Frontiers and hotspots evolution between air pollution and Alzheimer's disease: A bibliometric analysis from 2013 to 2023

Abstract

In recent years, the study of air pollution has received increasing attention from researchers, but a summary of Alzheimer's disease (AD) and air pollution is missed. Through combing the documents in the core dataset of Web of Science, this study analyzes current research based on specific keywords. CiteSpace and VOSviewer perform statistical analysis of measurement metrics to visualize a network of relevant content elements. The research devotes discussion to the relationship between air pollution and AD. Keyword hotspots include AD, children, oxidative stress, and system inflammation. Overall, 304 documents on air pollution and AD from 2013 to 2023 were retrieved from Web of Science. One hundred twenty-two journals published relevant articles, and the number of articles has increased gradually since the past decade. Research and development in AD and air pollution are progressing rapidly, but there is still a need for more connections with multidisciplinary technologies to explore cutting-edge hotspots.

Keywords

air pollution Alzheimer's disease bibliometric ozone particulate matter

Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by cognitive dysfunction and amnesia.^1–3 Research indicates that the major pathological features of AD include intracellular neurofibrillary tangles of hyperphosphorylated tau,⁴ and deposition of senile plaques (amyloid-β, Aβ).^5,6 AD typically has a subtle onset and is often initially unrecognizable due to its mild cognitive deficits, which may be attributed to altered functional connectivity and synaptic plasticity.^7–9 Functional connectivity in brain networks has been shown to contribute to the propagation of amyloid and tau in humans, and functional connectivity allows for the assessment of the integration of brain activity in distant brain regions regardless of their structural connectivity.^10,11 The etiology of AD is complex, and although many medications have been shown to exist that can improve AD symptoms, such as Tacrine or donepezil,¹² there is still no complete treatment for AD.^13–15 AD can negatively impact the quality of life of people with AD and place a heavy burden on family finances, and the occurrence of AD gradually rises with age.¹⁶ So, it has thus become a pressing public health concern.^17,18

In recent years, many studies have shown that air pollution affects AD. Air pollution, resulting from human activities or natural processes, involves chemical, physical, or biological factors altering the natural characteristics of the atmosphere. Common sources of air pollution include coal combustion, vehicle emissions, industrial production, and forest fires. Notably, particulate matter (PM), carbon monoxide (CO), ozone, nitrogen dioxide, and sulfur dioxide stand out as major pollutants, posing significant risks to public health.¹⁴

Bibliometrics is a valuable tool for analyzing research trends in a specific field over a defined period of time.¹⁹ By employing mathematical and statistical methods to quantitatively and qualitatively analyze literature in the field, bibliometrics can uncover research hotspots and frontiers.^20,21 It has been successfully applied to literature reviews in the environmental domain, aiding in the identification of connections between various topics and providing essential background knowledge for the subject of study.²² Moreover, CiteSpace and VOSviewer are two common data visualization tools, gained widespread usage in bibliometric analysis.^17,23–26

As research progresses, investigations into the mechanisms by which air pollution impacts AD have been cautiously explored. Studies have shown a correlation between increased prevalence of AD and higher levels of ambient air pollution, with elevated exposure to sulfur dioxide (SO2) or CO amplifying the risk of dementia.²⁶ Although variants in the apolipoprotein E (APOE) gene and neighboring regions on chromosome 19q13.3 are themselves associated with AD risk, air pollution can accelerate the rate of cognitive decline in APOE4 carriers.^27–29 Furthermore, air pollution promotes the appearance of diffuse plaques of Aβ.³⁰ As we all know, AD is characterized by accumulation of Aβ.³¹ Aβ deposition triggers a series of neuroinflammatory disorders with activation of microglia, and activation of microglia and astrocytes triggers a variety of inflammatory and anti-inflammatory cytokines to be expressed.³² Neuroinflammation is one of the main mechanisms of AD.³³ Consequently, chronic inflammation, which is observed prior to the onset of clinical dementia, is a characteristic feature of AD. Air pollution contributes to an excessive production of reactive oxygen species (ROS) and oxidative stress, and ROS and oxidative stress play significant roles in the mechanisms underlying AD.^34,35

Our study aims to provide an overview of various aspects research conducted in the past 10 years on the relationship between air pollution and AD and helps other researchers to understand the mechanisms of occurrence and therapeutic strategies of currently existing studies in this field of AD, avoiding them from duplicating studies.

Data capture and literature search strategy

The publications on air pollution and AD are available in Web of Science until December 31, 2023. Data sources and search methods are shown in Figure 1. Publications were retrieved using the screening strategies described in the Supplementary Material and were published between January 1, 2013 to December 31, 2023. Information gleaned from each article included author, region, journal, keywords, and citations.

Figure 1.

Searching strategies in this research.

