Environmental neurotoxicants as accelerators of brain ageing: exposomic mechanisms linking pollution to amyloidogenesis and Alzheimer’s disease

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterised by progressive cognitive decline, amyloid-β (Aβ) deposition, tau hyperphosphorylation, synaptic dysfunction, and chronic neuroinflammation. While rare familial cases are genetically driven, most AD is sporadic, underscoring the critical role of environmental determinants. Emerging evidence from epidemiological, experimental, and exposomic studies identifies environmental neurotoxicants, including air pollutants, heavy metals, pesticides, and emerging contaminants such as micro- and nanoplastics, as significant accelerators of brain ageing and AD pathogenesis.These toxicants access the central nervous system via systemic circulation, olfactory translocation, and gut–brain axis interactions, converging on shared pathogenic mechanisms such as oxidative stress, mitochondrial dysfunction, impaired proteostasis, and neuroimmune activation. Together, these processes promote amyloidogenic processing of amyloid precursor protein, enhance Aβ aggregation, and drive tau pathology, accelerating neurodegenerative cascades. Notably, early-life exposures induce persistent epigenetic and metabolic reprogramming, increasing lifelong vulnerability, particularly in genetically susceptible markers such as APOE ε4 carriers. Although preclinical models robustly demonstrate pollutant-induced AD-like phenotypes, translation into clinical interventions remains limited. Integrating environmental exposures into AD pathogenesis frameworks highlights the exposome as a modifiable risk factor and emphasizes the urgent need for longitudinal human studies, mechanistic validation, and preventive public health strategies targeting environmental risk reduction.