Exposure to particulate matter (PM) pollution damages the human brain. Fossil fuel burning for transportation energy accounts for a significant fraction of urban air and climate pollution. While current United States (US) standards limit PM ambient concentrations and emissions, they do not regulate explicitly ultrafine particles (UFP ≤ 100 nm in diameter). There is a growing body of evidence suggesting UFP may play a bigger role inflicting adverse health impacts than has been recognized, and in this perspective, we highlight effects on the brain, particularly of young individuals. UFP penetrate the body through nasal/olfactory, respiratory, gastrointestinal, placenta, and brain–blood barriers, translocating in the bloodstream and reaching the glymphatic and central nervous systems. We discuss one case study. The 21.8 million residents in the Metropolitan Mexico City (MMC) are regularly exposed to fine PM (PM_2.5) above the US 12 μg/m³ annual average standards. Alzheimer’s disease (AD), Parkinson’s disease (PD), and TAR DNA-binding protein (TDP-43) pathologies and nanoparticles (NP ≤ 50 nm in diameter) in critical brain organelles have been documented in MMC children and young adult autopsies. MMC young residents have cognitive and olfaction deficits, altered gait and equilibrium, brainstem auditory evoked potentials, and sleep disorders. Higher risk of AD and vascular dementia associated with residency close to high traffic roadways have been documented. The US is not ready or prepared to adopt ambient air quality or emission standards for UFP and will continue to focus regulations only on the total mass of PM_2.5 and PM₁₀. Thus, this approach raises the question: are we dropping the ball? As research continues to answer the remaining questions about UFP sources, exposures, impacts, and controls, the precautionary principle should call us to accelerate and expand policy interventions to abate or eliminate UFP emissions and to mitigate UFP exposures. For residents of highly polluted cities, particularly in the developing world where there is likely older and dirtier vehicles, equipment, and fuels in use and less regulatory oversight, we should embark in a strong campaign to raise public awareness of the associations between high PM pollution, heavy traffic, UFP, NP, and neuropsychiatric outcomes, including dementia. Neurodegenerative diseases evolving from childhood in polluted, anthropogenic, and industrial environments ought to be preventable.

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.

Quadruple aberrant hyperphosphorylated tau, beta-amyloid, α-synuclein and TDP-43 neuropathology and metal solid nanoparticles (NPs) are documented in the brains of children and young adults exposed to Metropolitan Mexico City (MMC) pollution. We investigated environmental NPs reaching noradrenergic and dopaminergic nuclei and the cerebellum and their associated ultrastructural alterations. Here, we identify NPs in the locus coeruleus (LC), substantia nigrae (SN) and cerebellum by transmission electron microscopy (TEM) and energy-dispersive X-ray spectrometry (EDX) in 197 samples from 179 MMC residents, aged 25.9 ± 9.2 years and seven older adults aged 63 ± 14.5 years. Fe, Ti, Hg, W, Al and Zn spherical and acicular NPs were identified in the SN, LC and cerebellar neural and vascular mitochondria, endoplasmic reticulum, Golgi, neuromelanin, heterochromatin and nuclear pore complexes (NPCs) along with early and progressive neurovascular damage and cerebellar endothelial erythrophagocytosis. Strikingly, FeNPs 4 ± 1 nm and Hg NPs 8 ± 2 nm were seen predominantly in the LC and SN. Nanoparticles could serve as a common denominator for misfolded proteins and could play a role in altering and obstructing NPCs. The NPs/carbon monoxide correlation is potentially useful for evaluating early neurodegeneration risk in urbanites. Early life NP exposures pose high risk to brains for development of lethal neurologic outcomes. NP emissions sources ought to be clearly recognized, regulated, and monitored; future generations are at stake.

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.

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.

Although the transition to electric vehicles (EVs) is well underway and expected to continue in global car markets, most vehicles on the world’s roads will be powered by internal combustion engine vehicles (ICEVs) and fossil fuels for the foreseeable future, possibly well past 2050. Thus, good environmental performance and effective emission control of ICE vehicles will continue to be of paramount importance if the world is to achieve the stated air and climate pollution reduction goals. In this study, we review 228 publications and identify four main issues confronting these objectives: (1) cheating by vehicle manufacturers, (2) tampering by vehicle owners, (3) malfunctioning emission control systems, and (4) inadequate in-service emission programs. With progressively more stringent vehicle emission and fuel quality standards being implemented in all major markets, engine designs and emission control systems have become increasingly complex and sophisticated, creating opportunities for cheating and tampering. This is not a new phenomenon, with the first cases reported in the 1970s and continuing to happen today. Cheating appears not to be restricted to specific manufacturers or vehicle types. Suspicious real-world emissions behavior suggests that the use of defeat devices may be widespread. Defeat devices are primarily a concern with diesel vehicles, where emission control deactivation in real-world driving can lower manufacturing costs, improve fuel economy, reduce engine noise, improve vehicle performance, and extend refill intervals for diesel exhaust fluid, if present. Despite the financial penalties, undesired global attention, damage to brand reputation, a temporary drop in sales and stock value, and forced recalls, cheating may continue. Private vehicle owners resort to tampering to (1) improve performance and fuel efficiency; (2) avoid operating costs, including repairs; (3) increase the resale value of the vehicle (i.e., odometer tampering); or (4) simply to rebel against established norms. Tampering and cheating in the commercial freight sector also mean undercutting law-abiding operators, gaining unfair economic advantage, and posing excess harm to the environment and public health. At the individual vehicle level, the impacts of cheating, tampering, or malfunctioning emission control systems can be substantial. The removal or deactivation of emission control systems increases emissions—for instance, typically 70% (NO_x and EGR), a factor of 3 or more (NO_x and SCR), and a factor of 25–100 (PM and DPF). Our analysis shows significant uncertainty and (geographic) variability regarding the occurrence of cheating and tampering by vehicle owners. The available evidence suggests that fleet-wide impacts of cheating and tampering on emissions are undeniable, substantial, and cannot be ignored. The presence of a relatively small fraction of high-emitters, due to either cheating, tampering, or malfunctioning, causes excess pollution that must be tackled by environmental authorities around the world, in particular in emerging economies, where millions of used ICE vehicles from the US and EU end up. Modernized in-service emission programs designed to efficiently identify and fix large faults are needed to ensure that the benefits of modern vehicle technologies are not lost. Effective programs should address malfunctions, engine problems, incorrect repairs, a lack of servicing and maintenance, poorly retrofitted fuel and emission control systems, the use of improper or low-quality fuels and tampering. Periodic Test and Repair (PTR) is a common in-service program. We estimate that PTR generally reduces emissions by 11% (8–14%), 11% (7–15%), and 4% (−1–10%) for carbon monoxide (CO), hydrocarbons (HC), and oxides of nitrogen (NO_x), respectively. This is based on the grand mean effect and the associated 95% confidence interval. PTR effectiveness could be significantly higher, but we find that it critically depends on various design factors, including (1) comprehensive fleet coverage, (2) a suitable test procedure, (3) compliance and enforcement, (4) proper technician training, (5) quality control and quality assurance, (6) periodic program evaluation, and (7) minimization of waivers and exemptions. Now that both particulate matter (PM, i.e., DPF) and NO_x (i.e., SCR) emission controls are common in all modern new diesel vehicles, and commonly the focus of cheating and tampering, robust measurement approaches for assessing in-use emissions performance are urgently needed to modernize PTR programs. To increase (cost) effectiveness, a modern approach could include screening methods, such as remote sensing and plume chasing. We conclude this study with recommendations and suggestions for future improvements and research, listing a range of potential solutions for the issues identified in new and in-service vehicles.