophy and neurofibrillary tangles. Brain 147, 1667\u20131679 (2024).","journal-title":"Brain"},{"key":"1162_CR61","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/S0197-4580(02)00065-9","volume":"24","author":"H Braak","year":"2003","unstructured":"Braak, H. et al. Staging of brain pathology related to sporadic Parkinson\u2019s disease. Neurobiol. Aging 24, 197\u2013211 (2003).","journal-title":"Neurobiol. Aging"},{"key":"1162_CR62","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/j.pneurobio.2011.09.005","volume":"95","author":"K Marek","year":"2011","unstructured":"Marek, K. et al. The Parkinson Progression Marker Initiative (PPMI). Prog. Neurobiol. 95, 629\u2013635 (2011).","journal-title":"Prog. Neurobiol."},{"key":"1162_CR63","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/S1474-4422(23)00405-2","volume":"23","author":"T Simuni","year":"2024","unstructured":"Simuni, T. et al. A biological definition of neuronal \u03b1-synuclein disease: towards an integrated staging system for research. Lancet Neurol. 23, 178\u2013190 (2024).","journal-title":"Lancet Neurol."},{"key":"1162_CR64","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1038\/s43587-022-00300-1","volume":"2","author":"M Del Campo","year":"2022","unstructured":"Del Campo, M. et al. CSF proteome profiling across the Alzheimer\u2019s disease spectrum reflects the multifactorial nature of the disease and identifies specific biomarker panels. Nat. Aging 2, 1040\u20131053 (2022).","journal-title":"Nat. Aging"},{"key":"1162_CR65","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1038\/s42003-019-0464-9","volume":"2","author":"S Enroth","year":"2019","unstructured":"Enroth, S. et al. High throughput proteomics identifies a high-accuracy 11 plasma protein biomarker signature for ovarian cancer. Commun. Biol. 2, 221 (2019).","journal-title":"Commun. Biol."},{"key":"1162_CR66","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","volume":"57","author":"Y Benjamini","year":"1995","unstructured":"Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Ser. B 57, 289\u2013300 (1995).","journal-title":"J. R. Stat. Soc. Ser. B"},{"key":"1162_CR67","unstructured":"Friedman, J. et al. glmnet: Lasso and elastic-net regularized generalized linear models (2021)."},{"key":"1162_CR68","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-77","volume":"12","author":"X Robin","year":"2011","unstructured":"Robin, X. et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 12, 77 (2011).","journal-title":"BMC Bioinformatics"}],"container-title":["Nature Aging"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s43587-026-01162-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43587-026-01162-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43587-026-01162-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T11:02:45Z","timestamp":1790161365000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s43587-026-01162-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,20]]},"references-count":68,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["1162"],"URL":"https:\/\/doi.org\/10.1038\/s43587-026-01162-7","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-6454116\/v1","asserted-by":"object"}]},"ISSN":["2662-8465"],"issn-type":[{"value":"2662-8465","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,20]]},"assertion":[{"value":"5 January 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 September 2026","order":5,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":6,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"In the version of the article initially published, the Synapse link in the Data Availability section was incorrect and has now been amended to","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/www.synapse.org\/Synapse:syn75233598","URL":"https:\/\/doi.org\/https:\/\/www.synapse.org\/Synapse:syn75233598","order":8,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"in the HTML and PDF versions of the article.","order":9,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A. Lle\u00f3 is an inventor on a patent application related to biomarkers of synaptopathy in neurodegenerative diseases (WO2019175379 A1, \u2018Markers of synaptopathy in neurodegenerative disease\u2019) and has served as a consultant to, or member of advisory boards for, Almirall, Biogen, Eisai, Fujirebio-Europe, Grifols, Lilly, Novartis, Nutricia and Roche, outside the submitted work. C.E.T. has research contracts with Acumen, ADx Neurosciences, AC Immune, Alamar, Aribio, Axon Neurosciences, Beckman Coulter, BioConnect, BioOrchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama and Vivoryon. She is Editor-in-Chief of\n                      Alzheimer\u2019s Research & Therapy\n                      , serves on the editorial boards of\n                      Molecular Neurodegeneration\n                      ,\n                      Neurology: Neuroimmunology & Neuroinflammatio\n                      n\n                      and Medidact Neurologie\/Springer Medizin, and serves on Dutch national committees developing guidelines for cognitive disorders and acute neurology. She has received consultancy or speaker fees from Aribio, Beckman Coulter, Biogen, Cognition Therapeutics, Eli Lilly, Merck, Novo Nordisk, Olink, Roche and Veravas. L.P. has served as an Advisory Board Member for Fujirebio, IBL, Roche and Merck. M.d.C. has received honoraria as an invited speaker from Eisai and Novo Nordisk and as an invited writer for Springer Healthcare. She is an Associate Editor of\n                      Alzheimer\u2019s Research & Therapy\n                      and serves as a scientific adviser to The Michael J. Fox Foundation. O.H. is employed by Lund University and Eli Lilly. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}