{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:54:06Z","timestamp":1768571646561,"version":"3.49.0"},"posted":{"date-parts":[[2025,9,30]]},"group-title":"Neurology","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,13]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Pathological changes in Alzheimer\u2019s disease (AD) begin years before the onset of clinical symptoms. Developing cost-effective and minimally invasive biomarkers for preclinical diagnosis remains a critical goal in the field. Lactoferrin, an iron-binding glycoprotein, has emerged as a promising candidate due to its multifunctional roles reported in previous studies. However, whether lactoferrin levels in biofluids are associated with established AD biomarkers, and whether it can serve as a reliable diagnostic indicator, remains controversial.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We analyzed SOMAscan proteomic data from 1,367 paired plasma and cerebrospinal fluid (CSF) samples from the ACE Alzheimer\u2019s Center Barcelona cohort to evaluate lactoferrin levels. Associations between two lactoferrin-targeting SOMAmers and classical AD biomarkers, including total tau (t-tau), phosphorylated tau (p-tau181), and amyloid-beta 42 (A\u03b242), were assessed. The age, sex, proteomic principal components were considered as covariates for sensitive analysis. The prognostic value of lactoferrin in predicting dementia progression was further evaluated using survival analysis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Findings<\/jats:title>\n                  <jats:p>Among the two lactoferrin-targeting SOMAmers, Seq.2780.35 (LTF2) showed a weak and exclusive association with CSF A\u03b242 and syndromic status, whereas Seq.14755.4 (LTF1) was weakly associated with CSF p-tau and t-tau AD biomarker levels displayed expression-dependent stratification consistent with a ventricular- volume\u2013related dilution effect rather than disease. Furthermore, lactoferrin levels were not significantly associated with the progression from mild cognitive impairment (MCI) to dementia.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interpretation<\/jats:title>\n                  <jats:p>Isoform-specific lactoferrin expression changes in cerebrospinal fluid (CSF), but not plasma, appears to have biological relevance and diagnostic biomarker potential for AD.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.09.24.25336349","type":"posted-content","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T20:35:11Z","timestamp":1759264511000},"source":"Crossref","is-referenced-by-count":0,"title":["Lactoferrin levels in cerebrospinal fluid exhibits isoform-specific associations with Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"given":"Feiyang","family":"Zhao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raquel","family":"Puerta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaxi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Beckett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0125-5403","authenticated-orcid":false,"given":"Pablo","family":"Garcia Gonzalez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6599-948X","authenticated-orcid":false,"given":"Sergi","family":"Valero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adelina","family":"Orellana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pilar","family":"Sanz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiffany F.","family":"Kautz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose E.","family":"Cavazos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Victoria","family":"Fernandez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Cano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sudha","family":"Seshadri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Merce","family":"Boada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina R.","family":"Garbarino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agustin","family":"Ruiz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025101506402742000_2025.09.24.25336349v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1104-1054"},{"key":"2025101506402742000_2025.09.24.25336349v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2016.09.008"},{"key":"2025101506402742000_2025.09.24.25336349v2.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-025-03605-x"},{"key":"2025101506402742000_2025.09.24.25336349v2.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2013.11.003"},{"issue":"4","key":"2025101506402742000_2025.09.24.25336349v2.5","doi-asserted-by":"crossref","first-page":"979","DOI":"10.3233\/JAD-160152","article-title":"Microbes and Alzheimer\u2019s Disease","volume":"51","year":"2016","journal-title":"J Alzheimers Dis"},{"issue":"3","key":"2025101506402742000_2025.09.24.25336349v2.6","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1097\/00005072-199405000-00003","article-title":"Glial cytokines as neuropathogenic factors in HIV infection: pathogenic similarities to Alzheimer\u2019s disease","volume":"53","year":"1994","journal-title":"J Neuropathol Exp Neurol"},{"key":"2025101506402742000_2025.09.24.25336349v2.7","doi-asserted-by":"publisher","DOI":"10.1097\/01.aids.0000161770.06158.5c"},{"key":"2025101506402742000_2025.09.24.25336349v2.8","doi-asserted-by":"publisher","DOI":"10.1007\/s13365-013-0225-3"},{"key":"2025101506402742000_2025.09.24.25336349v2.9","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.1994.tb01168.x"},{"key":"2025101506402742000_2025.09.24.25336349v2.