Alzheimer's disease (AD), Parkinson's disease (PD) and TAR DNA-binding protein (TDP-43) neuropathological hallmarks are documented in children and young adults exposed lifelong to Metropolitan Mexico City (MMC) air pollution; together with brain high metal concentrations (especially iron)-rich nanoparticles and industrial nanoparticles (NPs, i.e., Ti nanorods). Aberrant hyperphosphorylated tau, ɑ synuclein and TDP-43 have been documented in the brainstem of Mexico City 27.29 ± 11.8y old residents. Critically, early and progressive neurovascular unit damage and involvement of critical organelles i.e., mitochondria are associated with the presence of NPs, acting as catalysts for reactive oxygen species formation, altered cell signaling, and protein misfolding, aggregation and fibril formation. Progressive development of Alzheimer starts in 11 month old babies, and in 99.25% of 202 consecutive autopsies ≤40 years we can stage the disease and its progression with age; 66% of ≤30 years urbanites have cognitive impairment and involvement of the brainstem is reflected by auditory central dysfunction in every subject studied. The average age for dementia using MoCA is 20.6 ± 3.4 years. Remarkably, the substantia nigrae (SN) is an early target of particulate matter pollution and progressive SN neurovascular unit damage is associated with dopaminergic neurons’ metal-rich NPs, also identified in neuroenteric neurons. Twenty-three % of MMC forensic autopsies show PD hallmarks and 18% TDP-43 pathology (associated with fronto-temporal dementia FTD and amyotrophic lateral sclerosis ALS).

Air pollution control should be prioritised-including the regulation of diesel vehicles- and the first two decades of life ought to be targeted for neuroprotective interventions. Control of NP sources becomes critical. Defining early environmental, nutritional, metabolic and genetic risk factor interactions is a multidisciplinary task of paramount importance to prevent fatal neurodegenerative diseases, including AD, PD, FTD and ALS. Current and future generations are at risk.