Cumulative and Interactive Effects of Heavy Metal Mixtures Across Neurodegenerative Diseases: A Comparative Review of Alzheimer, Parkinson, Amyotrophic Lateral Sclerosis and Multiple Sclerosis

Abstract

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—Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)—asking 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–June 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–vanadium 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.