Data analysis and visualization images

In this study, we collected data from Web of Science and utilized VOSviewer Version 1.6.18 to create a visualization of web images. Data visualization was further facilitated by the Data wrapper website.³⁶ The most commonly employed bibliometric methods include co-authorship analysis, co-occurrence analysis, and co-citation analysis. Co-authorship analysis reveals collaboration patterns among authors, institutions, and countries, shedding light on collaborative networks.³⁷ Co-citation analysis assists in constructing a knowledge base for a particular field.³⁸

These visual maps serve as valuable tools for researchers to identify important bibliometric information, including authors, journals, region, key concepts, hotspots of study, and emerging frontiers in a specific topic. In the visualization of web images generated by VOSviewer, each node is represented by a labeled circle, and the bigger circles are, the higher frequencies of occurrence are. Different colors of circles indicate distinct clusters, while the thickness and length of the lines connecting the nodes represent their strength and correlation. To ensure data accuracy, the authors, institutions, categories, and keywords underwent a rigorous cleaning process. Duplicate entries and similar expressions are eliminated to enhance the reliability of the data analysis. In addition, the literature is subjected to remove duplications using the CiteSpace 6.2.R7 software's duplicate deletion function. The analysis is focused on the time from January 1, 2013 to December 31, 2023. The Strategies for searching are illustrated in Figure 1, providing a visual representation of the steps involved in the data retrieval process (https://bibliometric.com/).

Results

Number of studies published

The quantities of publications per year can serve as an indicator of the level of interest and research activity in a particular field. In Web of Science, there are 602 publications on the relationship between air pollution and AD. After the search strategy was completed, a total of 304 documents were retained, and all 304 articles were in English. Of these, 232 are articles and 72 are reviews. The annual global published trend is depicted in Figure 2. It is clear that the number of publications in the field has been gradually increasing over the past two years. In 2015, only 14 related reports were published, indicating that the subject was just beginning to garner attention. Higher number of articles have been published since 2020 and it has remained around 47 in subsequent years. This indicates that the field continues to hold promising avenues for exploration, with many unresolved issues that warrant further investigation.

Figure 2.

Trends in publications per year on air pollution in AD from 2013 to 2023.

Analysis of countries/regions and institution

Table 1 presents the top 10 countries with the highest productivity of medical publications in this field. Among them, the United States has the highest number of publications (163 articles) with a total of 5902 citations. Mexico follows with 40 articles and 1744 citations, and China with 63 articles and 1611 citations. Table 1 also highlights the significant contributions made by the top 10 countries in the domain of air pollution and AD research. Based on the statistical data, the United States continues to play a central and influential role in research, It reaffirms its position as a leading country in numerous scientific fields.³⁹ A total of 1389 organizations have contributed to the publication of literature in the field. Table 2 presents the top 9 institution with the highest number of publications. In terms of average citations per publication, the organizations with the highest scores are the Carleton University (83 citations) and the Boise State University (56 citations), closely followed by the National Autonomous University of Mexico (54 citations).

Table 1.

The top 10 productive countries/region.

Rank	Country	Publications	Citations
1	USA	163	5902
2	Mexico	40	1744
3	China	63	1611
4	Canada	17	1281
5	England	25	1012
6	Germany	19	796
7	Sweden	14	620
8	Italy	16	620
9	Spain	14	349
10	India	18	338

Table 2.

Top 9 institutions with maximum publication.

Institution	Citation	Publication	Avg citation
University of Montana (USA)	1663	38	44
National Autonomous University of Mexico (Mexico)	1413	26	54
Universidad del Valle de México (Mexico)	1227	31	40
University of Southern California (USA)	1013	26	39
Instituto Nacional de Pediatría (Mexico)	845	20	42
Boise State University (USA)	723	13	56
University of Washington (USA)	696	25	28
The University of North Carolina System (USA)	673	13	52
Carleton University (Canada)	581	7	83

VOSviewer was employed to analyze the co-authored publications by country. The co-authorship network of the top 17 countries is depicted in Figure 3, where 17 countries/regions are divided into three distinct clusters denoted by different colors. The largest cluster (represented in red) comprises seven countries centered around the UK, France, and Germany, while the United States has the highest number of collaborative partners (n = 16). The analysis of countries/regions enables the identification of entities with significant impact in the field of research. Furthermore, in today's era of information and communication technologies, cooperative research in science and technology at the international level is on the rise.⁴⁰

Figure 3.

The country/region of the publication. Different colors represent different years. For example, purple (including Germany, Mexico, and India) represents 2018–2019 and red (except purple part, Canada, Iran, and France) represents 2020–2021. The largest cluster (represented in red) comprises seven countries centered around the UK, France, and Germany, while the United States has the highest number of collaborative partners.

Principal investigator and co-cited journal analysis

A total of 1651 authors have made contributions to the field of AD and air pollution. The top three authors based on the number of publications are Lilian Calderon-Garcidueñas (33 publications), Ricardo Torres-Jardón (23 publications), and Partha S. Mukherjee (22 publications). Furthermore, Lilian Calderon-Garcidueñas has received a total of 1486 citations, with an average of 45.03 citations per publication. Additionally, Calderon-Garcidueñas has achieved an H-index of 49, showing the significant impact within the field. Among the authors, Torres-Jardón has the highest average citation score of 53.17. Calderon-Garcidueñas follows with an average citation score of 45.03, and Mukherjee follows with an average citation score of 37.82.

