First nationwide analysis of the link between fine particulate (PM2.5) pollution and neurodegenerative diseases in the U.S.


Air pollution was significantly associated with an increased risk of hospital admissions for several neurological disorders, including Parkinson’s disease, Alzheimer’s disease, and other dementias, in a long-term study of more than 63 million older U.S. adults, led by researchers at Harvard T.H. Chan School of Public Health.

The study, conducted with colleagues at Emory University’s Rollins School of Public Health and Columbia University’s Mailman School of Public Health, is the first nationwide analysis of the link between fine particulate (PM2.5) pollution and neurodegenerative diseases in the U.S.

The researchers leveraged an unparalleled amount of data compared to any previous study of air pollution and neurological disorders.

The study will be published online October 19, 2020 in The Lancet Planetary Health.

“The 2020 report of the Lancet Commission on dementia prevention, intervention, and care has added air pollution as one of the modifiable risk factors for these outcomes,” said Xiao Wu, doctoral student in biostatistics at Harvard Chan School and co-lead author of the study.

“Our study builds on the small but emerging evidence base indicating that long-term PM2.5 exposures are linked to an increased risk of neurological health deterioration, even at PM2.5 concentrations well below the current national standards.”

Researchers looked at 17 years’ worth (2000-2016) of hospital admissions data from 63,038,019 Medicare recipients in the U.S. and linked these with estimated PM2.5 concentrations by zip code.

Taking into account potential confounding factors like socioeconomic status, they found that, for each 5 microgram per cubic meter of air (μg/m3) increase in annual PM2.5 concentrations, there was a 13% increased risk for first-time hospital admissions both for Parkinson’s disease and for Alzheimer’s disease and related dementias.

This risk remained elevated even below supposedly safe levels of PM2.5 exposure, which, according to current U.S. Environmental Protection Agency standards, is an annual average of 12 μg/m3 or less.

Women, white people, and urban populations were particularly susceptible, the study found.

The highest risk for first-time Parkinson’s disease hospital admissions was among older adults in the northeastern U.S. For first-time Alzheimer’s disease and related dementias hospital admissions, older adults in the Midwest faced the highest risk.

“Our U.S.-wide study shows that the current standards are not protecting the aging American population enough, highlighting the need for stricter standards and policies that help further reduce PM2.5 concentrations and improve air quality overall,” said Antonella Zanobetti, principal research scientist in Harvard Chan School’s Department of Environmental Health and co-senior author of the study.

The role of environmental pollutants as an important determinant of health is being increasingly recognized. As recently outlined by the Lancet Commission on pollution and health, air pollution is the leading environmental cause of disease and premature death [1].

In this setting, diseases caused by all forms of pollution annually account for 16% of global deaths, representing 15 times more deaths than from all wars and other forms of violence as well as three times more than from AIDS, tuberculosis, and malaria combined. Likewise, the World Health Organization (WHO) concludes that 12.6 million premature deaths per year are attributable to unhealthy environments. 8.2 million of them are due to noncommunicable diseases, with cardiovascular disorders (including stroke) being here the largest contributor to the health burden, accounting for nearly 5 million of these deaths [2].

Among all environmental stressors, air pollution is the most important risk factor and ambient outdoor air pollution due to particulate matter < 2.5 µm (PM2.5) exposure ranks on the fifth position among all global health risk factors in 2015, leading to 4.2 million deaths annually (Figure 1) [3].

This is further supported by recent data from the WHO, suggesting that 9 out of 10 people worldwide breathe polluted air [4]. We recently used a novel hazard ratio function, the estimate of Global Exposure-Mortality Model (GEMM), to calculate 8.79 million global premature deaths in 2019 as well as 790,000 excess deaths per year in Europe only due to exposure to air pollution (mostly PM2.5), thereby indicating that the premature death estimates are increasing over the years [5].

However, besides being a leading cause of the global burden of noncommunicable diseases, including cardiovascular diseases, respiratory diseases, metabolic diseases, and cancer, recent studies indicated the adverse effects of air pollutants, especially of the ultrafine fraction of PM2.5, on the central nervous system (CNS) and brain health [1,6].

In this context, ultrafine particles (<0.1 µm) can translocate from the pulmonary system to the CNS by crossing the blood–brain barrier (BBB) and, ultimately, reach the brain, inducing pathophysiological alterations in the CNS due to the physical characteristics of the particle itself (relatively large reactive surface) or by toxic compounds that are bound to the particles.

These mechanisms might contribute to the development of cerebrovascular and neurological disorders such as stroke, dementia, and Parkinson’s disease.

Increasing evidence suggests neuroinflammation and cerebral oxidative stress to be key factors in the relationship between air pollution and cerebrovascular and neurological disorders [7], driven by the enhanced production of proinflammatory mediators and reactive oxygen species (ROS) in response to exposure to air pollutants [8,9].

Here, we provide an updated overview of the impact of air pollutants on cerebrovascular and neurological and mental disorders, along with pathophysiological insight from human and animal studies centered on inflammatory and oxidative stress pathways.

