Aging in a highly polluted world: challenges and solutions to prevent Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder globally and a leading cause of disability and death among the elderly. As populations age worldwide, the epidemiological burden of AD is expected to more than double by 2050, surpassing 150 million affected individuals. While genetic susceptibility, particularly the apolipoprotein E ε4 (APOE4) allele, modulates individual risk, most AD cases are late-onset and shaped by complex interactions between genetic background and modifiable environmental exposures. Environmental pollution has emerged as a critical and potentially preventable contributor to this burden. The 2024 Lancet Commission on Dementia Prevention, Intervention, and Care has identified 14 modifiable risk factors, with air pollution explicitly included. Drawing on evidence from human epidemiological cohorts, experimental animal models, and in vitro neuronal/glial systems, the present review aims to synthesize mechanistic evidence linking environmental pollutant classes to AD-relevant neuropathology. The review examines the growing body of evidence linking major categories of environmental pollutants (ambient particulate matter, heavy metals, pesticides, PFAS, and emerging contaminants including microplastics and nanoplastics) to AD risk and pathogenesis. Special attention is given to studies showing that the characteristic neuropathological features of AD may emerge in children and young adults chronically exposed to heavily polluted urban environments, which highlights critical concerns about when and how these changes develop throughout life. Shared mechanistic pathways through which environmental pollutants promote neurodegeneration are discussed, including neuroinflammation, oxidative stress, blood-brain barrier disruption, tau kinase dysregulation, epigenetic reprogramming, and gut-brain axis dysbiosis. The review also examines the amplifying role of biological aging on neurotoxic vulnerability and proposes a comprehensive, multi-level prevention framework addressing individual exposure reduction, clinical risk identification, and population-level policy interventions.