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.06.030"},{"key":"2025101506402742000_2025.09.24.25336349v2.11","doi-asserted-by":"crossref","unstructured":"Miklossy J . Alzheimer\u2019s disease - a neurospirochetosis. Analysis of the evidence following Koch\u2019s and Hill\u2019s criteria. J Neuroinflammation. 2011;8:90.","DOI":"10.1186\/1742-2094-8-90"},{"key":"2025101506402742000_2025.09.24.25336349v2.12","unstructured":"Hill JM , Clement C , Pogue AI , Bhattacharjee S , Zhao Y , Lukiw WJ . Pathogenic microbes, the microbiome, and Alzheimer\u2019s disease (AD). Front Aging Neurosci. 2014;6:127."},{"issue":"1","key":"2025101506402742000_2025.09.24.25336349v2.13","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.jalz.2013.12.020","article-title":"Potential role of antimicrobial peptides in the early onset of Alzheimer\u2019s disease","volume":"11","year":"2015","journal-title":"Alzheimers Dement"},{"key":"2025101506402742000_2025.09.24.25336349v2.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01637-0"},{"issue":"1","key":"2025101506402742000_2025.09.24.25336349v2.15","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41392-024-02071-0","article-title":"Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases","volume":"10","year":"2025","journal-title":"Signal Transduct Target Ther"},{"key":"2025101506402742000_2025.09.24.25336349v2.16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0009505"},{"key":"2025101506402742000_2025.09.24.25336349v2.17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0101364"},{"key":"2025101506402742000_2025.09.24.25336349v2.18","doi-asserted-by":"publisher","DOI":"10.1007\/s10522-014-9538-8"},{"issue":"4","key":"2025101506402742000_2025.09.24.25336349v2.19","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.3233\/JAD-150652","article-title":"Protective Effect of Amyloid-beta Peptides Against Herpes Simplex Virus-1 Infection in a Neuronal Cell Culture Model","volume":"50","year":"2016","journal-title":"J Alzheimers Dis"},{"key":"2025101506402742000_2025.09.24.25336349v2.20","doi-asserted-by":"publisher","DOI":"10.1080\/10408398.2017.1381583"},{"key":"2025101506402742000_2025.09.24.25336349v2.21","doi-asserted-by":"crossref","unstructured":"Yong SJ , Veerakumarasivam A , Lim WL , Chew J . Neuroprotective Effects of Lactoferrin in Alzheimer\u2019s and Parkinson\u2019s Diseases: A Narrative Review. ACS Chem Neurosci. 2023.","DOI":"10.1021\/acschemneuro.2c00679"},{"key":"2025101506402742000_2025.09.24.25336349v2.22","doi-asserted-by":"crossref","unstructured":"Qian ZM , Li W , Guo Q . Lactoferrin\/lactoferrin receptor: Neurodegenerative or neuroprotective in Parkinson\u2019s disease? Ageing Res Rev. 2024;101:102474.","DOI":"10.1016\/j.arr.2024.102474"},{"key":"2025101506402742000_2025.09.24.25336349v2.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01248-1"},{"key":"2025101506402742000_2025.09.24.25336349v2.24","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1978.tb03620.x"},{"key":"2025101506402742000_2025.09.24.25336349v2.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(01)00216-9"},{"issue":"1","key":"2025101506402742000_2025.09.24.25336349v2.26","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s10020-025-01094-9","article-title":"Lactoferrin alleviates the adverse effects of early-life inflammation on depression in adults by regulating the activation of microglia","volume":"31","year":"2025","journal-title":"Mol Med"},{"key":"2025101506402742000_2025.09.24.25336349v2.27","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.dadm.2017.04.002","article-title":"Early diagnosis of mild cognitive impairment and Alzheimer\u2019s disease based on salivary lactoferrin","volume":"8","year":"2017","journal-title":"Alzheimers Dement (Amst"},{"key":"2025101506402742000_2025.09.24.25336349v2.28","doi-asserted-by":"crossref","unstructured":"Gonzalez-Sanchez M , Bartolome F , Antequera D , Puertas-Martin V , Gonzalez P , Gomez- Grande A , et al. Decreased salivary lactoferrin levels are specific to Alzheimer\u2019s disease. EBioMedicine. 2020;57:102834.","DOI":"10.1016\/j.ebiom.2020.102834"},{"issue":"1","key":"2025101506402742000_2025.09.24.25336349v2.29","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/s13195-021-00891-8","article-title":"Salivary lactoferrin is associated with cortical amyloid-beta load, cortical integrity, and memory in aging","volume":"13","year":"2021","journal-title":"Alzheimers Res Ther"},{"key":"2025101506402742000_2025.09.24.25336349v2.30","doi-asserted-by":"crossref","unstructured":"Gleerup HS , Jensen CS , Hogh P , Hasselbalch SG , Simonsen AH . Lactoferrin in cerebrospinal fluid and saliva is not a diagnostic biomarker for Alzheimer\u2019s disease in a mixed memory clinic population. EBioMedicine. 