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Methods: In this nested pilot study of a ferroalloy worker cohort, we investigated the impact of chronic occupational Mn exposure on cognitive function through \u03b2-amyloid (A\u03b2) deposition and multi-omics profiling. We evaluated six male Mn-exposed workers (median age 63, exposure duration 31 years) and five historical controls (median age: 60 years), all of whom had undergone brain PET scans. Exposed individuals showed significantly higher A\u03b2 deposition in exposed individuals (p &lt; 0.05). The average annual cumulative respirable Mn was 329.23 \u00b1 516.39 \u00b5g\/m3 (geometric mean 118.59), and plasma Mn levels were significantly elevated in the exposed group (0.704 \u00b1 0.2 ng\/mL) compared to controls (0.397 \u00b1 0.18 in controls). Results: LC-MS\/MS-based pathway analyses revealed disruptions in olfactory signaling, mitochondrial fatty acid \u03b2-oxidation, biogenic amine synthesis, transmembrane transport, and choline metabolism. Simoa analysis showed notable alterations in ADRD-related plasma biomarkers. Protein microarray revealed significant differences (p &lt; 0.05) in antibodies targeting neuronal and autoimmune proteins, including A\u03b2 (25\u201335), GFAP, serotonin, NOVA1, and Siglec-1\/CD169. Conclusion: These findings suggest Mn exposure is associated with neurodegenerative biomarker alterations and disrupted biological pathways relevant to cognitive decline.<\/jats:p>","DOI":"10.3390\/brainsci15080829","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T15:09:53Z","timestamp":1754492993000},"page":"829","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Impact of Manganese on Neuronal Function: An Exploratory Multi-Omics Study on Ferroalloy Workers in Brescia, Italy"],"prefix":"10.3390","volume":"15","author":[{"given":"Somaiyeh","family":"Azmoun","sequence":"first","affiliation":[{"name":"Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5606-8926","authenticated-orcid":false,"given":"Freeman C.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Shoieb","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Specialties, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Jin","sequence":"additional","affiliation":[{"name":"St. Jude Children Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Colicino","sequence":"additional","affiliation":[{"name":"Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isha","family":"Mhatre-Winters","sequence":"additional","affiliation":[{"name":"Isakson Center for Neurological Disease Research and Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiwei","family":"Gu","sequence":"additional","affiliation":[{"name":"College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7832-8423","authenticated-orcid":false,"given":"Hari","family":"Krishnamurthy","sequence":"additional","affiliation":[{"name":"Vibrant Sciences LLC., San Carlos, CA 94070, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason R.","family":"Richardson","sequence":"additional","affiliation":[{"name":"Isakson Center for Neurological Disease Research and Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1606-5397","authenticated-orcid":false,"given":"Donatella","family":"Placidi","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Specialties, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Lambertini","sequence":"additional","affiliation":[{"name":"Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9723-0237","authenticated-orcid":false,"given":"Roberto G.","family":"Lucchini","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL 33199, USA"},{"name":"Occupational Medicine, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Martins, A.C., Morcillo, P., Ijomone, O.M., Venkataramani, V., Harrison, F.E., Lee, E., Bowman, A.B., and Aschner, M. 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