The mediating role of inflammation and oxidative stress,as well as vascular-related factors,in the association between air pollution and dementia or related cognitive outcomes: A systematic review

Abstract

Background

Air pollution is a growing global concern and has now been identified as a significant risk factor for dementia. While the mechanisms underlying this relationship remain unclear, inflammation and oxidative stress, as well as vascular-related factors have been hypothesised as being involved.

Objective

This systematic review aimed to investigate these factors as potential mediators between particulate matter air pollution and dementia or related cognitive outcomes.

Methods

This review was registered with PROSPERO. A systematic search of Medline, Embase, PsycINFO, and grey literature was conducted in May 2024, adhering to the PRISMA guidelines.

Results

Of 1098 articles retrieved, 14 studies met the inclusion criteria, involving a total of 143,124 participants. The majority of studies investigated vascular-related factors (n = 12), a smaller number examined inflammation and oxidative stress (n = 5). A meta-analysis was not performed due to high study heterogeneity in terms of exact exposures, mediators, and outcomes. Some evidence suggested that hypertension may partially mediate the association between indoor air pollution and cognitive decline, and stroke may contribute to the impact of air pollution on dementia risk. However, the evidence for both was conflicting and limited. No consistent evidence supported the involvement of other mediators.

Conclusions

Due to the limited studies undertaken, there is insufficient evidence about whether inflammation and oxidative stress, or vascular-related factors mediate the effects of air pollution on dementia and related cognitive outcomes. Further longitudinal studies are needed to address this research gap, elucidate the underlying mechanisms, enhance disease understanding, and inform prevention and risk reduction strategies.

Keywords

air pollution Alzheimer's disease cardiovascular risk factors cognition dementia inflammation oxidative stress

Introduction

The global increase in life expectancy has resulted in a growing population living with dementia. Currently, more than 55 million people worldwide are affected by this condition, with approximately 10 million new cases diagnosed annually.¹ These alarming figures underscore the critical importance of prevention efforts and highlight the need to deepen our understanding of the factors contributing to dementia, especially given the absence of a cure. Air pollution has been identified as a significant and emerging risk factor for dementia in late life, with a recent 2024 Lancet report further emphasizing the potential of reducing air pollution in preventing or delaying the onset of dementia.²

Air pollution is a complex mixture of pollutants, including particulate matter (PM), ozone (O₃), nitrogen oxides (NO_x), nitrogen dioxide (NO₂), carbon monoxide (CO), and sulphur dioxide (SO₂). Of particular concern are particulate matters with aerodynamic diameters of less than 2.5 µm (PM2.5) and 10 µm (PM10). These particles, predominantly generated from fuel combustion and vehicle emissions, are small enough to be inhaled and cause neurological damage through both direct and indirect pathways. The larger PM10 particles primarily deposit in the upper respiratory tract, triggering local inflammation that may contribute to broader systemic effects. While smaller PM2.5 particles can further translocate to the brain, potentially causing direct neurological damage to the central nervous system, via the olfactory epithelium, lung, circulatory system, and the blood-brain barrier.^3,4

Recent reviews and meta-analyses have linked air pollution to an increased risk of dementia and cognitive decline.^5–9 However, the precise causal pathways through which air pollution contributes to these conditions remain unclear. Inflammation and oxidative stress are recognized as early contributors to dementia pathogenesis,^10–12 exacerbating amyloid-β (Aβ) deposition and hyperphosphorylation of tau proteins—key pathological markers of Alzheimer's disease.^13–15 Moreover, air pollution has been associated with elevated inflammation and oxidative stress, as evidenced by both animal models and human studies.^16–22 These findings support the hypothesis that air pollution may drive the development of dementia and cognitive decline through mechanisms involving inflammation and oxidative stress.^23–25 However, robust epidemiological evidence supporting the involvement of these mechanisms is lacking.

Additionally, research suggests a critical role for vascular mechanisms in the impact of air pollution on brain health.^23,26 Air pollution has been consistently linked to impaired vascular function, such as cardiovascular diseases (CVDs),^27,28 which in turn are adversely associated with cognitive decline and increased dementia risk.^29,30 This raises the question of whether vascular-related factors mediate the relationship between air pollution and dementia or related cognitive outcomes. Epidemiologic studies exploring this potential mechanism have yielded inconsistent results; while some studies suggested a significant mediating role of vascular dysfunction,^31,32 others found no such effect.^33,34

To date, no systematic review has specifically investigated the mediating roles of inflammation and oxidative stress, as well as vascular-related factors in the association between air pollution and dementia or related cognitive outcomes. Understanding these causal pathways could provide insights into the pathophysiology of dementia and inform potential targets for preventive strategies. Therefore, the aim of this study is to systematically identify and synthesize current evidence to determine whether the detrimental effects of air pollution on dementia and cognitive decline are mediated by inflammation and oxidative stress and vascular-related factors.

Methods

Protocol registration

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISM) guidelines.³⁵ The protocol for the systematic review was registered with the International Prospective Register of Ongoing Systematic reviews (PROSPERO),³⁶ under the registration number CRD42024536958.

