{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T10:02:30Z","timestamp":1789552950924,"version":"build-2803163510"},"reference-count":123,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006472","name":"Grigore T. Popa University of Medicine and Pharmacy","doi-asserted-by":"publisher","award":["7383\/31.03.2026"],"award-info":[{"award-number":["7383\/31.03.2026"]}],"id":[{"id":"10.13039\/501100006472","id-type":"DOI","asserted-by":"publisher"}]},{"award":["7383\/31.03.2026"],"award-info":[{"award-number":["7383\/31.03.2026"]}],"id":[{"id":"https:\/\/ror.org\/03hd30t45","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Xenobiotics","JoX"],"abstract":"<jats:p>Heavy metals and metalloids are persistent environmental contaminants that accumulate in the central nervous system and interact with endogenous essential metals, yet most neurotoxicological research continues to treat metals as independent agents rather than as co-occurring mixtures. This review systematically compares the evidence for cumulative and interactive effects of heavy metal mixtures across four major neurodegenerative diseases\u2014Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)\u2014asking which metal combinations have been directly documented for each disease, and whether these patterns are disease-specific or shared. Following a PubMed search (January 2016\u2013June 2026), 93 unique studies were included (AD: 49; PD: 38; ALS: 19; MS: 18; 31 shared across diseases). Combined exposure to lead, cadmium, arsenic, and mercury is linked to amyloid-beta accumulation and dementia risk in AD; manganese\u2013vanadium co-exposure produces more severe dopaminergic damage in PD than either metal alone, with manganese activating the familial PD gene LRRK2; a multi-metal mixture in ALS was associated with a three-fold higher disease risk independent of genetic susceptibility; and MS showed almost no designed mixture studies despite considerable single-metal data, with conflicting findings across cohorts. Three general mechanisms were identified: competition at shared membrane transporters (notably DMT1), sequestration by metal-binding proteins, and direct synergistic or antagonistic interactions, in which essential elements can modulate toxic-metal handling. Mixture-statistics approaches (WQS, BKMR), already established for AD and PD, should be extended to MS to close this evidence gap.<\/jats:p>","DOI":"10.3390\/jox16050174","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T07:58:59Z","timestamp":1789545539000},"page":"174","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cumulative and Interactive Effects of Heavy Metal Mixtures Across Neurodegenerative Diseases: A Comparative Review of Alzheimer, Parkinson, Amyotrophic Lateral Sclerosis and Multiple Sclerosis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2370-3166","authenticated-orcid":false,"given":"Ivona","family":"Mitu","sequence":"first","affiliation":[{"name":"Department of Morpho-Functional Sciences II, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, Universit\u0103tii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1615-4824","authenticated-orcid":false,"given":"Ioana-Cezara","family":"Caba","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences II, Faculty of Pharmacy, Grigore T. Popa University of Medicine and Pharmacy, Universit\u0103tii Street, 700115 Iasi, Romania"},{"name":"Advanced Research and Development Center for Experimental Medicine \u201cProf. Ostin C. Mungiu\u201d\u2014CEMEX, Grigore T. Popa University of Medicine and Pharmacy, 16 Universit\u0103tii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2827-3217","authenticated-orcid":false,"given":"Irina","family":"Macovei","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences II, Faculty of Pharmacy, Grigore T. Popa University of Medicine and Pharmacy, Universit\u0103tii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/jcb.26234","article-title":"Prevalence of exposure of heavy metals and their impact on health consequences","volume":"119","author":"Rehman","year":"2018","journal-title":"J. Cell Biochem."},{"key":"ref_2","first-page":"1","article-title":"Neurotoxic effects of metals on blood brain barrier impairment and possible therapeutic approaches","volume":"126","author":"Zahoor","year":"2024","journal-title":"Vitam. Horm."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"C44","DOI":"10.1152\/ajpcell.00184.2002","article-title":"Effect of DMT1 knockdown on iron, cadmium, and lead uptake in Caco-2 cells","volume":"284","author":"Bannon","year":"2003","journal-title":"Am. J. Physiol. 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