The use of VOSviewer for visual analysis enables an exploration of the interrelationships between literature, thereby providing insights into the present state and developmental trends within a research field. By identifying author groups, it becomes possible to establish essential communication networks among scientific peers, facilitating information exchange and academic collaboration (Figure 4). In terms of literature coupling, the prominent researchers include Calderon-Garcidueñas (citations = 1468, total link strength = 60,620), Torres-Jardón (citations = 1,223, total link strength = 46,702), Mukherjee (citations = 832, total link strength = 44,559), and Reynoso-Robles (citations = 421, total link strength = 15,895). In the author literature coupling network, it is divided into 3 groups based on the year of publication and suggests that these authors began to develop concerns about AD and air pollution during the same period of time, and that the findings of the earlier studies in AD and air pollution may have laid some of the groundwork for the later studies. The yellow group (from 2020 to 2021) has the most authors, including Diana Younan, Xinhui Wang, Joann E Manson, and Andrew J Petkus. This is followed by the green group (from 2018 to 2020) and blue group (from 2017 to 2018).

Figure 4.

Coupling relationship. Different colors of nodes and connecting wires represent different years. Purple 2017–2018, cyan represents 2018–2019, green 2019–2020, Yellow 2020–2021. From right to left, representing the period from 2018 to 2021.

After screening, a total of 304 publications on AD and air pollution research have been published in the last decade. The pattern of output indicates a consistent growth of output of research publications.⁴¹ A total of 122 journals have published literature on air pollution and AD, and the top 8 journals with the most articles are shown in Table 3. The Journal of Alzheimer's Disease (SJR 2022 1.146) has the highest number of articles with 1669 citations and an impact factor of 4.00, followed by Environmental Research with 1124 citations and Environment Health Perspectives with 731 citations. The SJR indicator is a useful tool for researchers to identify high-quality journals in their field. The SJR index, based on Scopus data, includes journal titles from a wider range of countries and languages compared to the IF Journal, which is based on Web of Science data.⁴²

Table 3.

The top 8 journals of publications on air pollution and AD.

Rank source	Category	IF (2023)	Total publications (percentage)	Total citation
Journal of Alzheimer's Disease	Neurosciences–Scie	4.0	15.13%	1669
Environmental Research	Environmental Sciences	8.3	10.85%	1124
Environmental Health Perspectives	Environmental Sciences	10.4	2.30%	731
Neurotoxicology	Neurosciences – Scie Pharmacology & Pharmacy - Scie; Toxicology – Scie	3.4	1.97%	718
Environment International	Environmental Sciences	11.8	5.26%	585
Science of the Total Environment	Environmental Sciences	9.8	2.63%	364
PLoS One	Multidisciplinary Sciences – Scie (Q2)	3.7	1.97%	236
International Journal of Environmental Research and Public Health	Environmental Sciences Public, Environmental & Occupational Health	4.6	3.94%	230

The study hotspots of air pollution and AD

Using VOSviewer analyzes and clusters the most relevant keywords in this research, as shown in Figure 5. Keyword co-occurrence analysis plays a valuable role in identifying research hotspots of the relationship between air pollution and AD. The co-occurrence network reveals five distinct clusters. The keywords “AD” (256 occurrences), “air pollution” (249 occurrences), and “PM” (201 occurrences) are located at the center of the visual network, indicating their significance within the research domain. In the keyword coupling network, the red cluster contains the highest number of keywords, including “PM”.

Figure 5.

The co-cited keywords. The co-occurrence network shows five different clusters. “AD” was the most frequent keyword with 256 occurrences, “air pollution” with 249 occurrences, and “particulate matter” with 201 occurrences, which are located in the center of the visual network, indicating their importance in the research area.

The burst of keywords analysis identifies emergent keywords that have emerged over the past decade, with “population,” and “children”, continuing to exhibit bursts of activity up to 2023 (Figure 6). Additionally, there has been a significant focus on systemic inflammation, Mexico City, oxidative stress, and major road in recent years. These burst keywords may indicate future research trends in the field.

Figure 6.

Burst keyword from 2013 to 2023.

By visualizing and analyzing the timeline diagram presented in Figure 7, the research frontiers pertaining to air pollution and AD can be further explored. Because node size indicates the frequency of occurrence of different research points in the last decade, and larger nodes mean higher frequency of occurrence. Therefore, we have identified research priorities for different years. Studies on AD and PM, oxidative stress, and systemic inflammation appeared near 2000 and have been followed at various times. In the early stages of research (2013), the primary keyword associated with the relationship between air pollution and AD was PM. Studies on synuclein, oxidative stress, Aβ, and inflammation appeared near 2015 and have been followed at various times. From 2015 to 2020, research had focused on factors such as air pollutants, particles, neuroinflammation, fine particulate matter, and ozone. From 2020 to 2023, research had been conducted mainly on nanoparticles and neurotoxicity, and a new hotspot is exploring the relationship between multiple sclerosis and AD.

Figure 7.

The timeline view of keywords. From 2013 to 2015, most research focused on systemic inflammation, oxidative stress, ultrafine particles, apolipoprotein E, and particulate matter; from 2015 to 2020, research focused on factors such as air pollutants, neuroinflammation, fine particulate matter, and ozone; from 2020 to 2023, research focuses on nanoparticles and neurotoxicity.

By analyzing the burst of references from 2013–2023 shown in Figure 8, it is possible to determine which articles laid the groundwork for scholars’ research between the decades and to understand which topics are of great interest to scholars. Among them, DP Bhatt, CR Jung, and Yun-Chun Wu are three of the important authors in the outbreak references. Jung's article had an outburst intensity of 15.53, the strongest outburst intensity of all the references. Bhatt and Wu, whose articles began to explode in 2017, are two of the authors who have continued to explode with the greatest intensity until the last few years.