Selection criteria

Types of studies

Included in this review were all types of quantitative population-based studies, including observational studies such as prospective cohort studies, cross-sectional studies, case-control studies, and randomized controlled trials.

Exposures

This review included studies that measured ambient particulate matter of any size (e.g., PM10, PM2.5) directly or through modeling. Investigations into indoor air pollution from sources like coal and wood, commonly used for cooking and heating, were also eligible due to their potential to release substantial quantities of particulate matters.³⁷ Studies were included regardless of the specific concentration or duration of particulate matter exposure reported. However, studies focused only on other air pollutant such as NO_x, O₃, CO, and SO₂, without measuring PM, were not eligible. Moreover, studies examining exposure to tobacco smoke, including passive smoking, as well as those concerning occupational exposure to pollutants, were excluded. These exclusions were based on the associated presence of other harmful pollutants, such as nicotine and volatile organic compounds (VOCs), which fall outside the scope of the current study.

Outcomes of interest

(1) All causes/types of dementia, including Alzheimer's disease (AD), vascular dementia (VaD), or mixed dementia. Studies assessing neuropathology causing dementia, such as Aβ, total tau (t-tau), phosphorylated tau (p-tau), and loss of brain volume, were also eligible for inclusion, regardless of whether the participants’ clinical symptoms fulfilled the formal diagnostic criteria for dementia. (2) Any domain of cognitive function, including but not limited to global cognition, processing speed, executive function, working memory, episodic memory, and verbal fluency.

Mediators

Based on existing literature,^23,24,38 we focused on two primary types of mediators. First, we examined inflammation and oxidative stress, which are closely interconnected and therefore grouped as a single mediator in this review. Second, we investigated vascular-related factors as a distinct mediator type. To enable a comprehensive literature search, we further identified key biomarkers, specific health conditions, and relevant measures associated with each mediator category. These included cytokines, leukocyte count, cyclooxygenase 2 (COX2), C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), growth differentiation factor 15 (GDF15), galectin-3 (Gal-3), troponin I, B-type natriuretic peptides (BNP), lipoprotein, fibrinogen, along with conditions such as cerebrovascular diseases, stroke, CVDs, hypertension, heart diseases, heart attack, heart failure, atrial fibrillation, and measures of blood pressure and cholesterol levels. Of note, however, that these lists are not exhaustive. Any mediator that could be classified under one of our areas of interest was considered eligible for inclusion.

Mediation analysis

Studies were included if they performed a formal mediation analysis. Ideally, eligible studies should analyze the pathways through which a risk factor influences an outcome variable via a mediator. This includes estimating direct effects (the pathway through which the risk factor impacts the outcome, controlling for the mediator), indirect effects (the influence of the risk factor on the outcome that operates through the mediator), and total effects (the impact of the risk factor on the outcome without controlling for the mediator). An example of such analysis is structural equation modelling (SEM). Studies that indirectly estimated the mediating effect by calculating the proportion of the total effect explained by the mediator, using estimations of sampling distribution such as the bootstrapping method to construct confidence intervals, standard deviations, and p-values, were also eligible. Studies that merely adjusted for mediators and observed changes in effect sizes were not considered a formal mediation analysis.

Exclusions

Animal or cell studies were not included, nor were studies of children (<18 years of age). Reviews were not eligible, and studies published in languages other than English were also excluded.

Search strategy

The search strategy was developed by integrating the exposure, mediator, outcome, and mediation analysis as described above. For example, the search string was: ((air pollut* or particulate matter*) AND (inflammat* or oxidative* or vascula*) AND (dement* or Alzheimer* or cogniti*) AND mediat*). A systematic search of MEDLINE, Embase, and PsycINFO for relevant studies was conducted from inception to May 7, 2024, using defined search terms. Both subject heading and text word searches were conducted where appropriate. The complete list of search terms in Medline is provided in Supplemental Table 1. Grey literature sources, including OpenGrey and Google Scholar, were manually searched using relevant keywords (e.g., “PM2.5”, “dementia”, “cognition”, “inflammation”, “oxidative stress”, “vascular”). Additionally, the reference lists of the retrieved articles were examined.

Two reviewers, A Zhou and Z Wu, independently screened all records retrieved from the literature search by reviewing the title and abstract to assess eligibility. For studies that are potentially eligible, they further reviewed the full texts to confirm their final eligibility. Any disagreements were resolved through discussion or by consulting a third reviewer, J Ryan.

Data extraction

A specifically designed data extraction form was used for this review, with data extracted independently by at least two authors (A Zhou, Z Wu, AZZ Phyo, S Vishwanath) for each study. Any discrepancies were addressed through discussion or, when necessary, by consulting a third author (J Ryan). The extracted information included, where available: study design, country, participant details (including sample size, whether a community-dwelling population or participants with health-related conditions, age, sex, race and ethnicity, and education level), specifics of the mediator assessed, mediation model applied, and the direct, indirect, and total effects measured by mediation analysis (including measures of effect size such as hazard ratio, risk ratio, odds ratio, and other risk estimates, along with their statistical significance and confidence intervals), the proportion of the effect mediated, and the covariates included in the mediation analysis.

