Interest is growing in the potential role of manganese (Mn) in Alzheimer’s Disease (ADRD). This nested pilot study of a ferroalloy workers cohort was aimed to investigate the effects of long-term occupational Mn exposure on cognitive function through β-amyloid (Aβ) modification and brain deposition, as well as metabolomic, lipidomic and proteomic profiling. We examined 6 male exposed workers (median age 63, exposure duration 31 yrs), and 5 historical controls (median age 60) who had undergone brain PET scan imaging showing higher Aβ deposition among the exposed compared to the controls (p < 0.05). The average annual cumulative respirable Mn of the ferroalloy workers was 329.23 ± 516.39 µg/m3 (geometric mean 118.59). Average Mn level in plasma of the exposed subjects (0.704 ± 0.2 ng/mL) was significantly higher than the controls (0.397 ± 0.18). Pathway analyses using LC-MS/MS results revealed impacted metabolomic pathways such as olfactory signaling, mitochondrial fatty acid beta-oxidation, biogenic amine synthesis, SLC-mediated transmembrane transport, and glycerophospholipid and choline metabolism in the Mn exposed group. Single molecule arrays (Simoa) analysis revealed notable modifications of AD-related plasma biomarkers; protein microarray (chip) showed significant changes (p < 0.05) in the levels of some plasma antibodies targeting autoimmune and neuronal associated proteins such as Aβ (25-35), GFAP, Serotonin, Human NOVA1, and Human Siglec-1/CD169 among the Mn exposed individuals. This data provides evidence on Mn-induced alterations of pathways and biomarkers associated with cognitive neurodegenerative diseases.

The authors have declared no competing interest.

The study was funded by the National Institutes of Health (NIH) grant numbers R01 ES019222, P30ES023515, RF1NS130713, R01AG085729, the University of Georgia Diane Isakson Distinguished Professorship, the European Union through its Sixth Framework Programme (contract number FOOD-CT-2006-016253).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Whole blood and plasma samples from Mn-exposed workers and controls were collected at the time of brain imaging and stored at –80˚C at the University of Brescia. Based on the participants consent, samples were shared with the Florida International University, Stempel College of Public Health and Social Work in 2023, after a Material Transfer Agreement and a Data Use Agreement were co-signed by both institutions and a new IRB was approved at FIU, USA, based on the original IRB approval from the University of Brescia.

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All data produced in the present work are contained in the manuscript, and Supplementary data file