Figure 8.

The strongest citation references burst from 2013 to 2023. Bhatt DP, Jung CR, and Wu YC are the three important authors for burst citation. Jung's article with burst intensity of 15.53 has the highest burst intensity among all references, whereas Bhatt DP and Yun-Chun Wu's articles have been exploding since 2017 and are the two authors with the highest intensity of sustained outbursts until the last few years. Both of them have made significant contributions to this decade's research.

Discussion

The quantities of research related to AD and air pollution showed a slow-growth trend until 2017. In the past 3 years, the number of published papers significantly increased and frequently updated in research hotspots. As a result, it is essential to summarize and analyze the progress in order to stay informed and up-to-date, and changing hotspots with this research field. The study employs two visual data analysis software tools, CiteSpace and VOSviewer, to conduct an in-depth analysis in developmental trends, keyword, and references involved in air pollution research in the context of AD. By utilizing these powerful analytical tools, the study aims to provide some insights into the dynamic landscape of research in this field.

Different keywords in each year

The timeline chart (Figure 7) shows that the keywords differ for each year.

From 2013 to 2015, much of the research focused on “systemic inflammation”, “oxidative stress”, “ultrafine particles (UFPs)”, “apolipoprotein E”, and “PM”. It has been found that the number of intact mitochondria is reduced in AD patients and that oxidative stress damages cells and leads to mitochondrial dysfunction.⁴³ So although AD involves multiple complex pathogenic mechanisms and hypotheses, oxidative stress and its damage to neurons is a central factor and important aspect of all mechanisms.⁴⁴ In addition, it has also been found that systemic inflammation leads to elevated levels of pro-inflammatory mediators.⁴⁵ These signals can be projected to the brain through the neural afferent and brain barriers. This can directly or indirectly induce neuronal cytotoxicity and affect Aβ transporters, leading to increased Aβ accumulation. Aggregated Aβ induces the initial activation of microglia, resulting in activated microglia with impaired Aβ clearance. In addition, activated microglia produce large amounts of pro-inflammatory cytokines, further exacerbating neuroinflammation. This worsening neuroinflammation promotes the development of brain pathology and ultimately leads to cognitive deficits.⁴⁶

From 2015 to 2020, research focuses on the impact of “fine particulate matter”, “ozone”, “iron oxide nanoparticles”, “neuroinflammation”, and “particles” on AD. Particles include PM, among others. PM includes particles between 2.5 and 30 μm in size (PM30, PM10, and PM2.5) and UFPs (less than 0.1 μm, including nanoparticles).⁴⁷ There is growing evidence that particles and UFPs (including nanoparticles) may play a larger role than recognized in causing adverse health effects. UFPs exposure is strongly associated with altered metabolic pathways involved in inflammation, oxidative stress, immunity, and nucleic acid damage and repair.⁴⁸ So, particles can lead to the exacerbation of AD. In addition, a new hotspot be the exploration of ozone's impact on AD. Cognition is affected by assessing high exposure to ozone and fine particulate matter like PM2.5 which is the PM in ambient air with an aerodynamic equivalent diameter of less than or equal to 2.5 microns. But there is a new study observing that ozone is capable of modulating inflammation and presenting extensively research and strengths on immune/anti-inflammation/anti-microbial and pro-neuroendocrine activities of O₃ that can have a significant clinical impact on AD. And the study proposes a new intervention natural treatment in terms of O₂-O₃ therapy that can be potentially used for AD pathology.⁴⁹

From 2020 to 2023, research has shifted towards investigating the effects of air pollution on neurons. It has been found that PM2.5 induces damage and increases permeability of endothelial monolayer tight junctions in vitro, leading to increased monocyte migration across the endothelial monolayer. In addition, PM2.5 treatment decreases cell viability and the neuronal antigen microtubule associated protein 2, suggesting that PM2.5 induces direct neurotoxicity. PM2.5 also induces indirect neurotoxicity by targeting macrophages. Macrophage-conditioned media was used for extracellular vesicle isolation, and elevated levels of glutaminase C (GAC) proteins were found in extracellular vesicles of PM2.5-treated macrophages compared to mock-treated control macrophages. These data suggest that PM2.5 may increase GAC release through extracellular vesicles and contribute to excessive glutamate production by macrophages, and that high levels of extracellular glutamate induce neuronal damage.⁵⁰

To summarize, in the past decade, the research hotspot has mainly been airborne particulate matter, and then neurotoxicity has also become a research hotspot.

The factors and the mechanisms of AD

Figure 9 focuses on the mechanisms of air pollution affecting on AD.

Figure 9.

Mechanisms of air pollution affecting on AD. Ozone reacts with lipids. This reaction produces primary lipids (LOPs) that activate immune cells to produce TNF, which leads to apoptosis through the NF-κB and c-Jun pathways. Diesel exhaust induces neuroinflammation and triggers disturbances in the expression of myeloid receptor 2 (TREM2) in the hippocampus and cortex (two brain regions affected by ADD), which modulates microglia-mediated responses to neurodegenerative processes. PM2.5 enters the bloodstream and remains in the brain, where it affects proinflammatory and stress pathways, including the formation of prostaglandins via the Cox-1 enzyme, induction of the Cox-1 enzyme, and induction of the Cox-2 enzyme. The enzymes Cox-1 and inducible Cox-2 are the first key steps in catalyzing the synthesis of prostaglandin E2, which leads to inflammation. In addition to this, ROS generated by copper oxide nanoparticles enhance pro-apoptotic factors, leading to apoptosis, and oxidative stress induced by copper oxide nanoparticles leads to severe changes in different regions of the brain such as the cerebrum, cerebellum and hippocampus.

