Heavy Metals as Accelerators of Dementia Progression: Evidence From a Stage‐Specific Systematic Review and Meta‐Analyses

Heavy metal exposure has been associated with dementia, though findings remain inconsistent and without stage-specific insight. We conducted a systematic review and meta-analyses of heavy metal levels in blood and serum to assess them across severities in dementia patients. Searches of Google Scholar, PubMed, and Cochrane Library (1954-2023) identified six studies, including 598 dementia patients and 622 controls. Thirteen metals were analyzed, with emphasis on lead, cadmium, copper, and mercury, most consistently reported across studies. Cognitive performance, which declines with increasing dementia severity, was measured using MMSE and MoCA scores. Pooled standardized mean differences (SMDs) were calculated mainly with random effects models. The dementia patients, overall, had significantly higher heavy metal levels in blood or serum than controls (SMD = 0.499, p = 0.000). Stage-specific analyses showed no significant differences in mild dementia but marked increases in moderate-to-severe (SMD = 0.617, p = 0.000), primarily driven by cadmium (SMD = 0.838, p = 0.019) and copper (SMD = 2.202, p = 0.001). Correlation analyses demonstrated that pooled heavy metals had a strong positive relationship with cognitive scores in mild dementia (r = 0.818, R2 = 0.670, p = 0.001), while weaker and varied associations were noted in overall and moderate-to-severe stages. Despite heterogeneity, sensitivity analyses reinforced the stability of results. This study provides novel stage-specific meta-analytical evidence that heavy metals act as accelerators rather than initiators of dementia. Cadmium and copper are significant contributors to advanced neurodegeneration, emphasizing the need for standardized assessments and targeted interventions to address environmental risks.