{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:03:19Z","timestamp":1789563799547,"version":"build-2803163510"},"reference-count":54,"publisher":"Frontiers Media SA","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\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Aluminium (Al) is a ubiquitous environmental neurotoxicant primarily recognized for its role in central nervous system (CNS) dysfunction. However, emerging evidence suggests that the autonomic (ANS) and peripheral (PNS) nervous systems may be susceptible to Al-induced damage earlier than the CNS, offering potential windows for early detection. This mechanistic systematic review synthesizes current human, animal, and mechanistic evidence to evaluate the multisystemic effects of Al beyond the CNS and to identify potential candidate markers of exposure. Following PRISMA guidelines, a comprehensive search was conducted across five databases (PubMed\/MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library). Sixteen primary studies that met strict inclusion criteria were analyzed. Given the heterogeneity of the data, a mechanistic synthesis was employed to map pathways and link them to clinical observations. Synthesis of the evidence reveals a consistent \u201cBarrier-Stress Axis.\u201d Mechanistically, Al targets tight junction proteins (e.g., occludin, claudin-5) in the blood-brain and blood-nerve barriers, leading to oxidative stress in the nucleus tractus solitarius and peripheral nerves. Clinically, this manifests as reduced heart rate variability (HRV) and impaired baroreflex sensitivity in both occupational human cohorts and experimental rat models. While peripheral nerve conduction changes are noted, human data remain limited by small sample sizes and confounding environmental factors. Preliminary evidence suggests that ANS and PNS dysregulation may precede overt cognitive decline in Al toxicity. HRV and baroreflex sensitivity are promising candidates for early-stage screening. However, these findings should currently be viewed as hypothesis-generating; longitudinal human studies are required to validate these markers and control for occupational co-exposures.<\/jats:p>","DOI":"10.3389\/fphys.2026.1891526","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T12:08:20Z","timestamp":1789560500000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Aluminium neurotoxicity beyond the brain: a mechanistic systematic review of autonomic and peripheral dysfunction"],"prefix":"10.3389","volume":"17","author":[{"given":"Trina","family":"Sengupta","sequence":"first","affiliation":[{"name":"Department of Physiology, Employees' State Insurance Post Graduate Institute of Medical Sciences and Research (ESI-PGIMSR) and ESIC Medical College and Hospital","place":["Joka, Kolkata, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tripti","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Physiology, All India Institute of Medical Sciences","place":["Jodhpur, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasunpriya","family":"Nayak","sequence":"additional","affiliation":[{"name":"Department of Physiology, All India Institute of Medical Sciences","place":["Jodhpur, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sovan","family":"Bagchi","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Gulf Medical University","place":["Ajman, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1159\/000094971","article-title":"The prevalence of autonomic symptoms in dementia and their association with physical activity, activities of daily living and quality of life","volume":"22","author":"Allan","year":"2006","journal-title":"Dement. 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