{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T07:25:49Z","timestamp":1764833149688,"version":"3.46.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"\n Background<\/jats:title>\n \n YKL-40 (\n CHI3L1<\/jats:italic>\n ) is a glycoprotein secreted by reactive astrocytes and peripheral immune cells, implicated in inflammation and tissue remodeling in Alzheimer\u2019s disease (AD). While elevated\n CHI3L1<\/jats:italic>\n levels have been observed in cerebrospinal fluid and plasma, its expression at the transcript level in peripheral blood - and modulation by genetic risk factors such as\n APOE<\/jats:italic>\n \u03b54 - remains poorly understood.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We analyzed peripheral blood\n CHI3L1<\/jats:italic>\n mRNA expression in a well-characterized cohort comprising individuals with biomarker-confirmed AD (\n n<\/jats:italic>\n \u202f=\u202f34), mild cognitive impairment (MCI;\n n<\/jats:italic>\n \u202f=\u202f31), and cognitively healthy controls (HC;\n n<\/jats:italic>\n \u202f=\u202f21).\n CHI3L1<\/jats:italic>\n expression levels were compared across diagnostic groups and stratified by\n APOE<\/jats:italic>\n \u03b54 status, age at onset (early-onset &lt; 65\u202fyears; late-onset \u2265 65), and sex. Correlations were examined between\n CHI3L1<\/jats:italic>\n and inflammatory gene transcripts (\n IL1B<\/jats:italic>\n ,\n TNF<\/jats:italic>\n ,\n MMP9<\/jats:italic>\n ,\n LRP1<\/jats:italic>\n , and\n TREM2<\/jats:italic>\n ).\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Peripheral\n CHI3L1<\/jats:italic>\n expression was elevated in individuals with early-onset AD (EOAD), particularly among\n APOE<\/jats:italic>\n \u03b54 carriers (EOAD\n APOE<\/jats:italic>\n \u03b54+,\n n<\/jats:italic>\n \u202f=\u202f13 vs. EOAD\n APOE<\/jats:italic>\n \u03b54-,\n n<\/jats:italic>\n \u202f=\u202f8;\n p<\/jats:italic>\n \u202f=\u202f0.026). Stratified analyses revealed an exploratory association between\n CHI3L1<\/jats:italic>\n expression,\n APOE<\/jats:italic>\n genotype, and sex, with the highest levels observed in female \u03b54 carriers with EOAD. Across diagnostic groups,\n CHI3L1<\/jats:italic>\n levels positively correlated with transcripts of\n IL1B<\/jats:italic>\n ,\n MMP9<\/jats:italic>\n , and\n LRP1<\/jats:italic>\n , with the strongest associations again in\n APOE<\/jats:italic>\n \u03b54\u202f+\u202findividuals. Notably, these effects were more pronounced in the MCI and AD groups than in healthy controls, indicating early immune activation in at-risk individuals.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Our exploratory findings indicate that peripheral\n CHI3L1<\/jats:italic>\n expression may reflect APOE \u03b54-linked immune activity, with a trend toward higher expression in EOAD and in female \u03b54 carriers. The observed genotype- and sex-dependent expression patterns indicate preliminary differences in peripheral immune activity that warrant replication in larger cohorts. Peripheral\n CHI3L1<\/jats:italic>\n may thus serve as a hypothesis-generating marker of genotype-linked inflammatory phenotypes rather than a validated biomarker.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fnagi.2025.1730319","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T06:34:01Z","timestamp":1764830041000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Peripheral CHI3L1 expression is associated with APOE \u03b54 status in early-onset Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Anja","family":"Steinmaurer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina","family":"Breit","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth","family":"St\u00f6gmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theresa","family":"K\u00f6nig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.jalz.2011.03.008","article-title":"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","volume":"7","author":"Albert","year":"2011","journal-title":"Alzheimers Dement."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"901","DOI":"10.3233\/JAD-140624","article-title":"Cerebrospinal fluid level of YKL-40 protein in preclinical and prodromal Alzheimer\u2019s disease","volume":"42","author":"Antonell","year":"2014","journal-title":"J Alzheimer's Dis"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/1742-2094-7-34","article-title":"In vivo CHI3L1 (YKL-40) expression in astrocytes in acute and chronic neurological diseases","volume":"7","author":"Bonneh-Barkay","year":"2010","journal-title":"J. Neuroinflammation"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2181","DOI":"10.1007\/s00415-011-6087-9","article-title":"Plasma level of chitinase 3-like 1 protein increases in patients with early Alzheimer\u2019s disease","volume":"258","author":"Choi","year":"2011","journal-title":"J. Neurol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.cca.2020.09.035","article-title":"YKL-40 as a novel biomarker in cardio-metabolic disorders and inflammatory diseases","volume":"511","author":"Deng","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.dadm.2016.12.002","article-title":"The APOE \u03b54 genotype modulates CSF YKL-40 levels and their structural brain correlates in the continuum of Alzheimer\u2019s disease but not those of sTREM2","volume":"6","author":"Gispert","year":"2017","journal-title":"Alzheimers Dement. Diagn. Assess. Dis. Monit."