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Figure 1
Global risk factors for global deaths in 1990 compared with 2015 outlined in the Global Burden of Disease Study (GDB). Reused from Münzel et al. [10] with permission. Copyright © 2020, Oxford University Press.

Air Pollution Mixtures and Sources

Air pollution is a heterogeneous mixture of various constituents resulting from the complex interaction of multiple emissions and chemical reactions.

This mixture comprises solid particles and liquid droplets suspended in the air, i.e., PM2.5, that can include organic carbon (OC), elemental or black carbon (EC), nitrates, sulfates, and metals (e.g., iron, vanadium, nickel, copper, and manganese) as well as gases (e.g., ground level ozone (O3), carbon monoxide (CO), sulfur dioxide (SO2), oxides of nitrogen (NOx)) gaseous organic compounds (e.g., non-methane volatile organic compounds (VOCs), polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs)), bacterial endotoxins (mostly bound to solid particles or liquid aerosols) [11].

In the urban environment, over 90% of the pollutant mass is from gases or vapor-phase compounds, while anthropogenic combustion-derived particles are of special concern from a public health perspective due to their potential systemic toxicity owing to features such as high particle counts, high surface area to mass ratio, inflammatory and oxidative stress potential, and insoluble components, leading to facile distal airway and systemic penetration [11].

Types of atmospheric particles include coarse particles with an aerodynamic diameter between 2.5 and 10 µm (PM10), fine particles with a diameter less than 2.5 µm (PM2.5), and ultrafine particles with a diameter less than 0.1 µm (PM0.1), interconnected with the general notion that smaller particles may be more potent in inducing adverse health effects than larger particles [10].

There are four main types of sources of air pollution with fossil fuels and biomass combustion, and industry, agriculture, and wind-blown dust are also predominant sources of fine particulates in the air (Figure 2).

Furthermore, it is important to note that, besides emission intensities related to e.g., the amount of fuel combusted, the number of animals in animal husbandry, industrial production levels, and distances traveled or similar activity data, air pollution is strongly influenced by climate and weather conditions [12].

For instance, factors such as wind direction and speed, atmospheric stability, and solar radiation are important determinants of the spatial (fine particles can travel more than 100 km from their place of generation) and temporal variation in air pollutants with some of the most aggressive of them being generated during hot periods with a high UV index [12].

Interestingly, air pollution and climate change influence each other via complex interactions in the atmosphere, both of which, in turn, affect public health [13]. Herein, increasing levels of pollutants such as sulfate and O3 can modify the energy balance of the atmosphere and earth’s surface, leading to climate change that alters the physical and chemical state of the atmosphere [14].

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Figure 2
There are four main types of air pollution sources including natural, area, stationary, and mobile sources producing PM0.1, PM2.5, PM10, reactive gases including volatile organic compounds (VOCs). Primary pollutants (the indicated gases and solid particles) may undergo further toxification in the environment, e.g., by photochemical reactions by UV light producing more reactive gases or more toxic carbohydrate products on the particle surface (termed particle “aging”) [12] as well as loading of the particles with heavy/transition metals and bacterial/fungal endotoxins, leading to secondary biological toxicity [15,16,17]. The majority of coarse particles come from sediments (desert sand) and pollen from plants. Modified from Münzel et al. [18] with permission. Copyright 2020, Mary Ann Liebert, Inc., publishers. Open access source for sandstorm and plant pollen images can be found at Pixabay (

Pathophysiology of Air-Pollution-Induced Disorders

Since cardiovascular risk factors and diseases are triggered to a large amount by air pollution and impact a high proportion of global deaths, e.g., by inducing noncommunicable diseases, great efforts were made to explore, understand, and prevent the adverse cardiovascular effects of sustained exposure to air pollutants.

On the basis of the Global Exposure-Mortality Model (GEMM), we have even shown that air pollution is a larger contributor to global mortality (8.79 million excess deaths) than one of the most important health risk factors, namely tobacco smoking (7.2 million excess deaths attributed to tobacco smoking as estimated by the WHO [19]), with a population average loss of life expectancy of 2.9 vs. 2.2 years for air pollution vs. tobacco smoking [20].

We recently reviewed the effects of gaseous and solid constituents of air pollution with a particular focus on the effect of fine particles on vascular endothelial function and clinical cardiovascular outcomes, indicating that vascular inflammation and oxidative stress are common denominators of the cardiovascular effects of air pollution [10].

Vascular endothelial dysfunction is regarded as an early subclinical key event in the development of dysregulated blood pressure and manifestation of atherosclerotic cardiovascular disease, which is not only due to classical risk factors (smoking, high cholesterol, diabetes mellitus, and hypertension) but also appears to be a consequence of environmental hazards such as air pollution [18,21].

Increasing evidence from human and animal studies suggests that exposure to ambient air pollutants leads to a pathological state of the vascular endothelium that is characterized by an imbalance between the formation and degradation of nitric oxide (•NO) [10].

Since the half-life and biological activity of •NO as a free radical is strongly related to the existence of ROS such as the superoxide ion, reduction and decreased activity of •NO as well as the direct physical damage to endothelial cells due to redox imbalance impairs several crucial functions of an intact endothelium to maintain its vasodilatory, antithrombotic, anti-inflammatory, and antioxidant effects.