Assessment of methodological quality

As there is no standard or validated risk assessment tool specifically for systematic reviews that evaluate studies incorporating mediation analysis, we adapted twelve study quality criteria. These are based on the Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses,³⁹ guidelines from mediation analysis methodology,⁴⁰ recommendations for reporting mediation analyses of randomized trials and observational studies,⁴¹ and suggestions from a systematic review that evaluated the quality of different bias assessment tools for mediation analysis.⁴² The criteria are listed in Table 1.

Table 1.

Risk of bias assessment.

Study ID	Registration^a	Objective^b	Population^c	Measurement^d	Absence of outcome at baseline^e	Statistical methods^f	Confounders^g	Mediation aspects^h	Resultsⁱ	Temporal order – predictor^j	Temporal order – mediator^k	Limitations^l
³¹	NA	Low	Low	Low	Low	Low	Low	Low	Low	Low	Low	Low
³²	NA	Low	Low	Low	Low	Low	Low	Low	Low	Low	Low	Low
³³	NA	Low	Low	Low	Low	Low	Low	Low	Low	High	Low	Low
³⁴	NA	Low	Low	Low	Low	Low	Low	Low	Low	High	Low	Low
⁴³	NA	Low	Low	Low	NA	Low	Low	Low	Low	Low	Unclear	Low
⁴⁴	NA	Low	High	Low	NA	Low	Low	Low	Low	Unclear	Unclear	Low
⁴⁵	NA	Low	Low	Unclear	NA	Low	High	Low	Low	Unclear	Unclear	Low
⁴⁶	NA	Low	Low	Unclear	Low	Low	High	High	Low	High	Low	Low
⁴⁷	NA	Low	Low	Low	Low	Low	Low	Low	Low	Low	Low	Low
⁴⁸	NA	Low	Low	Low	Low	Low	Low	Low	Low	Low	Low	Low
^{49 m}	NA	Low	Low	Low	NA	Unclear	High	Low	Low	High	High	Low
^{50 m}	NA	Low	Low	Low	High	Low	Low	High	Low	Low	High	Low
^{51 m}	NA	Low	Low	Low	NA	Low	High	Low	Low	Unclear	High	Low
^{52 m}	NA	Low	Low	Low	NA	Low	Low	Low	Low	Low	High	Low

If the study is a clinical trial, did it register pre-defined hypotheses regarding mediators?

Is there a clear description of the objectives specific to the mechanisms of interest?

Is there a clear description of the target population, eligibility criteria specific to mediation analysis, start date of participant enrolment, and end of follow-up?

Is there a clear description of the measurement of exposures, mediators, and outcomes?

Is there a demonstration that the outcome of interest was not present at start of study?

Is there a clear description of the statistical methods used to estimate the mediating effect, including the effects of interest?

Were confounders (including exposure-outcome, exposure-mediator, and especially mediator-outcome confounders) adequately controlled?

Did the study examine all relevant aspects of mediation, including the direct, indirect, and total effects of the exposures on the outcomes?

ⁱ

Did the study report point estimates and uncertainty estimates for the results?

Did changes in the predictor variable precede changes in the mediator and the outcome variable?

Did changes in the mediator variable precede changes in the outcome variable?

Did the study discuss the limitations, including potential sources of bias?

Cross-sectional study.

Notably, we specifically designed two questions, criteria j and k, to evaluate the temporal relationship among the exposure, mediator, and outcome. This evaluation is crucial for causal inference and for assessing the robustness of the mediating effects observed in each study. Two authors (A Zhou, L Cribb) independently conducted risk of bias assessments for the studies considered for inclusion. Each criterion was rated with a risk level of high, low, or unclear. Additionally, NA (Not Applicable) was assigned when a question was irrelevant to the study. For example, the question ‘Is there a demonstration that the outcome of interest was not present at start of study?’ received an ‘NA’ for studies where the outcome was change in cognitive score since baseline.

Data synthesis

Heterogeneity was evaluated in terms of characteristics of the study population, types of mediators examined, as well as measures of exposure and outcome. Due to significant methodological heterogeneity among the eligible studies, meta-analysis was not performed. Instead, the results for different categories of mediators and outcomes were organized into separate tables and were summarized narratively, including effect sizes when available. Any estimates of effect sizes, such as hazard ratios, risk ratios, odds ratios, and coefficients from other regression models, were reported where available.

Results

Search results

We identified 1098 records through database searches. After removing 363 duplicates, 735 records underwent title and abstract screening, of which 706 were considered irrelevant, leaving 29 records to be further screened for full text (Figure 1). Of these, 8 studies were excluded for not conducting a formal mediation analysis, 3 for measuring mediators not relevant to our interests, 2 for being review articles, 1 for assessing air pollutants other than particulate matter, and 1 for measuring outcomes not of interest. Ultimately, 14 records were included in our systematic review.^{31–34,43–52}

Figure 1.