2021;67:103361.","DOI":"10.1016\/j.ebiom.2021.103361"},{"key":"2025101506402742000_2025.09.24.25336349v2.31","doi-asserted-by":"publisher","DOI":"10.1139\/o11-056"},{"issue":"3","key":"2025101506402742000_2025.09.24.25336349v2.32","doi-asserted-by":"crossref","first-page":"769","DOI":"10.3233\/JAD-122002","article-title":"A longitudinal follow-up of 550 mild cognitive impairment patients: evidence for large conversion to dementia rates and detection of major risk factors involved","volume":"34","year":"2013","journal-title":"J Alzheimers Dis"},{"key":"2025101506402742000_2025.09.24.25336349v2.33","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12316"},{"key":"2025101506402742000_2025.09.24.25336349v2.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.02.018"},{"key":"2025101506402742000_2025.09.24.25336349v2.35","doi-asserted-by":"crossref","unstructured":"Morato X , Puerta R , Cano A , Orellana A , de Rojas I , Capdevila M , et al. Associations of plasma SMOC1 and soluble IL6RA levels with the progression from mild cognitive impairment to dementia. Brain Behav Immun Health. 2024;42:100899.","DOI":"10.1016\/j.bbih.2024.100899"},{"issue":"1","key":"2025101506402742000_2025.09.24.25336349v2.36","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s10142-025-01581-6","article-title":"Linking genomic and proteomic signatures to brain amyloid burden: insights from GR@ACE\/DEGESCO","volume":"25","year":"2025","journal-title":"Funct Integr Genomics"},{"key":"2025101506402742000_2025.09.24.25336349v2.37","doi-asserted-by":"crossref","unstructured":"Puerta R , Cano A , Garcia-Gonzalez P , Garcia-Gutierrez F , Capdevila M , de Rojas I , et al. Head-to-Head Comparison of Aptamer- and Antibody-Based Proteomic Platforms in Human Cerebrospinal Fluid Samples from a Real-World Memory Clinic Cohort. Int J Mol Sci. 2024;26(1).","DOI":"10.1101\/2024.07.18.24310563"},{"key":"2025101506402742000_2025.09.24.25336349v2.38","unstructured":"Imam F , Saloner R , Vogel JW , Krish V , Abdel-Azim G , Ali M , et al. The Global Neurodegeneration Proteomics Consortium: biomarker and drug target discovery for common neurodegenerative diseases and aging. Nat Med. 2025."},{"key":"2025101506402742000_2025.09.24.25336349v2.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-14755-5"},{"key":"2025101506402742000_2025.09.24.25336349v2.40","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01024-z"},{"key":"2025101506402742000_2025.09.24.25336349v2.41","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1210-1248"},{"key":"2025101506402742000_2025.09.24.25336349v2.42","unstructured":"Garc\u00eda-Gonz\u00e1lez P , Puerta R , de Rojas I , Marqui\u00e9 M , Emon A , Smets B , et al. Integrative multi-omics analysis reveals physiological and genetic drivers of CSF biomarker variability: implications in neurodegeneration studies. Alzheimer\u2019s Association International Conference; 2025 Jul 30; Toronto, Canada 2025."},{"key":"2025101506402742000_2025.09.24.25336349v2.43","doi-asserted-by":"crossref","unstructured":"Hammerschlag BL , Butts B , Likos K , Verble DD , Nimmagadda N , Virani R , et al. Pilot: Salivary Lactoferrin as a Biomarker of Alzheimer\u2019s Disease. medRxiv. 2024.","DOI":"10.1101\/2024.11.22.24317405"},{"key":"2025101506402742000_2025.09.24.25336349v2.44","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3475"},{"key":"2025101506402742000_2025.09.24.25336349v2.45","doi-asserted-by":"crossref","unstructured":"Legrand D . Overview of Lactoferrin as a Natural Immune Modulator. J Pediatr. 2016;173 Suppl:S10-5.","DOI":"10.1016\/j.jpeds.2016.02.071"},{"key":"2025101506402742000_2025.09.24.25336349v2.46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.6.2198"},{"key":"2025101506402742000_2025.09.24.25336349v2.47","doi-asserted-by":"publisher","DOI":"10.1139\/o11-070"},{"key":"2025101506402742000_2025.09.24.25336349v2.48","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.22650"},{"key":"2025101506402742000_2025.09.24.25336349v2.49","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20070393"},{"key":"2025101506402742000_2025.09.24.25336349v2.50","doi-asserted-by":"crossref","unstructured":"Tian M , Han YB , Yang GY , Li JL , Shi CS , Tian D . The role of lactoferrin in bone remodeling: evaluation of its potential in targeted delivery and treatment of metabolic bone diseases and orthopedic conditions. Front Endocrinol (Lausanne). 2023;14:1218148.","DOI":"10.3389\/fendo.2023.1218148"},{"issue":"1","key":"2025101506402742000_2025.09.24.25336349v2.51","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1139\/bcb-2016-0039","article-title":"Role of CXC chemokine receptor type 4 as a lactoferrin receptor","volume":"95","year":"2017","journal-title":"Biochem Cell Biol"},{"key":"2025101506402742000_2025.09.24.25336349v2.52","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-005-5373-z"},{"key":"2025101506402742000_2025.09.24.25336349v2.53","doi-asserted-by":"crossref","unstructured":"Zheng J , Xie Y , Li F , Zhou Y , Qi L , Liu L , et al. Lactoferrin improves cognitive function and attenuates brain senescence in aged mice. Journal of Functional Foods. 2020;65:103736.","DOI":"10.1016\/j.jff.2019.103736"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.09.24.25336349","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:46:51Z","timestamp":1768510011000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.09.24.25336349"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,30]]},"references-count":53,"URL":"https:\/\/doi.org\/10.1101\/2025.09.24.25336349","relation":{},"subject":[],"published":{"date-parts":[[2025,9,30]]},"subtype":"preprint"}}