{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T02:15:47Z","timestamp":1794449747246,"version":"4.9.1"},"reference-count":80,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"vor","delay-in-days":0,"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":["P50AG047366"],"award-info":[{"award-number":["P50AG047366"]}],"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":["P30AG066515"],"award-info":[{"award-number":["P30AG066515"]}],"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":["AG072255"],"award-info":[{"award-number":["AG072255"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"publisher","award":["ADSF-25-1451396-C"],"award-info":[{"award-number":["ADSF-25-1451396-C"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"publisher","award":["ZEN-22-848604"],"award-info":[{"award-number":["ZEN-22-848604"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Additional funding from the Milky Way Research Foundation and the Knight Initiative for Brain Resilience"},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["T32MH020016"],"award-info":[{"award-number":["T32MH020016"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["F99AG088431"],"award-info":[{"award-number":["F99AG088431"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["T32HG000044"],"award-info":[{"award-number":["T32HG000044"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG048076"],"award-info":[{"award-number":["R01AG048076"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R21AG058859"],"award-info":[{"award-number":["R21AG058859"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG044546"],"award-info":[{"award-number":["R01AG044546"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["P01AG003991"],"award-info":[{"award-number":["P01AG003991"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["RF1AG053303"],"award-info":[{"award-number":["RF1AG053303"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["RF1AG058501"],"award-info":[{"award-number":["RF1AG058501"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["U01AG058922"],"award-info":[{"award-number":["U01AG058922"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS115114"],"award-info":[{"award-number":["NS115114"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Stanford Wu Tsai Neurosciences Institute Stanford Center for Precision Health and Integrated Diagnostics"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2025,8]]},"DOI":"10.1038\/s41591-025-03831-3","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T15:03:32Z","timestamp":1752591812000},"page":"2578-2589","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Disruption of the cerebrospinal fluid\u2013plasma protein balance in cognitive impairment and aging"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6697-8883","authenticated-orcid":false,"given":"Amelia","family":"Farinas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarod","family":"Rutledge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5060-1142","authenticated-orcid":false,"given":"Veronica Augustina","family":"Bot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3725-9553","authenticated-orcid":false,"given":"Daniel","family":"Western","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kejun","family":"Ying","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7304-8318","authenticated-orcid":false,"given":"Kathryn A.","family":"Lawrence","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8192-7593","authenticated-orcid":false,"given":"Hamilton Se-Hwee","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2780-7465","authenticated-orcid":false,"given":"Seonghyun","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisy Yi","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6400-544X","authenticated-orcid":false,"given":"Andy P.","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Moran-Losada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jigyasha","family":"Timsina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6649-8364","authenticated-orcid":false,"given":"Yann","family":"Le Guen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"The Global Neurodegeneration Proteomics Consortium (GNPC)","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5200-3903","authenticated-orcid":false,"given":"Stephen B.","family":"Montgomery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7896-6217","authenticated-orcid":false,"given":"David","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3424-7143","authenticated-orcid":false,"given":"Kathleen L.","family":"Poston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0624-4543","authenticated-orcid":false,"given":"Anthony D.","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Mormino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0276-2899","authenticated-orcid":false,"given":"Carlos","family":"Cruchaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5893-0831","authenticated-orcid":false,"given":"Tony","family":"Wyss-Coray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,15]]},"reference":[{"key":"3831_CR1","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/s41582-019-0244-7","volume":"15","author":"Y Hou","year":"2019","unstructured":"Hou, Y. et al. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 15, 565\u2013581 (2019).","journal-title":"Nat. Rev. Neurol."},{"key":"3831_CR2","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1016\/j.cger.2013.07.002","volume":"29","author":"CN Harada","year":"2013","unstructured":"Harada, C. N., Natelson Love, M. C. & Triebel, K. Normal cognitive aging. Clin. Geriatr. Med. 29, 737\u2013752 (2013).","journal-title":"Clin. Geriatr. Med."},{"key":"3831_CR3","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.neuron.2014.12.032","volume":"85","author":"A Montagne","year":"2015","unstructured":"Montagne, A. et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85, 296\u2013302 (2015).","journal-title":"Neuron"},{"key":"3831_CR4","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/s43587-021-00043-5","volume":"1","author":"WA Banks","year":"2021","unstructured":"Banks, W. A., Reed, M. J., Logsdon, A. F., Rhea, E. M. & Erickson, M. A. Healthy aging and the blood-brain barrier. Nat. Aging 1, 243\u2013254 (2021).","journal-title":"Nat. Aging"},{"key":"3831_CR5","doi-asserted-by":"publisher","first-page":"108119","DOI":"10.1016\/j.pharmthera.2022.108119","volume":"234","author":"G Nehra","year":"2022","unstructured":"Nehra, G., Bauer, B. & Hartz, A. M. S. Blood-brain barrier leakage in Alzheimer\u2019s disease: from discovery to clinical relevance. Pharmacol. Ther. 234, 108119 (2022).","journal-title":"Pharmacol. Ther."},{"key":"3831_CR6","doi-asserted-by":"publisher","first-page":"2911","DOI":"10.1111\/j.1582-4934.2008.00434.x","volume":"13","author":"JK Ryu","year":"2009","unstructured":"Ryu, J. K. & McLarnon, J. G. A leaky blood\u2013brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer\u2019s disease brain. J. Cell. Mol. Med. 13, 2911\u20132925 (2009).","journal-title":"J. Cell. Mol. Med."},{"key":"3831_CR7","doi-asserted-by":"crossref","unstructured":"Al-Bachari, S., Naish, J. H., Parker, G. J. M., Emsley, H. C. A. & Parkes, L. M. Blood\u2013brain barrier leakage Is increased in Parkinson\u2019s disease. Front. Physiol. 11, 593026 (2020).","DOI":"10.3389\/fphys.2020.593026"},{"key":"3831_CR8","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1038\/s41593-022-01124-3","volume":"25","author":"E Gerrits","year":"2022","unstructured":"Gerrits, E. et al. Neurovascular dysfunction in GRN-associated frontotemporal dementia identified by single-nucleus RNA sequencing of human cerebral cortex. Nat. Neurosci. 25, 1034\u20131048 (2022).","journal-title":"Nat. Neurosci."},{"key":"3831_CR9","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/s12987-020-00230-3","volume":"17","author":"H Kadry","year":"2020","unstructured":"Kadry, H., Noorani, B. & Cucullo, L. A blood\u2013brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS 17, 69 (2020).","journal-title":"Fluids Barriers CNS"},{"key":"3831_CR10","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1038\/s41586-020-2453-z","volume":"583","author":"AC Yang","year":"2020","unstructured":"Yang, A. C. et al. Physiological blood-brain transport is impaired with age by a shift in transcytosis. Nature 583, 425\u2013430 (2020).","journal-title":"Nature"},{"key":"3831_CR11","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1002\/prca.200780040","volume":"2","author":"S Roche","year":"2008","unstructured":"Roche, S., Gabelle, A. & Lehmann, S. Clinical proteomics of the cerebrospinal fluid: towards the discovery of new biomarkers. Proteomics Clin. Appl. 2, 428\u2013436 (2008).","journal-title":"Proteomics Clin. Appl."