PRISMA flow diagram.

Study characteristics

Nine studies focused on dementia risk and related neuropathology, including incident dementia,^{31–34,46,48} AD-related proteins,⁵¹ medial temporal lobe (MTL) atrophy,⁴⁷ and post-mortem evaluation of neuropathology markers associated with Alzheimer's disease.⁵² Five studies focused on cognitive performance,^{43–45,49,50} assessing various cognitive functions such as global cognition, episodic memory, verbal memory, mental status, visual scanning, intelligence, orientation, and mathematical ability. Thirteen studies used a single population sample, while one study reported findings from three separate cohorts.⁴⁵ Most studies were conducted in the USA,^{33,34,43,47,50,52} followed by China,^44,45,49,51 Sweden,^31,48 Canada,³² Italy,⁴⁶ and Mexico.⁴⁵ A total of 143,124 individuals were included across all studies.

Study design and participants

Ten studies had a prospective cohort design,^{31–34,43–48} involving 118,641 participants and follow-up periods ranging from five^43,47 to eighteen years.⁴⁴ The remaining four studies were cross-sectional^49–52 and included a total of 24,483 participants. The overall sample sizes varied across studies, from 159⁵² to 34,391,³² with a majority of studies enrolling between 2500 and 15,000. Mean participant age ranged from 55⁴⁶ to 78 years,³³ with half of the studies (n = 7) focusing on participants aged 65 and over.^{31,33,43,44,47,48,52} Most studies included both men and women; however, one cohort exclusively recruited women from the Women's Health Initiative Memory Study of Magnetic Resonance Imaging.⁴⁷ Of the nine studies that reported race and ethnicities, four conducted in China included solely Chinese participants,^44,45,49,51 while the remaining US-based studies predominantly included white participants (69.1% to 96.7%).^{33,34,43,47,52}

Risk of bias assessment

The results of risk of bias assessment for prospective and cross-sectional analyses are summarized in Table 1. All of the studies were observational, and thus none of them reported pre-registration of mediation hypotheses. Beyond this criterion, 40% of prospective studies (4 out of 10) exhibited low risk of bias across all criteria,^31,32,47,48 whereas all four cross-sectional studies^49–52 were rated as high risk because the temporal order of the exposure-mediator-outcome could not be determined. Furthermore, four studies lacked detailed information regarding eligibility criteria specific to mediation analysis,⁴⁴ mediator measurement,^45,46 or the appropriate mediation method employed.⁴⁹ Four studies were at high risk because air pollution and mediators were measured simultaneously,^33,34,46,49 while another four provided inadequate information on the temporal order either between exposures and mediators,^44,45,51 or between mediators and the outcome.^43–45 Although most studies excluded the outcome of interest at the start, one exception was noted.⁵⁰ Additionally, two studies did not directly quantify the indirect effect of the mediation analysis,^46,50 and four studies insufficiently controlled for confounders.^45,46,49,51

Exposure assessment

Eight studies specifically focused on PM2.5 exposure, with one examining traffic-related PM2.5⁵² and the others assessing general PM2.5 levels.^{31,32,34,43,47,48,51} Additionally, one study evaluated the combined effects of neighborhood socioeconomic status and mixed air pollution, collectively including PM2.5 and another eleven pollutants such as nitrogen oxides, nitrogen dioxide, and ozone.⁵⁰ Only one study exclusively investigated PM10,⁴⁶ and one concurrently measured both PM2.5 and PM10.³³ Moreover, three studies explored indoor air pollution by analyzing cooking fuel type; of these, one focused on the transition from unclean to clean fuels,⁴⁴ and the other two compared clean and solid fuel use.^45,49 The duration of air pollution exposure evaluated in these studies ranged from one⁴³ to twenty years.³³

Mediator assessment

Ten studies investigated vascular-related factors as potential mediators.^{31–34,43–45,47,48,50} One of these also examined inflammation and oxidative stress,⁴³ while four exclusively focused on mediators related to inflammation and oxidative stress.^46,49,51,52

Vascular-related factors were evaluated using a variety of indicators, including CVD,^31,32 hypertension,^{33,34,43–45} diabetes,^44,45 stroke,³⁴ dyslipidemia,⁴⁵ myocardial infarction,⁴⁴ apoplexy,⁴⁴ heart failure,³¹ ischemic heart disease,³¹ atrial fibrillation,³¹ blood pressure,^43,50 pulse pressure,⁴⁴ body mass index (BMI),⁴⁵ cholesterol levels,⁵⁰ high-density lipoprotein cholesterol (HDL-C),⁴⁵ homocysteine (tHcy),⁴⁸ and methionine.⁴⁸ Additionally, a neuroimaging proxy for cerebrovascular damage was employed by measuring the volume of whole-brain white matter small-vessel ischemic disease (WM-SVID).⁴⁷ Hypertension was the most frequently measured mediator, but studies varied in their assessment of incident versus prevalent cases. Furthermore, approaches to analyzing mediators differed. For example, while both Ilango et al.³² and Grande et al.³¹ examined CVD events, Ilango et al. analyzed all events collectively without differentiating among specific conditions, whereas Grande et al. examined specific CVD conditions, such as stroke and heart failure, individually.

