We appraise newly accumulated evidence of the impact of particle pollution on the brain, the portals of entry, the neural damage mechanisms, and ultimately the neurological and psychiatric outcomes statistically associated with exposures. PM pollution comes from natural and anthropogenic sources such as fossil fuel combustion, engineered nanoparticles (NP ≤ 100 nm), wildfires, and wood burning. We are all constantly exposed during normal daily activities to some level of particle pollution of various sizes—PM_2.5 (≤2.5 µm), ultrafine PM (UFP ≤ 100 nm), or NPs. Inhalation, ingestion, and dermal absorption are key portals of entry. Selected literature provides context for the US Environmental Protection Agency (US EPA) ambient air quality standards, the conclusions of an Independent Particulate Matter Review Panel, the importance of internal combustion emissions, and evidence suggesting UFPs/NPs cross biological barriers and reach the brain. NPs produce oxidative stress and neuroinflammation, neurovascular unit, mitochondrial, endoplasmic reticulum and DNA damage, protein aggregation and misfolding, and other effects. Exposure to ambient PM_2.5 concentrations at or below current US standards can increase the risk for TIAs, ischemic and hemorrhagic stroke, cognitive deficits, dementia, and Alzheimer’s and Parkinson’s diseases. Residing in a highly polluted megacity is associated with Alzheimer neuropathology hallmarks in 99.5% of residents between 11 months and ≤40 y. PD risk and aggravation are linked to air pollution and exposure to diesel exhaust increases ALS risk. Overall, the literature supports that particle pollution contributes to targeted neurological and psychiatric outcomes and highlights the complexity of the pathophysiologic mechanisms and the marked differences in pollution profiles inducing neural damage. Factors such as emission source intensity, genetics, nutrition, comorbidities, and others also play a role. PM_2.5 is a threat for neurological and psychiatric diseases. Thus, future research should address specifically the potential role of UFPs/NPs in inducing neural damage.

This Review emphasizes the impact of APOE4—the most significant genetic risk factor for Alzheimer’s disease (AD)—on peripheral and neural effects starting in childhood. We discuss major mechanistic players associated with the APOE alleles’ effects in humans to understand their impact from conception through all life stages and the importance of detrimental, synergistic environmental exposures. APOE4 influences AD pathogenesis, and exposure to fine particulate matter (PM_2.5), manufactured nanoparticles (NPs), and ultrafine particles (UFPs) associated with combustion and friction processes appear to be major contributors to cerebrovascular dysfunction, neuroinflammation, and oxidative stress. In the context of outdoor and indoor PM pollution burden—as well as Fe, Ti, and Al alloys; Hg, Cu, Ca, Sn, and Si UFPs/NPs—in placenta and fetal brain tissues, urban APOE3 and APOE4 carriers are developing AD biological disease hallmarks (hyperphosphorylated-tau (P-tau) and amyloid beta 42 plaques (Aβ₄₂)). Strikingly, for Metropolitan Mexico City (MMC) young residents ≤ 40 y, APOE4 carriers have 4.92 times higher suicide odds and 23.6 times higher odds of reaching Braak NFT V stage versus APOE4 non-carriers. The National Institute on Aging and Alzheimer’s Association (NIA-AA) framework could serve to test the hypothesis that UFPs and NPs are key players for oxidative stress, neuroinflammation, protein aggregation and misfolding, faulty complex protein quality control, and early damage to cell membranes and organelles of neural and vascular cells. Noninvasive biomarkers indicative of the P-tau and Aβ₄₂ abnormal protein deposits are needed across the disease continuum starting in childhood. Among the 21.8 million MMC residents, we have potentially 4 million APOE4 carriers at accelerated AD progression. These APOE4 individuals are prime candidates for early neuroprotective interventional trials. APOE4 is key in the development of AD evolving from childhood in highly polluted urban centers dominated by anthropogenic and industrial sources of pollution. APOE4 subjects are at higher early risk of AD development, and neuroprotection ought to be implemented. Effective reductions of PM_2.5, UFP, and NP emissions from all sources are urgently needed. Alzheimer’s Disease prevention ought to be at the core of the public health response and physicians-scientist minority research be supported.

