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The objective of our study was to explore the seroprevalence of naturally occurring autoantibodies (Aabs) targeting a panel of 14 antigens broadly involved in neurodegenerative diseases such as Alzheimer\u2019s Disease, Parkinson\u2019s Disease, frontotemporal dementia, and vascular dementia. Commonly associated proteins with underlying neuronal pathology of the brain include amyloid-beta (A\u03b2), tau, alpha-synuclein (\u03b1-syn), TDP-43, and FUS. Proteins associated with glial and astrocytic involvement\u2014TREM2 and Chi3Li; proteins related to myelin damage and axonal degeneration\u2014light neurofilaments (NFL), myelin basic protein (MBP); synaptic loss reflected by neurogranin (NRGN), a marker of neuronal injury\u2014neuron specific enolase (NSE); and markers of disturbed calcium homeostasis\u2014VSNL1 and neuroinflammation\u2014MCP-1. Presence and levels of plasma IgG against these antigens were examined using enzyme-linked immunosorbent assay (ELISA) method in patients with dementia, patients with mild cognitive impairment (MCI), and healthy age-matched controls. Aabs against all selected antigens were detected across all groups, including healthy control, with varied seroprevalence levels. For the first time, we report the presence of anti-FUS, anti-TREM2, anti-NRGN, anti-VSNL1, anti-NSE, and anti-MCP1 Aabs. Elevated anti-Chi3Li Aabs in individuals with MCI indicate a disease-associated immune signature linked to early neurodegenerative processes. Overall, these results provide evidence of systemic immune activation accompanying neurodegeneration, underscore the complexity of immune involvement, and highlight the importance of targeting multiple pathological pathways in future immunomodulatory strategies.<\/jats:p>","DOI":"10.3390\/biom16040518","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T09:26:12Z","timestamp":1775121972000},"page":"518","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Plasma Autoantibodies Against Neurodegeneration-Related Antigens in Dementia and Elevated Chi3Li Autoantibodies in Mild Cognitive Impairment"],"prefix":"10.3390","volume":"16","author":[{"given":"Gabriela","family":"Kocurova","sequence":"first","affiliation":[{"name":"Experimental Neurobiology Program, National Institute of Mental Health, 250 67 Klecany, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzana","family":"Svabenska","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics of the Czech Academy of Sciences, 142 20 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Klaschka","sequence":"additional","affiliation":[{"name":"Institute of Computer Science of the Czech Academy of Sciences, 182 00 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8020-8252","authenticated-orcid":false,"given":"Ales","family":"Bartos","sequence":"additional","affiliation":[{"name":"Department of Neurology, Third Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic"},{"name":"Department of Neurology, University Hospital Kralovske Vinohrady, 100 00 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2625-057X","authenticated-orcid":false,"given":"Jan","family":"Ricny","sequence":"additional","affiliation":[{"name":"Experimental Neurobiology Program, National Institute of Mental Health, 250 67 Klecany, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"ref_1","unstructured":"(2025, November 27). 2025 NIH Alzheimer\u2019s Disease and Related Dementias Research Progress Report: Advances and Achievements, Available online: https:\/\/www.nia.nih.gov\/about\/2025-nih-dementia-research-progress-report."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e080952","DOI":"10.1136\/bmj-2024-080952","article-title":"Projections for Prevalence of Parkinson\u2019s Disease and Its Driving Factors in 195 Countries and Territories to 2050: Modelling Study of Global Burden of Disease Study 2021","volume":"388","author":"Su","year":"2025","journal-title":"BMJ"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.cger.2022.07.005","article-title":"Neuropathology of the Common Forms of Dementia","volume":"39","author":"Mehta","year":"2023","journal-title":"Clin. 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