Similarly, measurements of mediators related to inflammation and oxidative stress varied. Direct measurements included soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF), peripheral immune cells such as white blood cells (WBC),^49,51 C-reactive protein (CRP),⁴³ and high-sensitivity C-reactive protein (hsCRP).^49,51 Whereas indirect methods involved calculating a composite inflammation score (INFLA-score) to assess systemic inflammation⁴⁶ and evaluating DNA methylation (DNAm) related to neuroinflammation.⁵²

Summary of outcomes

The overall mediation effects of all studies are summarized in Table 2. Further detailed findings are organized by the type of mediators: inflammation and oxidative stress versus vascular-related factors, with the latter further categorized according to their investigated outcomes – dementia or cognitive function. For each study, we present characteristics of the study design and population, exposure, mediator, outcome, main findings, and adjusted covariates (Supplemental Tables 2–4).

Table 2.

Brief summary of overall mediation effects.

Author Year Ref.	Study Design	Sample Size	Exposure	Outcome	Mediators	Mediation Effects
Studies investigating the mediating role of inflammation and oxidative stress
Tallon 2017 ⁴³	L	2133	PM2.5	Cognition	CRP	No
Gialluisi 2023 ⁴⁶	L	24195	PM10	AD	INFLA-score	No
Du 2022 ⁴⁹	CS	8803	Cooking fuel use Cooking fuel use	Cognition Cognition	WBC hsCRP	No No
Li 2022 ⁵¹	CS	1131	PM2.5	AD	CSF sTREM2	Yes
			PM2.5	AD	hsCRP	No
			PM2.5	AD	immune cells	No
Li 2024 ⁵²	CS	159	PM2.5	AD	Neuroinflammation-related DNAm	Yes
Studies investigating the mediating role of vascular-related factors
Grande 2020 ³¹	L	2927	PM2.5	AD	Stroke Heart failure Ischemic heart disease Atrial fibrillation	Yes No No No
Ilango 2020 ³²	L	34391	PM2.5	AD	CVD	Yes
Libby 2024 ³³	L	2564	PM2.5 PM10	AD AD	Hypertension Hypertension	No No
Zhang 2023 ³⁴	L	27857	PM2.5	AD	Hypertension Stroke	No No
Petkus 2023 ⁴⁷	L	627	PM2.5	AD	WM-SVID volume	No
Grande 2023 ⁴⁸	L	2512	PM2.5	AD	tHcy Methionine	Yes No
Tallon 2017 ⁴³	L	2133	PM2.5	Cognition	Systolic BP Diastolic BP Hypertension	No No No
Cong 2021 ⁴⁴	L	7112	Cooking fuel transition	Cognition	Hypertension Diabetes Myocardial infarction Apoplexy	Yes No No No
Xu 2023 ⁴⁵	L	4831	Cooking fuel use	Cognition	Hypertension Diabetes BMI Dyslipidemia	No No No No
Xu 2023 ⁴⁵	L	3412	Cooking fuel use	Cognition	Hypertension Diabetes BMI Dyslipidemia HDL-C	No No No No Yes
Xu 2023 ⁴⁵	L	6080	Cooking fuel use	Cognition	Hypertension Diabetes BMI Dyslipidemia	Yes Yes No Yes
Mei 2024 ⁵⁰	CS	14390	Joint of air pollution + N-SES	Cognition	High cholesterol High blood pressure	Yes Yes

CS: Cross-sectional; L: Longitudinal; CSF: Cerebrospinal fluid; sTREM2: soluble triggering receptor expressed on myeloid cells 2; hsCRP: high sensitivity C-reactive protein; INFLA: inflammation; DNAm: DNA methylation; CRP: C-reactive protein; WBC: white blood cells count; WM-SVID: white matter small-vessel ischemic disease; CVD: cardiovascular disease; tHcy: homocysteine; N-SES: Neighborhood socioeconomic status; BP: blood pressure; BMI: body mass index; HDL-C: high-density lipoprotein cholesterol.

The mediating role of inflammation and oxidative stress

Five studies explored inflammation and oxidative stress as a mediator (Supplemental Table 2); three of them^46,51,52 (n = 25,485 participants) focused on dementia-related risk. A large longitudinal study⁴⁶ involving 24,195 participants found no significant mediating effect of INFLA-score on the relationship between PM10 exposure and incident AD or other forms of dementia. Conversely, two smaller cross-sectional analyses, one on CSF sTREM2⁵¹ and the other on post-mortem neuroinflammation-related DNA methylation,⁵² provided some evidence of mediation. CSF sTREM2 accounted for 14.22% and 47.15% of the association between PM 2.5 exposure and CSF Aβ₄₂ and CSF p-tau/Aβ₄₂ ratios, respectively, while 22 CpG sites demonstrated a significant mediating effect between PM2.5 exposure and the ABC score, a proxy for Alzheimer's disease neuropathology. Of note however, these studies^46,51,52 differed in the size of particulate matter involved.