},{"key":"3831_CR12","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1038\/s41586-023-06802-1","volume":"624","author":"HS-H Oh","year":"2023","unstructured":"Oh, H. S.-H. et al. Organ aging signatures in the plasma proteome track health and disease. Nature 624, 164\u2013172 (2023).","journal-title":"Nature"},{"key":"3831_CR13","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/nrd.2015.21","volume":"15","author":"WA Banks","year":"2016","unstructured":"Banks, W. A. From blood\u2013brain barrier to blood\u2013brain interface: new opportunities for CNS drug delivery. Nat. Rev. Drug Discov. 15, 275\u2013292 (2016).","journal-title":"Nat. Rev. Drug Discov."},{"key":"3831_CR14","doi-asserted-by":"publisher","first-page":"6976","DOI":"10.1016\/j.biomaterials.2009.08.049","volume":"30","author":"W Ke","year":"2009","unstructured":"Ke, W. et al. Gene delivery targeted to the brain using an Angiopep-conjugated polyethyleneglycol-modified polyamidoamine dendrimer. Biomaterials 30, 6976\u20136985 (2009).","journal-title":"Biomaterials"},{"key":"3831_CR15","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1124\/jpet.107.131318","volume":"324","author":"M Demeule","year":"2008","unstructured":"Demeule, M. et al. Identification and design of peptides as a new drug delivery system for the brain. J. Pharmacol. Exp. Ther. 324, 1064\u20131072 (2008).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"3831_CR16","doi-asserted-by":"publisher","first-page":"1330484","DOI":"10.3389\/fneur.2023.1330484","volume":"14","author":"T Seeliger","year":"2024","unstructured":"Seeliger, T. et al. Comparative analysis of albumin quotient and total CSF protein in immune-mediated neuropathies: a multicenter study on diagnostic implications. Front. Neurol. 14, 1330484 (2024).","journal-title":"Front. Neurol."},{"key":"3831_CR17","doi-asserted-by":"publisher","first-page":"429","DOI":"10.3233\/JAD-200168","volume":"75","author":"CS Musaeus","year":"2020","unstructured":"Musaeus, C. S. et al. Cerebrospinal fluid\/plasma albumin ratio as a biomarker for blood-brain barrier impairment across neurodegenerative dementias. J. Alzheimers Dis. 75, 429\u2013436 (2020).","journal-title":"J. Alzheimers Dis."},{"key":"3831_CR18","doi-asserted-by":"publisher","DOI":"10.1186\/s12883-016-0564-9","volume":"16","author":"SM LeVine","year":"2016","unstructured":"LeVine, S. M. Albumin and multiple sclerosis. BMC Neurol. 16, 47 (2016).","journal-title":"BMC Neurol."},{"key":"3831_CR19","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1038\/nsb971","volume":"10","author":"M Huang","year":"2003","unstructured":"Huang, M. et al. Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins. Nat. Struct. Mol. Biol. 10, 751\u2013756 (2003).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"3831_CR20","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/jcbfm.2008.117","volume":"29","author":"R Deane","year":"2009","unstructured":"Deane, R. et al. Endothelial protein C receptor-assisted transport of activated protein C across the mouse blood-brain barrier. J. Cereb. Blood Flow. Metab. 29, 25\u201333 (2009).","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"3831_CR21","doi-asserted-by":"publisher","first-page":"e30","DOI":"10.1212\/WNL.0000000000207358","volume":"101","author":"C Cicognola","year":"2023","unstructured":"Cicognola, C. et al. Associations of CSF PDGFR\u03b2 with aging, blood-brain barrier damage, neuroinflammation, and Alzheimer disease pathologic changes. Neurology 101, e30\u2013e39 (2023).","journal-title":"Neurology"},{"key":"3831_CR22","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1002\/jnr.490180206","volume":"18","author":"JB Fishman","year":"1987","unstructured":"Fishman, J. B., Rubin, J. B., Handrahan, J. V., Connor, J. R. & Fine, R. E. Receptor-mediated transcytosis of transferrin across the blood-brain barrier. J. Neurosci. Res. 18, 299\u2013304 (1987).","journal-title":"J. Neurosci. Res."