See 2020 in ‘PM2.5’ Timeline [#7] in Figure 7. Studies have shown that once fine particles such as PM2.5 enter the blood stream, they remain in the brain longer than they do in other major metabolic organs. The number of small particles, which enters the brain from the lungs through the bloodstream, may be eight times greater than those entering the brain directly through the nose.⁵¹ There are studies demonstrating pro-inflammatory and stress pathways affected by PM2.5 exposure, including prostaglandin-forming cyclooxygenase (COX-1/2), inducible nitric oxide synthase, nitroso-protein stress markers, and oxidized protein stress markers, which are formed in the brains of AD animals in the cornu ammonis2 to cornu ammonis3 pyramidal elevated immunostaining for COX-2 in neurons.⁵² And the enzymes Cox-1 and inducible Cox-2 are the first critical steps that catalyze the synthesis of prostaglandin E2, leading to inflammation.⁵³ So prolonged exposure to PM in ambient air at National Ambient Air Quality Standards levels alters the inflammatory profile of the brain and promotes changes in early AD.⁵⁴ Another research has shown that individuals exposed to high PM2.5 exhibit an increase in amyloid protein load. Cognitive impairment caused by long-term exposure to PM2.5 may be mediated by abnormal amyloid protein in cerebrospinal fluid, such as Aβ₄₂/Aβ₄₀, P-tau/Aβ₄₂, and T-tau/Aβ₄₂.⁵⁵ Cerebrospinal fluid T-tau/Aβ₄₂ and p-tau181/Aβ42 ratios, the most promising potential discriminators of clinical diagnosis, are assessed for their sensitivity and specificity.⁵⁶ Plasma Aβ₄₂/Aβ40, especially when combined with age and APOE ε4 status, accurately diagnoses brain amyloidosis and can be used to screen cognitively normal individuals for brain amyloidosis.⁵⁷ Aβ is able to be seen in 2015 Timeline [#8] Figure 7. Aβ induces [Ca²⁺] changes in astrocytes that significantly increase neurotoxicity.⁵⁸ Aβ also affects neurons by inducing calcium-dependent ROS production in astrocytes.⁵⁹ Many different mechanisms explain how Aβ induces ROS production, e.g., stimulation of ROS production in mitochondria, production of superoxide in Aβ aggregated in the presence of copper.^60–62 Statins can lead to neuroprotection by inhibiting Aβ-induced calcium signaling in astrocytes and neurons. Based on this aspect, AD can be treated with statins.⁶³

See 2020 in ‘nanoparticles’ Timeline [#4] in Figure 7. Nanoparticles cause changes in cellular respiration and redox homeostasis. Even at the lowest applied concentration of 0.1 µg/mL, CdSe/ZnS nanoparticles depolarize the mitochondrial membrane, reaching over 50% depletion at the highest tested concentration of 10 µg/mL, corresponding to a virtual collapse of the respiratory potential. Similarly, the intracellular production of ROS increase in cells treated even with the lowest concentration of quantum dots, with a corresponding rise in this effect at higher concentrations.⁶⁴ ROS generated by copper oxide nanoparticles prompts enhancement of pro-apoptotic factors, leading to apoptosis, and the oxidative stress induced by copper oxide nanoparticles causes severe alterations in different regions of the brain including cerebrum, cerebellum, and hippocampus.⁶⁵ Diesel particulate matter is also composed of fine particles, including a large number of UFPs.⁶⁶ Studies have demonstrated that during month-long diesel exhaust-induced neuroinflammation, the expression of triggering receptor on myeloid cells 2 (TREM2) is disrupted in the hippocampus and cortex, these two brain regions are affected by AD.⁶⁷ TREM2 is a myeloid cell membrane receptor and a key regulator of disease-associated microglial (DAM) cells. TREM2 regulates microglia-mediated responses to neurodegenerative processes,⁶⁸ such as chemotactic microglia responses to amyloid plaques,⁶⁹ pro-inflammatory responses of microglia,⁷⁰ microglia survival⁷¹ and DAM phenotype,⁷² and loss-of-function TREM2 mutations. All of these cellular responses have been associated with an increased risk of AD.