The remaining two studies^43,49 (n = 10,936 participants) investigated the influence of air pollution on cognitive function through peripheral inflammatory pathways. Although both studies found no significant mediating associations, methodological differences limited direct combinations. Tallon et al.⁴³ observed no evidence of a mediating effect for CRP on the association between PM2.5 exposure and global cognition, while Du et al.⁴⁹ reported insignificant influence of clean or solid cooking fuel type on episodic memory or mental status through WBC or hsCRP.

The mediating role of vascular-related factors associated with dementia

Six studies^{31–34,47,48} (n = 70,878 participants) investigated whether vascular-related factors played a mediating role in the association between PM2.5 exposure and dementia risk (Supplemental Table 3). Two studies specifically examined prevalent hypertension as a mediator, consistently finding no significant mediating effects.^33,34 Findings for stroke were inconsistent: one Swedish study³¹ reported that 49.4% of the association between PM2.5 exposure and incident dementia was attributable to the mediating effect of incident stroke, while another US study³⁴ found no such effect associated with prevalent stroke. When considering CVD events collectively, including coronary heart disease, stroke, arrhythmia, and congestive heart failure, these events explained 21% of the association between PM2.5 exposure and incident dementia.³² Additionally, a neuroimaging study examining the mediating role of WM-SVID as a proxy for global cerebrovascular damage found no significant mediating associations between PM2.5 exposure and changes in MTL volumes.⁴⁷ Furthermore, a small but significant mediating effect of homocysteine (tHcy) on the association between PM2.5 exposure and dementia (6.6%) was identified, but no effect was found for methionine.⁴⁸

The mediating role of vascular-related factors associated with cognitive function

Six cohorts from four studies^43–45,50 (n = 37,958 participants) examined the mediating role of vascular-related factors in the link between air pollution exposure and cognitive function (Supplemental Table 4). Two studies focused on PM2.5 exposure and global cognition: one directly measured PM2.5 concentrations⁵⁰ and observed small mediating effects for high cholesterol (up to 5%) and high blood pressure (up to 8%), while the other assessed the combined effects of multiple air pollutants (including PM2.5) and neighborhood socioeconomic status⁴³ without finding any mediation by blood pressure or hypertension.

The remaining four analyses, conducted in middle-income countries like China and Mexico, assessed indoor air pollution through cooking fuel use. Cong et al.⁴⁴ found that transitioning from unclean to clean cooking fuels was associated with improved global cognition and verbal memory, with hypertension explaining over half of these associations (55.1% and 56.1%, respectively) and pulse pressure accounting for a smaller proportion (4.0% and 1.0%, respectively). Xu et al.⁴⁵ conducted mediation analyses on three separate cohorts, reporting only small proportions of the association between baseline clean or solid fuel use and individual cognitive domains attributable to HDL-C (4.3%), hypertension (−1.5%), diabetes (−4.7%), and dyslipidemia (5.7%).

Discussion

This systematic review is the first to comprehensively assess the evidence for the mediating effects of inflammation and oxidative stress, as well as vascular-related factors, on the association between air pollution and dementia or related cognitive outcomes. Of the 14 included studies, 2 examined mediation related to PM10 and found insignificant association,^33,46 while the mediation in the remaining studies, related to PM2.5^{31–34,43,47,48,50–52} and cooking fuel use,^44,45,49 was inconsistent. The majority of included studies explored mediating role of vascular-related factors. While indicators such as CVD, hypertension, diabetes, stroke, dyslipidemia, and blood pressure were examined in at least two studies, their mediating effects were inconsistent.^{31–34,43–45,50} There is some evidence that hypertension may partially mediate the association between indoor air pollution and cognitive decline, as reported in 2 of 4 studies.^44,45 Similarly, stroke may mediate the impact of general PM2.5 exposure on dementia risk, with 2 of 3 studies reporting such mediation.^31,32 However, the evidence for both was conflicting and limited. Other vascular-related indicators were assessed in only one study and typically demonstrated no or minimal mediating effects, limiting the strength of the evidence. A smaller number of studies considered mediation by inflammation and oxidative stress, predominantly measured by immune cells or CRP, and commonly reported insignificant mediating effects between PM2.5 exposure and cognitive outcomes. Regarding dementia risk, some evidence suggests a significant mediating role of inflammation and oxidative stress in the association with PM2.5 exposure. However, this evidence is limited due to small sample sizes (a total of 1290 individuals across studies), cross-sectional study design, and variation in how the mediators were measured.^51,52 Due to heterogeneity between studies in terms of specific exposures, mediators, and outcomes, a meta-analysis could not be performed.