},{"key":"3831_CR23","doi-asserted-by":"publisher","first-page":"2860","DOI":"10.3390\/ijms22062860","volume":"22","author":"Y Moon","year":"2021","unstructured":"Moon, Y., Lim, C., Kim, Y. & Moon, W.-J. Sex-related differences in regional blood\u2013brain barrier integrity in non-demented elderly subjects. Int. J. Mol. Sci. 22, 2860 (2021).","journal-title":"Int. J. Mol. Sci."},{"key":"3831_CR24","doi-asserted-by":"publisher","first-page":"RP96155","DOI":"10.7554\/eLife.96155.3","volume":"13","author":"X Shao","year":"2024","unstructured":"Shao, X. et al. Age-related decline in blood-brain barrier function is more pronounced in males than females in parietal and temporal regions. eLife 13, RP96155 (2024).","journal-title":"eLife"},{"key":"3831_CR25","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.metabol.2014.08.004","volume":"64","author":"H-K Park","year":"2015","unstructured":"Park, H.-K. & Ahima, R. S. Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism 64, 24\u201334 (2015).","journal-title":"Metabolism"},{"key":"3831_CR26","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1038\/nm1029","volume":"10","author":"Y Qi","year":"2004","unstructured":"Qi, Y. et al. Adiponectin acts in the brain to decrease body weight. Nat. Med. 10, 524\u2013529 (2004).","journal-title":"Nat. Med."},{"key":"3831_CR27","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1152\/physrev.00007.2010","volume":"91","author":"GJ Morton","year":"2011","unstructured":"Morton, G. J. & Schwartz, M. W. Leptin and the central nervous system control of glucose metabolism. Physiol. Rev. 91, 389\u2013411 (2011).","journal-title":"Physiol. Rev."},{"key":"3831_CR28","doi-asserted-by":"crossref","unstructured":"Oh, H. S.-H. et al. A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer\u2019s disease. Nat. Med. 31, 1592\u20131603 (2025).","DOI":"10.1038\/s41591-025-03565-2"},{"key":"3831_CR29","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2025.02.014","author":"M Ali","year":"2025","unstructured":"Ali, M. et al. Multi-cohort cerebrospinal fluid proteomics identifies robust molecular signatures across the Alzheimer disease continuum. Neuron https:\/\/doi.org\/10.1016\/j.neuron.2025.02.014 (2025).","journal-title":"Neuron"},{"key":"3831_CR30","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1038\/nrn.2018.13","volume":"19","author":"MA Petersen","year":"2018","unstructured":"Petersen, M. A., Ryu, J. K. & Akassoglou, K. Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics. Nat. Rev. Neurosci. 19, 283\u2013301 (2018).","journal-title":"Nat. Rev. Neurosci."},{"key":"3831_CR31","doi-asserted-by":"publisher","first-page":"33211","DOI":"10.1074\/jbc.M804440200","volume":"283","author":"AY Kim","year":"2008","unstructured":"Kim, A. Y. et al. SCCRO (DCUN1D1) Is an essential component of the E3 complex for neddylation*. J. Biol. Chem. 283, 33211\u201333220 (2008).","journal-title":"J. Biol. Chem."},{"key":"3831_CR32","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1186\/s40478-021-01257-9","volume":"9","author":"P Marazuela","year":"2021","unstructured":"Marazuela, P. et al. MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid angiopathy. Acta Neuropathol. Commun. 9, 154 (2021).","journal-title":"Acta Neuropathol. Commun."},{"key":"3831_CR33","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1038\/s41586-022-05440-3","volume":"612","author":"J Wagner","year":"2022","unstructured":"Wagner, J. et al. Medin co-aggregates with vascular amyloid-\u03b2 in Alzheimer\u2019s disease. Nature 612, 123\u2013131 (2022).","journal-title":"Nature"},{"key":"3831_CR34","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1007\/s00406-013-0405-4","volume":"263","author":"L-H Guo","year":"2013","unstructured":"Guo, L.-H., Alexopoulos, P. & Perneczky, R. Heart-type fatty acid binding protein and vascular endothelial growth factor: cerebrospinal fluid biomarker candidates for Alzheimer\u2019s disease. Eur. Arch. Psychiatry Clin. Neurosci. 