Ozone is able to be seen in 2018–2019 Timeline [#5]. Ozone can react with biomolecules of the respiratory tract and produce reactive ROS. ROS and other ozone mediators including pro-inflammatory cytokines can alter the blood-brain barrier (BBB) (BBB is able to be seen in 2013 Timeline [#0] Figure 7) function and may reach the brain through an intact or altered BBB, or through the circumventricular organs or choroid plexus, and eventually expand oxidative stress and inflammation to those tissues if its defense mechanisms are exceeded.^73–75 In addition, ozone can cause a decrease in TREM2 expression by destroying microglia, which further reduces amyloid plaque clearance, exacerbates plaque number, size, and loading, and also shifts the Aβ₄₂/Aβ₄₀ ratio.⁷⁶ Cytokines, chemokines, and systemic inflammatory soluble mediators, which are soluble mediators, can open the BBB through the periventricular organs, entering the central nervous system through the bloodstream, leading to the displacement of inflammatory mediators and interfering with the health of neurons and glia. For example, tumor necrosis factor (TNF) cross-linking with TNFR1 and activate NF-κB and c-Jun pathways. When TNF binds to TNFR1, then the intracellular structural domain of TNFR1 releases protein silencer of death domain. TNFR1-ICD is then recognized by the junction protein TNFR1-associated death domain, which recruits the additional junction proteins Fas-associating protein with a novel death domain (FADD), TNF receptor associated factor 2 (TRAF2) and receptor-interacting protein (RIP). FADD, TRAF2, and RIP recruit various key enzymes to the TNFR1 complex periphery. For example, caspase8 is recruited to the TNFR1 complex by FADD and activated by self-cleavage. Activated caspase8 then initiates the protease cascade that leads to apoptosis. research has found that the high baseline level of TNF is associated with a fourfold increase in the rate of cognitive decline. The entire study shows that acute and chronic systemic inflammation is associated with an increase in serum tumor necrosis factor and an increase in cognitive decline in AD.⁷⁷

Tau protein is a microtubule related protein mainly distributed in the axons of central nervous system neurons. The excessive phosphorylation of tau protein leads to its loss of ability to bind to microtubules, leading to microtubule depolymerization and axonal transport disorders, forming tau aggregates, leading to neuronal apoptosis and typical pathological symptoms of AD.⁶⁴ Phosphorylated tau proteins (pTau) can be degraded by the proteasome, but this function of the proteasome is not implemented in patients with AD.⁷⁸ At the same time, undegraded pTau can inhibit proteasomal function,⁷⁹ and the inhibited proteasome can lead to accelerated formation of tau inclusion bodies,^80,81 which can have a negative effect on neuronal health. The pTau interacts with vesicular ATPase leading to lysosomal dysfunction in AD, also to the accumulation of many different waste proteins in the cell and damage to neurons.⁸²

Treatment strategies of AD

AD is a multifactorial neurodegenerative disease; therefore, multi-targeted drugs will be the best choice for the treatment of AD. Researchers are currently working on AD therapeutics that act on different targets, and multi-targeted therapeutics for AD are a current point of interest.⁸³ The FDA has approved six clinically available targeted agents for symptomatic relief in AD patients; tacrine, donepezil, rivastigmine and galantamine are acetyl-cholinesterase-inhibitors, and memantine is an N-methyl-D-aspartic acid receptor antagonist.¹² Lecanemab is an IgG1 monoclonal antibody. Some new targeted drugs are also trying to be developed, such as targeting Aβ drugs, anti-tau drugs, mitochondria-targeted drugs, etc., and also some multi-targeted drugs.⁸⁴ In addition to this, APOE4 is a major genetic risk factor for AD, and the APOE gene could also serve as an ideal therapeutic target for AD because it affects multiple pathological pathways of AD risk and disease progression.^85,86 For example, by using immunotherapy to reduce APOE, especially APOE4, and thereby attenuate Aβ deposition. It has been demonstrated that amyloid deposition can be reduced through the use of HJ6.3, a monoclonal antibody specific for APOE,⁸⁷ the use of HJ6.3 also can reduce Aβ pathology and improve spatial learning ability.⁸⁸ In addition, targeting aggregated pools of APOE and/or APOE self-aggregation or inhibiting APOE receptor binding through mimetic peptides can prevent or minimize the development of AD pathology by acting on APOE.⁸⁹

However, there are two limitations in the current treatment of AD. One of which is the inefficiency of drugs to cross the BBB, but many strategies have been proposed to address this problem.⁹⁰ The second may be due to the fact that they are administered late in the course of AD.⁹¹

In the future, as depicted above, AD induced by air pollution can be treated by using currently available AD treatment strategies. Second, by elucidating the mechanisms of AD occurrence described above, it may be possible in the future to treat AD therapeutically by interfering with the production and inflammatory of key proteins in the mechanism of AD development or by promoting the metabolism of key proteins and accelerating their clearance.

Future research perspectives

In the field of air pollution promoting AD, the most studied mechanisms by researchers are ROS and systemic inflammation, and many related studies have been conducted.

Current research is devoted to the development of AD in different human populations exposed to air pollution. A study has investigated that the prevalence of AD varies among different ethnic groups under the influence of air pollution.⁹² It suggests that different humans have different susceptibilities to AD driven by air pollution. However, a problem exists here at the same time, because there are differences in air pollution exposure in different populations,^93,94 so there is a lack of evidence that different populations are differently susceptible to air pollution-induced AD, which needs to be further explored.

Prolonged exposure to severe air pollutions can lead to the development of AD-like pathology.⁹⁵ Notably, if exposed to high levels of air pollution at an early stage, AD begins to develop gradually during childhood. The average age of onset of dementia for those exposed to air pollution at an early stage, as assessed by Montreal Cognitive Assessment, is 20.6 ± 3.4 years.⁹⁶ For instance, Exposure to PM2.5 and O3 in children and young adults in metropolitan Mexico City leads to the development of AD at an early age.⁹⁷ A recent report has highlighted the presence of cognitive impairment in 55% of young adults residing in Mexican cities with fine particulate matter concentrations surpassing the current U.S. Environmental Protection Agency annual standard of 12 μg/m³.⁹⁸

In short, the analysis of burst keywords allows objective prediction of future research hotspots and guides researchers in choosing future research directions.