Thus, the persistent physiological detriments from the long-term exposure to air pollution can lead to atherosclerotic plaque formation and, over time, subsequently to various cerebro/cardiovascular disease phenotypes such as stroke, arterial hypertension, coronary heart disease, myocardial infarction, heart failure, and arrhythmia [22].

Likewise, emerging evidence from human and animal studies suggests an increased risk of cerebrovascular and neuropsychiatric disorders with sustained exposure to air pollutants affecting the CNS by a variety of cellular, molecular, inflammatory, and oxidative stress pathways. However, the understanding of the underlying mechanisms remains still incomplete and complex interactions with other risk and lifestyle factors are very likely.

Deeper insight into these associations is of great importance and should receive more attention, since neurological, cerebrovascular and mental disorders are among the largest causes of disability-adjusted life years and global deaths with 30% of all strokes being related to air pollution [23].

There are two possible ways by which air pollutants enter the CNS, either through direct transport of particles into the CNS or via systemic inflammation upon initial recruitment of immune cells in the lung tissue [24]. Herein, nasal inhalation and airflow constitute a direct access route in humans with the olfactory region being unique in the CNS due to its direct contact with the environmental air.

Smaller particles may cross the nose-brain barrier and reach the brain via olfactory receptor neurons or the trigeminal nerve, which then can travel across the CNS and reach other brain regions. On the other hand, particles can enter the circulation via the lungs through breathing and reach the alveolar region.

At this point, they can translocate to the systemic circulation through a transition process (nanoparticles probably directly, microparticles most likely via uptake by phagocytic cells and their transmigration from the lung tissue to the circulation) [25] and subsequently across the BBB to the brain parenchyma by simple diffusion or energy-dependent active transport.

Once in the organism, the adverse effects of fine particulates on the brain rely mainly on three mechanisms [26]. First, they can induce the release of proinflammatory mediators leading to chronic respiratory and systemic inflammation [27], thereby affecting the BBB and ultimately triggering neural-immune interaction and resulting in increased production of ROS and chronic oxidative stress contributing to an Alzheimer phenotype in exposed children [28].

Second, the particles can damage the BBB through the direct formation of ROS and thereby alter the permeability of the barrier [29,30]. Third, there can be mechanical stimulation of specific mechano-receptors in pulmonary tissue leading to the lung arc reflex [31,32] and sympathetic activation with the release of vasoconstrictors such as catecholamines [33].

Taken together, these mechanisms are central in promoting brain inflammation, neuronal dysfunction, and neuropathology (Figure 3) (reviewed in [34,35,36,37]).

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Figure 3
Summary of pathophysiological mechanisms by which air pollutants cause increased oxidative stress, and inflammation, thereby contributing to cerebrovascular, neurological, mental, and cardiorespiratory disorders. (A) Uptake and cardiorespiratory health effects triggered by air pollution constituents. (B) Key events that contribute to neurological and mental by air pollution constituents. Ambient PM particles are often loaded with environmental toxins stemming from particle “aging” by UV-induced photoreactions or modifications upon interaction with reactive gases in the atmosphere [12]. In addition, loading of the particles with environmental endotoxins and heavy metals enhances their direct biochemical reactivity [15,16,17]. Summarized from Münzel et al. 10 and Daiber et al. 38 with permission. Copyright © 2020, Oxford University Press (A) and © 2020 International Union of Biochemistry and Molecular Biology (B). SNS, sympathetic nervous system; UF, ultrafine.
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Figure 5
Proposed concept how air pollution constituents contribute to neurological and mental disorders. Uptake of fine particulate matter, reactive gases or secondary environmental toxins (bound to the solid or liquid aerosol particles) such as heavy metals, endotoxins or photoreaction/atmospheric chemistry products (e.g., reactive aldehydes, nitrated VOCs) by three major pathways (indirect or direct). Neuroinflammation and cerebral oxidative stress by microglia activation impairs vital pathways in the brain initiating pathophysiological processes such as amyloid deposition and neuron damage and loss. BBB, blood-brain barrier; iNOS, inducible nitric oxide synthase; TNFα, tumor necrosis factor alpha; IL-1β, interleukin 1beta; COX-2, (inducible) cyclooxygenase 2; NFκB, nuclear factor ‘kappa-light- chain-enhancer’ of activated B-cells; NOX-2, NADPH oxidase isoform 2 (phagocytic NADPH oxidase); oxLDL, oxidized low density lipoprotein; 4-HNE, 4-hydroxynonenal; 8-oxoG, 8-hydroxyguanosine; Aβ, amyloid beta peptide.

reference link :

More information: “Long-term effects of PM2.5 on neurological disorders in the American Medicare population: a longitudinal cohort study,” Liuhua Shi, Xiao Wu, Mahdieh Danesh Yazdi, Danielle Braun, Yara Abu Awad, Yaguang Wei, Pengfei Liu, Qian Di, Yun Wang, Joel Schwartz, Francesca Dominici, Marianthi-Anna Kioumourtzoglou, Antonella Zanobetti, The Lancet Planetary Health, online October 19, 2020, doi:


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