263, 553\u2013560 (2013).","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"3831_CR35","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1038\/s41380-019-0458-5","volume":"26","author":"ER Mahoney","year":"2021","unstructured":"Mahoney, E. R. et al. Brain expression of the vascular endothelial growth factor gene family in cognitive aging and alzheimer\u2019s disease. Mol. Psychiatry 26, 888\u2013896 (2021).","journal-title":"Mol. Psychiatry"},{"key":"3831_CR36","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1089\/rej.2006.9.485","volume":"9","author":"M Chiappelli","year":"2006","unstructured":"Chiappelli, M. et al. VEGF gene and phenotype relation with Alzheimer\u2019s disease and mild cognitive impairment. Rejuv. Res. 9, 485\u2013493 (2006).","journal-title":"Rejuv. Res."},{"key":"3831_CR37","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/S0197-4580(01)00285-8","volume":"23","author":"E Tarkowski","year":"2002","unstructured":"Tarkowski, E. et al. Increased intrathecal levels of the angiogenic factors VEGF and TGF-\u03b2 in Alzheimer\u2019s disease and vascular dementia. Neurobiol. Aging 23, 237\u2013243 (2002).","journal-title":"Neurobiol. Aging"},{"key":"3831_CR38","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1001\/jamaneurol.2014.4761","volume":"72","author":"TJ Hohman","year":"2015","unstructured":"Hohman, T. J., Bell, S. P., Jefferson, A. L. & for the Alzheimer\u2019s Disease Neuroimaging Initiative. The role of vascular endothelial growth factor in neurodegeneration and cognitive decline: exploring interactions with biomarkers of Alzheimer Disease. JAMA Neurol. 72, 520\u2013529 (2015).","journal-title":"JAMA Neurol."},{"key":"3831_CR39","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/nm1233","volume":"11","author":"J-S Silvestre","year":"2005","unstructured":"Silvestre, J.-S. et al. Lactadherin promotes VEGF-dependent neovascularization. Nat. Med. 11, 499\u2013506 (2005).","journal-title":"Nat. Med."},{"key":"3831_CR40","doi-asserted-by":"publisher","first-page":"1712","DOI":"10.1038\/s41588-021-00978-w","volume":"53","author":"E Ferkingstad","year":"2021","unstructured":"Ferkingstad, E. et al. Large-scale integration of the plasma proteome with genetics and disease. Nat. Genet. 53, 1712\u20131721 (2021).","journal-title":"Nat. Genet."},{"key":"3831_CR41","doi-asserted-by":"publisher","first-page":"2672","DOI":"10.1038\/s41588-024-01972-8","volume":"56","author":"D Western","year":"2024","unstructured":"Western, D. et al. Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer\u2019s disease. Nat. Genet. 56, 2672\u20132684 (2024).","journal-title":"Nat. Genet."},{"key":"3831_CR42","first-page":"D845","volume":"48","author":"J Pi\u00f1ero","year":"2020","unstructured":"Pi\u00f1ero, J. et al. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res. 48, D845\u2013D855 (2020).","journal-title":"Nucleic Acids Res."},{"key":"3831_CR43","doi-asserted-by":"publisher","first-page":"eadl3758","DOI":"10.1126\/scitranslmed.adl3758","volume":"16","author":"JV Pluvinage","year":"2024","unstructured":"Pluvinage, J. V. et al. Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency. Sci. Transl. Med. 16, eadl3758 (2024).","journal-title":"Sci. Transl. Med."},{"key":"3831_CR44","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s12263-018-0591-9","volume":"13","author":"S Surendran","year":"2018","unstructured":"Surendran, S. et al. An update on vitamin B12-related gene polymorphisms and B12 status. Genes Nutr. 13, 2 (2018).","journal-title":"Genes Nutr."},{"key":"3831_CR45","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1373\/49.7.1195","volume":"49","author":"H Zetterberg","year":"2003","unstructured":"Zetterberg, H. et al. The transcobalamin (TC) codon 259 genetic polymorphism influences holo-TC concentration in cerebrospinal fluid from patients with Alzheimer disease. Clin. Chem. 49, 1195\u20131198 (2003).","journal-title":"Clin. Chem."},{"key":"3831_CR46","doi-asserted-by":"publisher","first-page":"138797","DOI":"10.1155\/2012\/138797","volume":"2012","author":"DC Kilpatrick","year":"2012","unstructured":"Kilpatrick, D. C. & Chalmers, J. D. Human l-ficolin (ficolin-2) and its clinical significance. J. Biomed. Biotechnol. 2012, 138797 (2012).","journal-title":"J. Biomed. Biotechnol."