Inflammation and oxidative stress, as well as vascular-related factors have been commonly proposed as key mechanisms linking air pollution to dementia and related cognitive outcomes.^24,53,54 Research indicates that inhaled particulate matter can induce the generation of reactive oxygen species (ROS) and trigger inflammatory responses in the lungs. Larger particles, such as PM10, are more likely to deposit in the upper respiratory tract, leading to these initial pulmonary effects. The resulting excess ROS and pro-inflammatory cytokines can then enter the bloodstream, increasing vascular burden, systemic inflammation, and oxidative stress. These systemic effects may compromise the blood-brain barrier, potentially allowing infiltration into the brain and accelerating microglial activation and neurodegenerative processes.^20,55,56 In contrast, smaller particles, particularly PM2.5, are capable of crossing alveolar barrier and entering systemic circulation directly. This offers a more direct pathway to the brain, where PM2.5 may further promote neuroinflammation and oxidative stress, in addition to the initial pulmonary responses.^3,4

Therefore, the mechanisms associated with particulate matter appear to differ based on size. PM10 primarily exerts indirect systemic effect on the central nervous system, whereas PM2.5 can affect neurological damage both directly and indirectly due to their potential for translocation to the brain. This mechanistic difference may partially explain our findings: while two studies consistently reported significant mediating effects of inflammation and oxidative stress in the association between PM2.5 exposure and dementia risk,^51,52 no study to date has found similar mediating effect related to PM10.⁴⁶ This also highlights the importance for future studies to consider these mechanistic distinctions related to particulate matter size when exploring the underlying biological pathways.

Epidemiological evidence supporting these mechanisms in population-based observational studies remains limited, as demonstrated by the findings of this review. Several factors may contribute to the limited evidence in this field. Firstly, a relatively small number of studies employed a formal mediation analysis. While numerous other studies, which were not eligible for inclusion in this review, attempted to investigate underlying mechanisms by simply adjusting for potential mediators,^57–59 such analyses cannot establish temporal sequences, differentiate between mediators and confounders, or quantify indirect effects. Secondly, even among studies that conducted formal mediation analysis, adherence to rigorous methodological standards proved challenging. For instance, cross-sectional studies^49–52 present significant limitations in establishing causal inferences, and the temporal order between mediator and outcome also appeared unclear in three longitudinal studies.^43–45 Additionally, while all studies in this review adjusted for basic covariates commonly associated with dementia and cognitive decline, only 70% presented directed acyclic graphs to visualize pathways among a set of variables or acknowledged their consideration of mediator-outcome confounders. These limitations potentially introduced bias in their analyses and may have restricted the ability to detect mediating effects. Thirdly, we noted that not all insignificant mediation results were due to an insignificant indirect effect through the mediator; some were due to insignificant total effect, indicating no association between the exposure and the outcome in that specific population,³⁴ or an insignificant association between the exposure and the mediator.^33,34,43 Furthermore, the diversity of measurements used to quantify the mediators has limited the capacity to group the evidence.

On the other hand, it is possible that additional mediators could be involved. For example, two of the studies included in this review also examined depression as a mediator. One study exploring potential mediators between PM2.5 exposure and cognition⁴³ identified depression as the only significant mediator. Another study⁵⁰ found that depression accounted for a higher proportion (up to 87%) of the joint effects of air pollution and neighborhood socioeconomic status on cognitive performance, compared to vascular dysfunction (less than 10%). Moreover, evidence from the UK Biobank⁶⁰ suggests a mediating role for pulmonary function, explaining 6% of the association between mixed air pollution and global cognition. Recent research also indicates potential mediating roles for physical activity⁴⁵ and Alzheimer's disease pattern similarity (AD-PS) scores.⁴⁷ Furthermore, DNA methylation may be an emerging biomarker explaining the biological mechanisms. A recent study⁶¹ reported its potential to mediate through systemic inflammation and cognitive impairment, which is largely consistent with the findings from one of our included studies reporting that neuroinflammation-related DNA methylation partially mediates the association between air pollution and dementia risk. Notably, these studies, as well as those included in this review, demonstrated only partial mediation, suggesting multiple pathways underlie the neurotoxicity of air pollution on brain health.

A major strength of this review lies in its preregistration on the PROSPERO (CRD42024536958)³⁶ and adherence to PRISMA guidelines.³⁵ This ensured a transparent, rigorous and reproducible search process. Defined inclusion and exclusion criteria were applied, with at least two reviewers independently screening studies and extracting data. This minimized bias in study selection, data extraction, and presentation. Furthermore, two reviewers independently assessed risk of bias in included studies using adapted mediation analysis criteria from established checklists and guidelines. This review specifically focused on studies that incorporated formal mediation analysis. These studies decomposed the effects of air pollution on dementia and cognition through direct and indirect pathways by considering potential mediators, thus providing relatively high-quality findings of mediating effects from eligible studies.