Co-cited reference

Highly cited articles (see Figure 10) are often important in guiding the conduct of research in certain areas. It can sometimes set the stage for a particular field.⁹⁹ The most cited article in the field is “the study investigates the association between long-term exposure to ozone (O-3) and PM with an aerodynamic diameter equal to or less than 2.5 mu m (PM2.5), and newly diagnosed AD in Taiwan”. It has found that the risk of AD also increased with each increasing in O-3/PM2.5, confirming that O-3 and PM2.5 do have an impact on AD, Further investigations may be necessary to fully elucidate the mechanisms. In addition, long-term exposure to PM2.5 promotes the development of AD¹⁰⁰ and air pollutants increase the risk of AD in the elderly population.¹⁰¹ Founding that individuals exposed to the highest tertiary of PM10 (≥49.23 μg/m³) or ozone (≥21.56 ppb) have an increased risk of developing AD. Interestingly, the association between AD risk remained significant for the highest tertiary of PM10 exposure even after stratification by APOE ε4 status and gender.¹⁰²

Figure 10.

The co-cited networks of reference.

Findings from Michelle L Block support the recognition of air pollution as a chronic contributor to neuro inflammation and the generation of ROS.¹⁰³ It provides key insights into how air pollution can have harmful effects in the brain (neurological effects of airborne particulate matter and ultrafine particulate matter). Since inflammation and ROS cause damage to the nervous system, blocking them may have a therapeutic effect on neurological disorders (as well as other diseases). For example, nuclear factor erythroid 2-related factor (NRF2) is one of the defense mechanisms against ROS developed in cells, and activation of the NRF2 system resists ROS and reduces brain damage.¹⁰⁴ NRF2 has been shown to exert neuroprotective effects^105,106 and to reduce soluble and insoluble Aβ levels, thereby improving working memory in patients.¹⁰⁷

Alarmingly, a number of studies have shown that carriers of the APOE4 allele may be at higher risk of developing AD if they live in contaminated environments.^108–110 Amyloid load was strongly correlated with APOE4 carrier status. Carriers of the APOE4 allele (APOE4 carriers) had a greater amyloid load than APOE4 noncarriers.¹¹¹ But the mechanism between APOE4 and amyloid plaque formation is not yet fully understood, and it is now suggested that it may be that the binding of lipidated APOE to the ApoER2 receptor triggers AβPP and beta-site AβPP cleaving enzyme-1 internalization, results in increased intracellular Aβ production.¹¹² In addition, obesity can enhance the APOE4 gene on AD disease risk by increasing Aβ deposition and gliosis, and the value here probes whether obese population carriers of APOE4 are more susceptible to air pollution-induced AD.¹¹³

Burst reference

Here are two highly cited articles to ponder, one of which is the study by Jung CR (titled “Ozone, particulate matter, and newly diagnosed Alzheimer's disease: a population-based cohort study in Taiwan”),⁹⁹ it confirms the effect of air pollution on AD. Another significant study is by Bhatt DP, titled “A Pilot Study to Assess the Effects of Long-Term Inhalation of Airborne Particulate Matter on Early Alzheimer's Disease in Mice”.⁵⁴ These references have played a significant role in advancing research within the field in recent years, and the following are the key elements summarized.

Aβpp and BACE

Beta-site AβPP cleaving enzyme (BACE) levels increase and AβPP levels decrease when exposed to ambient air particulate matter for long periods of time.⁵⁴ And early AβPP and BACE are altered in AD patients.¹¹⁴ An additional study was also shown that PM2.5 exposure may increase AβPP processing of Aβ, leading to a significant increase in Aβ plaque density and thus affecting AD.¹¹⁵ It is worth noting that BACE plays a role in the processing of AβPP and BACE activity is regulated by DNA methylation.¹¹⁶ Is it possible here to influence BACE expression by affecting DNA methylation to reduce BACE cleavage of AβPP to produce Aβ, arriving at the alleviation of AD. However, alterations regarding BACE and AβPP were not apparent in the brains of mice that had been inhaling ambient particulate matter for only 3 months.⁵⁴ Further exploration needed to prove if short-term exposure to environmental pollutants does not have a significant effect on AD. For example, a study discusses the link between short-term exposure to PM2.5, NO2, and warm-season ozone and AD. NO2 was found to have a significant effect on AD in the short term, but PM2.5 and warm-season ozone had little effect, when the level of current-day exposure was not considered.¹¹⁷ This result suggests that NO2 exposure may lead to the development of AD like pathologies. PM2.5 and warm season ozone may yield disparate outcomes due to the involvement of distinct pathways in AD when compared to NO2, which deserves to be explored.

COX-2 and COX-2 proteins

It is worth noting that AD patients have been reported to exhibit increased COX-2 levels in neuron in the hippocampus.⁵² Furthermore, study shows that COX2 expression is significantly higher in the frontal cortex and hippocampus of residents of cities with high air pollution.⁹⁵ Collectively, COX-2 proteins play important roles in the development of PM-induced AD pathology, such as PM2.5 may trigger the activation of the COX-2 inflammatory pathway in vascular endothelial cells, leading to cell apoptosis and inflammatory response.¹¹⁸ COX-2 converts arachidonic acid to prostaglandins, leading to inflammation, studying the connection between the prostaglandin D2 pathway and AD reveals that selective DP2 antagonists could have therapeutic potential for AD,¹¹⁹ future options can be to quantitatively assess specific prostaglandin levels across different brain regions and exposure periods, correlating them with the observed protein changes in COX-1/2 and AD-like pathology. This can stimulate further investigations into the potential preventive effects of COX-1/2 inhibitors or prostaglandin receptor antagonists.