},{"key":"3831_CR47","doi-asserted-by":"publisher","first-page":"712545","DOI":"10.3389\/fnagi.2021.712545","volume":"13","author":"L Shi","year":"2021","unstructured":"Shi, L. et al. Plasma proteomic biomarkers relating to Alzheimer\u2019s disease: a meta-analysis based on our own studies. Front. Aging Neurosci. 13, 712545 (2021).","journal-title":"Front. Aging Neurosci."},{"key":"3831_CR48","doi-asserted-by":"publisher","first-page":"2560","DOI":"10.1089\/neu.2016.4941","volume":"34","author":"M Osthoff","year":"2017","unstructured":"Osthoff, M., Walder, B., Delhumeau, C., Trendelenburg, M. & Turck, N. Association of lectin pathway protein levels and genetic variants early after injury with outcomes after severe traumatic brain injury: a prospective cohort study. J. Neurotrauma 34, 2560\u20132566 (2017).","journal-title":"J. Neurotrauma"},{"key":"3831_CR49","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1177\/0271678X18758881","volume":"39","author":"D De Blasio","year":"2019","unstructured":"De Blasio, D. et al. Human brain trauma severity is associated with lectin complement pathway activation. J. Cereb. Blood Flow. Metab. 39, 794\u2013807 (2019).","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"3831_CR50","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1186\/s40478-020-01041-1","volume":"8","author":"D Mercurio","year":"2020","unstructured":"Mercurio, D. et al. Targeted deletions of complement lectin pathway genes improve outcome in traumatic brain injury, with MASP-2 playing a major role. Acta Neuropathol. Commun. 8, 174 (2020).","journal-title":"Acta Neuropathol. Commun."},{"key":"3831_CR51","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42682-9","volume":"14","author":"J \u00c5kesson","year":"2023","unstructured":"\u00c5kesson, J. et al. Proteomics reveal biomarkers for diagnosis, disease activity and long-term disability outcomes in multiple sclerosis. Nat. Commun. 14, 6903 (2023).","journal-title":"Nat. Commun."},{"key":"3831_CR52","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1002\/ana.25670","volume":"87","author":"Y Zhou","year":"2020","unstructured":"Zhou, Y. et al. Impairment of the glymphatic pathway and putative meningeal lymphatic vessels in the aging human. Ann. Neurol. 87, 357\u2013369 (2020).","journal-title":"Ann. Neurol."},{"key":"3831_CR53","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.neuron.2024.09.017","volume":"113","author":"L-F Jiang-Xie","year":"2025","unstructured":"Jiang-Xie, L.-F., Drieu, A. & Kipnis, J. Waste clearance shapes aging brain health. Neuron 113, 71\u201381 (2025).","journal-title":"Neuron"},{"key":"3831_CR54","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/2045-8118-8-3","volume":"8","author":"Z Redzic","year":"2011","unstructured":"Redzic, Z. Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences. Fluids Barriers CNS 8, 3 (2011).","journal-title":"Fluids Barriers CNS"},{"key":"3831_CR55","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1038\/s41593-022-01238-8","volume":"26","author":"G Bieri","year":"2023","unstructured":"Bieri, G., Schroer, A. B. & Villeda, S. A. Blood-to-brain communication in aging and rejuvenation. Nat. Neurosci. 26, 379\u2013393 (2023).","journal-title":"Nat. Neurosci."},{"key":"3831_CR56","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s12987-020-0173-2","volume":"17","author":"M Castellazzi","year":"2020","unstructured":"Castellazzi, M. et al. Increased age and male sex are independently associated with higher frequency of blood\u2013cerebrospinal fluid barrier dysfunction using the albumin quotient. Fluids Barriers CNS 17, 14 (2020).","journal-title":"Fluids Barriers CNS"},{"key":"3831_CR57","doi-asserted-by":"publisher","first-page":"5151","DOI":"10.1111\/jcmm.13767","volume":"22","author":"C Parrado-Fern\u00e1ndez","year":"2018","unstructured":"Parrado-Fern\u00e1ndez, C. et al. Evidence for sex difference in the CSF\/plasma albumin ratio in 20\u2009000 patients and 335 healthy volunteers. J. Cell. Mol. Med. 22, 5151\u20135154 (2018).","journal-title":"J. Cell. Mol. Med."},{"key":"3831_CR58","doi-asserted-by":"publisher","first-page":"3365","DOI":"10.1002\/alz.12962","volume":"19","author":"J Gong","year":"2023","unstructured":"Gong, J. et al. Sex differences in dementia risk and risk factors: Individual-participant data analysis using 21 cohorts across six continents from the COSMIC consortium. Alzheimers Dement. 