However, several limitations exist in this review. First, due to the heterogeneity among the studies in terms of specific outcome measurements, as well as the variability in mediators and exposures, a meta-analysis was not feasible. This study therefore presents a qualitative summary of the findings rather than a quantitative effect estimate. Second, ambient particulate matter levels vary significantly across regions with different industrial developments, temperatures, humidity, and sources. The national ambient air quality standards for PM2.5 vary across countries, with the lowest annual mean standards adopted by Canada (8.8 µg/m³)⁶² and the USA (9 µg/m³),⁶³ followed by Mexico (12 µg/m³),⁶⁴ China (15 µg/m³),⁶⁴ and Sweden and Italy (both of which adopted the EU annual limit value of 25 µg/m³).⁶⁵ Over 70% of the studies in this review were conducted in the USA and China and examined general PM2.5 exposure, while the remaining studies were predominately conducted in Europe. Thus, the overall pollutant levels included in this review tend to be low to moderate, potentially limiting the generalizability of current evidence to highly polluted areas. Third, while all studies adjusted for sex, only 30% explored sex-specific differences in the association between air pollution and dementia or cognition.^44,45,48,51 Moreover, none of these studies considered sex-specific mediating effects. A recent study⁶⁶ revealed a significant mediating effect of glial fibrillary acidic protein, an inflammation biomarker, in the relationship between air pollution and changes in attention and executive functions in women but not in men. This underscores the importance of exploring sex-specific mediations to better understand the biological mechanisms linking air pollution to dementia and cognition. Finally, positive publication bias remains a concern. Studies with significant findings are more likely to be published, potentially leading to an overrepresentation of such results in this review. The existence of unpublished studies with insignificant results could suggest a stronger possibility of a null mediating effect for inflammation and oxidative stress and vascular-related factors in the association between air pollution and dementia or related cognitive outcomes.

Consequently, we propose three main suggestions for future studies. Firstly, given the potential heterogeneity in causal pathways across different dementia types,^67,68 analyses that differentiate between subtypes are recommended. While most studies on incident dementia have not distinguished between subtypes, two studies^31,33 have made such distinctions. These studies identified the associations between air pollution and VaD,³¹ or VaD with or without AD (VaD/AD mixed),³³ but not with AD alone.^31,33 These findings align with previous meta-analysis indicating a higher risk of VaD compared to AD with increasing PM2.5 levels.⁷ Secondly, considering that brain development and function vary between sexes,⁶⁹ and that women are disproportionately affected by AD and other dementias,⁷⁰ it is important to explore sex-specific differences in how air pollution influences dementia and cognitive processes. Thirdly, studies investigating mediators related to inflammation and oxidative stress should consider the specific types of biological samples used, as findings from this review suggested that the choice of specimen may potentially influence outcomes. For example, two studies included in this review that measured such mediators in blood samples reported no significant mediating effects.^43,49 In contrast, analyses using brain tissue for neuroinflammation-related DNA methylation⁵² or cerebrospinal fluid to measure sTREM2⁵¹ indicated some potential mediating associations. These considerations could facilitate a more granular investigation of the disease's underlying biology.

Conclusion

Although inflammation and oxidative stress, as well as vascular-related factors have been hypothesized to contribute to the association between air pollution and dementia, due to the limited studies undertaken, current evidence remains insufficient. Further research, particularly large-scale, population-based longitudinal studies employing formal mediation analysis, is crucial to address this gap. These studies should ensure a clear temporal sequence in the exposure-mediator-outcome relationship and ideally utilize directed acyclic graphs to systematically account for confounders and mediators.

Supplemental Material

sj-docx-1-alz-10.1177_13872877251361862 - Supplemental material for The mediating role of inflammation and oxidative stress, as well as vascular-related factors, in the association between air pollution and dementia or related cognitive outcomes: A systematic review

Supplemental material, sj-docx-1-alz-10.1177_13872877251361862 for The mediating role of inflammation and oxidative stress, as well as vascular-related factors, in the association between air pollution and dementia or related cognitive outcomes: A systematic review by Aoshuang Zhou, Zimu Wu, Lachlan Cribb, Aung Zaw Zaw Phyo, Swarna Vishwanath, Zhen Zhou and Joanne Ryan in Journal of Alzheimer's Disease

Footnotes

Acknowledgements

We acknowledge Dr Lorena Romero, a senior librarian at the Alfred Hospital, for her assistance with the development of search terms.

ORCID iDs

Aoshuang Zhou

Zimu Wu

Aung Zaw Zaw Phyo

Swarna Vishwanath

Zhen Zhou

Joanne Ryan

Author contributions

Aoshuang Zhou: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Resources; Writing – original draft; Writing – review & editing.

Zimu Wu: Data curation; Investigation; Writing – review & editing.

Lachlan Cribb: Data curation; Investigation; Writing – review & editing.

Aung Zaw Zaw Phyo: Data curation; Investigation; Writing – review & editing.

Swarna Vishwanath: Data curation; Investigation; Writing – review & editing.

Zhen Zhou: Investigation; Writing – review & editing.

Joanne Ryan: Conceptualization; Methodology; Supervision; Writing – review & editing.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

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

Data availability statement

All data included in this systematic review is publicly available from the original studies cited within the work.

Supplemental material

Supplemental material for this article is available online.

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