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.1212\/01.wnl.0000187068.92184.63","article-title":"Comparison of family histories in FTLD subtypes and related tauopathies","volume":"65","author":"Goldman","year":"2005","journal-title":"Neurology"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"2783","DOI":"10.1038\/s41380-025-02939-9","article-title":"Neuroinflammatory fluid biomarkers in patients with Alzheimer\u2019s disease: a systematic literature review","volume":"30","author":"Heneka","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"e12377","DOI":"10.1002\/trc2.12377","article-title":"ARIA in patients treated with lecanemab (BAN2401) in a phase 2 study in early Alzheimer\u2019s disease","volume":"9","author":"Honig","year":"2023","journal-title":"Alzheimers Dement."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"112290","DOI":"10.1016\/j.intimp.2024.112290","article-title":"Anesthesia\/surgery activate MMP9 leading to blood-brain barrier disruption, triggering neuroinflammation and POD-like behavior in aged mice","volume":"135","author":"Hu","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA research framework: toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimers Dement."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"261","DOI":"10.14712\/fb2014060060261","article-title":"Protein and mRNA levels of YKL-40 in high-grade glioma","volume":"60","author":"Kazakova","year":"2014","journal-title":"Folia Biol. (Praha)"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/s13195-015-0142-1","article-title":"Cerebrospinal fluid VILIP-1 and YKL-40, candidate biomarkers to diagnose, predict and monitor Alzheimer\u2019s disease in a memory clinic cohort","volume":"7","author":"Kester","year":"2015","journal-title":"Alzheimer's Res Ther"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"754","DOI":"10.3389\/fimmu.2020.00754","article-title":"The important interface between apolipoprotein E and neuroinflammation in Alzheimer\u2019s disease","volume":"11","author":"Kloske","year":"2020","journal-title":"Front. Immunol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"3399","DOI":"10.1038\/s41380-018-0224-0","article-title":"Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series","volume":"25","author":"Koriath","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1007\/s00115-006-2098-7","article-title":"Reliabilit\u00e4t und Validit\u00e4t des revidierten Beck-Depressionsinventars (BDI-II)","volume":"78","author":"K\u00fchner","year":"2007","journal-title":"Nervenarzt"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1017\/S1041610214002245","article-title":"Awareness of memory deficits in subjective cognitive decline, mild cognitive impairment, Alzheimer\u2019s disease and Parkinson\u2019s disease","volume":"27","author":"Lehrner","year":"2015","journal-title":"Int. Psychogeriatr."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/s13024-017-0226-4","article-title":"YKL-40 in the brain and cerebrospinal fluid of neurodegenerative dementias","volume":"12","author":"Llorens","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"3151","DOI":"10.1084\/jem.20171406","article-title":"Alzheimer\u2019s disease: a matter of blood-brain barrier dysfunction?","volume":"214","author":"Montagne","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1111\/j.1523-1755.2004.00900.x","article-title":"TNF-alpha and IL-1beta-mediated regulation of MMP-9 and TIMP-1 in renal proximal tubular cells","volume":"66","author":"Nee","year":"2004","journal-title":"Kidney Int."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"e105","DOI":"10.1016\/S2468-2667(21)00249-8","article-title":"Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the global burden of disease study 2019","volume":"7","author":"Nichols","year":"2022","journal-title":"Lancet Public Health"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"e208075","DOI":"10.1212\/WNL.0000000000208075","article-title":"Association of Plasma YKL-40 with MRI, CSF, and cognitive markers of brain health and dementia","volume":"102","author":"Pase","year":"2024","journal-title":"Neurology"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1016\/j.apradiso.2011.04.010","article-title":"Optimization of the radiosynthesis of the Alzheimer tracer 2-(4-N-[11C]methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB)","volume":"69","author":"Philippe","year":"2011","journal-title":"Appl. Radiat. Isot."