19, 3365\u20133378 (2023).","journal-title":"Alzheimers Dement."},{"key":"3831_CR59","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1038\/s41586-021-04369-3","volume":"603","author":"AC Yang","year":"2022","unstructured":"Yang, A. C. et al. A human brain vascular atlas reveals diverse mediators of Alzheimer\u2019s risk. Nature 603, 885\u2013892 (2022).","journal-title":"Nature"},{"key":"3831_CR60","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-69096-7","volume":"10","author":"HW Song","year":"2020","unstructured":"Song, H. W. et al. Transcriptomic comparison of human and mouse brain microvessels. Sci. Rep. 10, 12358 (2020).","journal-title":"Sci. Rep."},{"key":"3831_CR61","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.2174\/1567201819666220303102614","volume":"19","author":"B Shah","year":"2022","unstructured":"Shah, B. & Dong, X. Current status of in vitro models of the blood-brain barrier. Curr. Drug Deliv. 19, 1034\u20131046 (2022).","journal-title":"Curr. Drug Deliv."},{"key":"3831_CR62","doi-asserted-by":"publisher","first-page":"eaay1359","DOI":"10.1126\/scitranslmed.aay1359","volume":"12","author":"MS Kariolis","year":"2020","unstructured":"Kariolis, M. S. et al. Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys. Sci. Transl. Med. 12, eaay1359 (2020).","journal-title":"Sci. Transl. Med."},{"key":"3831_CR63","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-57108-x","volume":"16","author":"N Khoury","year":"2025","unstructured":"Khoury, N. et al. Fc-engineered large molecules targeting blood-brain barrier transferrin receptor and CD98hc have distinct central nervous system and peripheral biodistribution. Nat. Commun. 16, 1822 (2025).","journal-title":"Nat. Commun."},{"key":"3831_CR64","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1002\/acn3.52034","volume":"11","author":"MJ Plastini","year":"2024","unstructured":"Plastini, M. J. et al. Multiple biomarkers improve diagnostic accuracy across Lewy body and Alzheimer\u2019s disease spectra. Ann. Clin. Transl. Neurol. 11, 1197\u20131210 (2024).","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"3831_CR65","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1212\/WNL.34.7.939","volume":"34","author":"G McKhann","year":"1984","unstructured":"McKhann, G. et al. Clinical diagnosis of Alzheimer\u2019s disease. Neurology 34, 939\u2013944 (1984).","journal-title":"Neurology"},{"key":"3831_CR66","doi-asserted-by":"publisher","first-page":"e15004","DOI":"10.1371\/journal.pone.0015004","volume":"5","author":"L Gold","year":"2010","unstructured":"Gold, L. et al. Aptamer-based multiplexed proteomic technology for biomarker discovery. PLoS ONE 5, e15004 (2010).","journal-title":"PLoS ONE"},{"key":"3831_CR67","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.1038\/s41591-019-0665-2","volume":"25","author":"SA Williams","year":"2019","unstructured":"Williams, S. A. et al. Plasma protein patterns as comprehensive indicators of health. Nat. Med. 25, 1851\u20131857 (2019).","journal-title":"Nat. Med."},{"key":"3831_CR68","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1126\/science.aaz1776","volume":"369","author":"The GTEx Consortium.","year":"2020","unstructured":"The GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science 369, 1318\u20131330 (2020).","journal-title":"Science"},{"key":"3831_CR69","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).","journal-title":"Genome Biol."},{"key":"3831_CR70","doi-asserted-by":"publisher","first-page":"1260419","DOI":"10.1126\/science.1260419","volume":"347","author":"M Uhl\u00e9n","year":"2015","unstructured":"Uhl\u00e9n, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015).","journal-title":"Science"},{"key":"3831_CR71","doi-asserted-by":"publisher","first-page":"711524","DOI":"10.3389\/fnagi.2021.711524","volume":"13","author":"S Peng","year":"2021","unstructured":"Peng, S. et al. Transcriptomic changes highly similar to Alzheimer\u2019s disease are observed in a subpopulation of individuals during normal brain aging. Front. Aging Neurosci. 13, 711524 (2021).","journal-title":"Front. Aging Neurosci."