Exposures to fine particulate matter PM_2.5 are associated with Alzheimer’s, Parkinson’s (AD, PD) and TDP-43 pathology in young Metropolitan Mexico City (MMC) residents. High-resolution structural T1-weighted brain MRI and/or Montreal Cognitive Assessment (MoCA) data were examined in 302 volunteers age 32.7 ± 6.0 years old. We used multivariate linear regressions to examine cortical surface area and thickness, subcortical and cerebellar volumes and MoCA in ≤30 vs. ≥31 years old. MMC residents were exposed to PM_2.5 ~ 30.9 µg/m³. Robust hemispheric differences in frontal and temporal lobes, caudate and cerebellar gray and white matter and strong associations between MoCA total and index scores and caudate bilateral volumes, frontotemporal and cerebellar volumetric changes were documented. MoCA LIS scores are affected early and low pollution controls ≥ 31 years old have higher MoCA vs. MMC counterparts (p ≤ 0.0001). Residency in MMC is associated with cognitive impairment and overlapping targeted patterns of brain atrophy described for AD, PD and Fronto-Temporal Dementia (FTD). MMC children and young adult longitudinal studies are urgently needed to define brain development impact, cognitive impairment and brain atrophy related to air pollution. Identification of early AD, PD and FTD biomarkers and reductions on PM2.5 emissions, including poorly regulated heavy-duty diesel vehicles, should be prioritized to protect 21.8 million highly exposed MMC urbanites.

Sustained exposures to ubiquitous outdoor/indoor fine particulate matter (PM_2.5), including combustion and friction ultrafine PM (UFPM) and industrial nanoparticles (NPs) starting in utero, are linked to early pediatric and young adulthood aberrant neural protein accumulation, including hyperphosphorylated tau (p-tau), beta-amyloid (Aβ_{1 − 42}), α-synuclein (α syn) and TAR DNA-binding protein 43 (TDP-43), hallmarks of Alzheimer's (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). UFPM from anthropogenic and natural sources and NPs enter the brain through the nasal/olfactory pathway, lung, gastrointestinal (GI) tract, skin, and placental barriers. On a global scale, the most important sources of outdoor UFPM are motor traffic emissions. This study focuses on the neuropathology heterogeneity and overlap of AD, PD, FTLD, and ALS in older adults, their similarities with the neuropathology of young, highly exposed urbanites, and their strong link with sleep disorders. Critical information includes how this UFPM and NPs cross all biological barriers, interact with brain soluble proteins and key organelles, and result in the oxidative, endoplasmic reticulum, and mitochondrial stress, neuroinflammation, DNA damage, protein aggregation and misfolding, and faulty complex protein quality control. The brain toxicity of UFPM and NPs makes them powerful candidates for early development and progression of fatal common neurodegenerative diseases, all having sleep disturbances. A detailed residential history, proximity to high-traffic roads, occupational histories, exposures to high-emission sources (i.e., factories, burning pits, forest fires, and airports), indoor PM sources (tobacco, wood burning in winter, cooking fumes, and microplastics in house dust), and consumption of industrial NPs, along with neurocognitive and neuropsychiatric histories, are critical. Environmental pollution is a ubiquitous, early, and cumulative risk factor for neurodegeneration and sleep disorders. Prevention of deadly neurological diseases associated with air pollution should be a public health priority.

Environmental exposures to fine particulate matter (PM_2.5) and ultrafine particle matter (UFPM) are associated with overlapping Alzheimer’s, Parkinson’s and TAR DNA-binding protein 43 (TDP-43) hallmark protein pathologies in young Metropolitan Mexico City (MMC) urbanites. We measured CSF concentrations of TDP-43 in 194 urban residents, including 92 MMC children aged 10.2 ± 4.7 y exposed to PM_2.5 levels above the USEPA annual standard and to high UFPM and 26 low pollution controls (11.5 ± 4.4 y); 43 MMC adults (42.3 ± 15.9 y) and 14 low pollution adult controls (33.1 ± 12.0 y); and 19 amyotrophic lateral sclerosis (ALS) patients (52.4 ± 14.1 y). TDP-43 neuropathology and cisternal CSF data from 20 subjects—15 MMC (41.1 ± 18.9 y) and 5 low pollution controls (46 ± 16.01 y)—were included. CSF TDP-43 exponentially increased with age (p < 0.0001) and it was higher for MMC residents. TDP-43 cisternal CSF levels of 572 ± 208 pg/mL in 6/15 MMC autopsy cases forecasted TDP-43 in the olfactory bulb, medulla and pons, reticular formation and motor nuclei neurons. A 16 y old with TDP-43 cisternal levels of 1030 pg/mL exhibited TDP-43 pathology and all 15 MMC autopsy cases exhibited AD and PD hallmarks. Overlapping TDP-43, AD and PD pathologies start in childhood in urbanites with high exposures to PM_2.5 and UFPM. Early, sustained exposures to PM air pollution represent a high risk for developing brains and MMC UFPM emissions sources ought to be clearly identified, regulated, monitored and controlled. Prevention of deadly neurologic diseases associated with air pollution ought to be a public health priority and preventive medicine is key.