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1016\/j.jalz.2011.12.009","article-title":"Prevalence of mild cognitive impairment subtypes in patients attending a memory outpatient clinic--comparison of two modes of mild cognitive impairment classification. Results of the Vienna conversion to dementia study","volume":"9","author":"Pusswald","year":"2013","journal-title":"Alzheimers Dement."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"26663","DOI":"10.18632\/oncotarget.5185","article-title":"APOE-by-sex interactions on brain structure and metabolism in healthy elderly controls","volume":"6","author":"Sampedro","year":"2015","journal-title":"Oncotarget"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"8296","DOI":"10.1007\/s12035-019-01672-z","article-title":"Influence of matrix metallopeptidase 9 on Beta-amyloid elimination across the blood-brain barrier","volume":"56","author":"Shackleton","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"4386","DOI":"10.1016\/j.cell.2023.08.037","article-title":"Human microglial state dynamics in Alzheimer\u2019s disease progression","volume":"186","author":"Sun","year":"2023","journal-title":"Cell"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1111\/j.1600-0404.2011.01592.x","article-title":"Alzheimer CSF biomarkers in routine clinical setting","volume":"125","author":"Tabaraud","year":"2012","journal-title":"Acta Neurol. Scand."},{"key":"ref33","first-page":"4364","article-title":"Gene expression microarray analysis reveals YKL-40 to be a potential serum marker for malignant character in human glioma1","volume":"62","author":"Tanwar","year":"2002","journal-title":"Cancer Res."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1186\/s13195-020-00619-0","article-title":"The combined effects of microglia activation and brain glucose hypometabolism in early-onset Alzheimer\u2019s disease","volume":"12","author":"Tondo","year":"2020","journal-title":"Alzheimer's Res Ther"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1056\/NEJMoa2212948","article-title":"Lecanemab in early Alzheimer\u2019s disease","volume":"388","author":"Van Dyck","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"7234","DOI":"10.1007\/s12035-019-1594-2","article-title":"LRP1 has a predominant role in production over clearance of a\u03b2 in a mouse model of Alzheimer\u2019s disease","volume":"56","author":"Van Gool","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"245","DOI":"10.3109\/13506120009146438","article-title":"Standardization of measurement of beta-amyloid(1-42) in cerebrospinal fluid and plasma","volume":"7","author":"Vanderstichele","year":"2000","journal-title":"Amyloid"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/S0304-3940(00)01036-3","article-title":"Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: a sandwich ELISA with a synthetic phosphopeptide for standardization","volume":"285","author":"Vanmechelen","year":"2000","journal-title":"Neurosci. Lett."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"3340","DOI":"10.1021\/acschemneuro.9b00333","article-title":"Understanding the role of systemic inflammation in Alzheimer\u2019s disease","volume":"10","author":"Walker","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"503","DOI":"10.3233\/JAD-231125","article-title":"Serum YKL-40 as a predictive biomarker of cerebral amyloid Angiopathy-related intracerebral hemorrhage recurrence","volume":"99","author":"Xu","year":"2024","journal-title":"J Alzheimer's Dis"},{"key":"ref9001","doi-asserted-by":"publisher","first-page":"148318","DOI":"10.1016\/j.brainres.2023.148318","article-title":"YKL-40 as a novel biomarker related to white matter damage and cognitive impairment in patients with cerebral small vessel disease","volume":"1807","author":"Zhang","year":"2023","journal-title":"Brain Res."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2025.1730319\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T06:34:01Z","timestamp":1764830041000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2025.1730319\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,4]]},"references-count":37,"alternative-id":["10.3389\/fnagi.2025.1730319"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2025.1730319","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,4]]},"article-number":"1730319"}}