},{"key":"3831_CR72","doi-asserted-by":"publisher","DOI":"10.1038\/s41597-024-03485-9","volume":"11","author":"MV Fernandez","year":"2024","unstructured":"Fernandez, M. V. et al. Genetic and multi-omic resources for Alzheimer disease and related dementia from the Knight Alzheimer Disease Research Center. Sci. Data 11, 768 (2024).","journal-title":"Sci. Data"},{"key":"3831_CR73","doi-asserted-by":"publisher","DOI":"10.25080\/Majora-92bf1922-011","author":"S Seabold","year":"2010","unstructured":"Seabold, S. & Perktold, J. Statsmodels: econometric and statistical modeling with Python. scipy https:\/\/doi.org\/10.25080\/Majora-92bf1922-011 (2010).","journal-title":"scipy"},{"key":"3831_CR74","doi-asserted-by":"publisher","first-page":"W191","DOI":"10.1093\/nar\/gkz369","volume":"47","author":"U Raudvere","year":"2019","unstructured":"Raudvere, U. et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 47, W191\u2013W198 (2019).","journal-title":"Nucleic Acids Res."},{"key":"3831_CR75","doi-asserted-by":"crossref","unstructured":"Chang, C. C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. GigaScience 4, s13742-015-0047\u20138 (2015).","DOI":"10.1186\/s13742-015-0047-8"},{"key":"3831_CR76","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1186\/s12859-022-04706-x","volume":"23","author":"EB Fauman","year":"2022","unstructured":"Fauman, E. B. & Hyde, C. An optimal variant to gene distance window derived from an empirical definition of cis and trans protein QTLs. BMC Bioinf. 23, 169 (2022).","journal-title":"BMC Bioinf."},{"key":"3831_CR77","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0974-4","volume":"17","author":"W McLaren","year":"2016","unstructured":"McLaren, W. et al. The Ensembl variant effect predictor. Genome Biol. 17, 122 (2016).","journal-title":"Genome Biol."},{"key":"3831_CR78","doi-asserted-by":"publisher","first-page":"e1004383","DOI":"10.1371\/journal.pgen.1004383","volume":"10","author":"C Giambartolomei","year":"2014","unstructured":"Giambartolomei, C. et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014).","journal-title":"PLoS Genet."},{"key":"3831_CR79","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","volume":"630","author":"J Abramson","year":"2024","unstructured":"Abramson, J. et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature 630, 493\u2013500 (2024).","journal-title":"Nature"},{"key":"3831_CR80","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1002\/pro.3943","volume":"30","author":"EF Pettersen","year":"2021","unstructured":"Pettersen, E. F. et al. UCSF ChimeraX: structure visualization for researchers, educators, and developers. Protein Sci. Publ. Protein Soc. 30, 70\u201382 (2021).","journal-title":"Protein Sci. Publ. Protein Soc."}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-025-03831-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-025-03831-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-025-03831-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,7]],"date-time":"2025-09-07T01:21:49Z","timestamp":1757208109000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-025-03831-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,15]]},"references-count":80,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["3831"],"URL":"https:\/\/doi.org\/10.1038\/s41591-025-03831-3","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,15]]},"assertion":[{"value":"21 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 July 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"T.W.-C., J.R. and H.S.O. are co-founders and scientific advisors of Teal Omics Inc. and have received equity stakes. T.W.-C. is a co-founder and scientific advisor of Alkahest Inc. and Qinotto Inc. and has received equity stakes in these companies. C.C. has received research support from GSK and EISAI. C.C. is a member of the scientific advisory board of Circular Genomics and owns stock and a member of the Scientific Advisory Board of ADmit. K.L.P. is on the Scientific Advisory Board for Amprion and is a consultant for Novartis, Biohaven, Curasen and Neuron23, where she receives consulting fees. S.B.M. is an advisor to MyOme, PhiTech and Valinor Discovery. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}