NVU dysfunction

The integrity of the neurovascular unit (NVU) in the prefrontal white matter is compromised in populations highly exposed to air pollutants (e.g., PM2.5 and ozone), and the damage affects urban young adults as well as short- and long-term brain health and leads to AD.¹²⁰ At the same time, cerebrovascular amyloid accumulation in AD patients may disrupt the NVU and worsen pathology.^121,122 Extensive caspase-5 is present in the cerebrovascular system in AD and caspase-5 is expressed at higher levels in regions of the vasculature that lack Aβ immunoreactivity,¹²³ which may also contribute to NVU damage in AD. But it has not been explored much at the moment. It needs to explore the mechanisms that high concentrations of PM10/PM2.5 or ozone cause damage to NVUs and how to prevent or minimize damage to NVUs from high concentrations of PM10/PM2.5 or ozone.

Road traffic noise, air pollution, and risk

Furthermore, there may be a link between road traffic noise, air pollution, and risk. A research conducted by Cantuaria et al. shows transportation noise associated with a higher risk of all dementia and dementia subtypes, especially AD.¹²⁴ And another study proves that simultaneous exposure to noise and air pollution increases the risk of AD.³⁴ But there's an article that makes the opposite point that noise has no effect on cognitive decline.¹²⁵ Currently, the relationship between noise, air pollution and AD is not clearly demonstrated.

Conclusion

This paper presents an initial analysis of 304 studies on air pollution in AD over the last ten years. However, a small amount of literature was collected at Web of Science, and the data was only sourced from Web of Science and not searched from other databases, which may limit the article. In this article, only thesis or review is selected as the research object; many other types of articles are not analyzed or not suitable for analysis, so the research has limitations. Bibliometrics is a quantitative method and is simpler in terms of content and factors to be considered. In terms of application, bibliometric methodology fails to address the problem of combining theory and practice. Because the types of articles filtered are not standardized, this may lead to different results. Also, there are not many precise mechanisms of AD, so many mechanisms have not been studied in depth, resulting in the lack of depth of discussion in this paper.

The new revision of the NIA-AA Revised Clinical Criteria for AD adds three new biomarker classifications. Because the small amount of literature published after the development of the new criteria studied in this article, this may lead us to draw biased and inaccurate conclusions, affecting the reader's ability to collect and study methods for the clinical diagnosis of AD.

In conclusion, the field of AD and air pollution is rapidly progressing. The Journal of Alzheimer's Disease stands out as a leading publication in this field. The United States has emerged as the highest productive countries in terms of scientific output, while there is room for improvement in scientific productivity for countries like Mexico and China. The United States also maintains the highest level of international collaborations, solidifying its influence in the field. Among institutions, the University of Montana demonstrates the highest scientific productivity. Notably, Calderon-Garciduenas emerges as the most influential author in this area of research. Current research hotspots revolve around investigating the role and underlying mechanisms of ozone and fine particulate matter as air pollutants in the development of AD. Acknowledging limitations of the current research between air pollution and AD are important. There is a scarcity of short-term research examining how air pollution impacts AD, and the specific mechanisms underlying this association have not been fully elucidated. More research is needed in the future to expand this area of AD and air pollution.

Supplemental Material

sj-docx-1-alz-10.1177_13872877241289381 - Supplemental material for Frontiers and hotspots evolution between air pollution and Alzheimer's disease: A bibliometric analysis from 2013 to 2023

Supplemental material, sj-docx-1-alz-10.1177_13872877241289381 for Frontiers and hotspots evolution between air pollution and Alzheimer's disease: A bibliometric analysis from 2013 to 2023 by Zhirong Liu, BingShuang Hu, Ju Tang, XinLian Liu, BaoJing Cheng, Cui Jia and LuShun Zhang in Journal of Alzheimer's Disease

Footnotes

Acknowledgments

The authors have no acknowledgments to report.

ORCID iD

LuShun Zhang

Author contributions

Zhirong Liu (Conceptualization; Investigation; Visualization; Writing – original draft); BingShuang Hu (Conceptualization; Investigation; Visualization; Writing – original draft); Ju Tang (Conceptualization; Investigation; Visualization; Writing – original draft); BaoJing Cheng (Conceptualization; Investigation; Supervision; Writing – original draft); XinLian Liu (Conceptualization; Investigation; Visualization; Writing – original draft); Cui Jia (Conceptualization; Investigation; Writing – original draft); LuShun Zhang (Funding acquisition; Supervision; Writing – review & editing).

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (No. 81401161), Chinese Ministry of Education Cooperative Education Project (231100882305626); Sichuan Provincial College Student Innovation and Entrepreneurship Training Program Project (S202213705082, S202313705089, S202413705087, S202413705092).

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability

The datasets generated during and/or analyzed during the current study are available in the Web of Science.

Supplemental material

Supplemental material for this article is available online.

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