Ebook: Alzheimer’s Disease and Air Pollution

A few years ago, looking at a coded slide stained for phosphorylated tau and seeing neurons in the frontal lobe with positive neurites and tangles gave me a sudden intense fear and I stopped to check the code: an 11-year-old boy from Mexico City killed by a car when he walked in front of it. What has followed is the realization that Alzheimer’s disease, defined by the neuropathology gold standard criteria, starts in childhood and progresses relentlessly in the first four decades for residents of Metropolitan Mexico City exposed to concentrations of air pollutants above EPA standards. It has also become clear that children and young adult residents in Mexico City have quadruple protein aggregates corresponding to Alzheimer’s, Parkinson’s, and transactive response DNA-binding protein (TDP-43) diseases. Thus, there is regional neurodegeneration with an overlap of proteinopathies going on in highly exposed young urbanites.

The concept of a long asymptomatic period decades prior to clinical cognitive impairment does not apply to the millions of people massively exposed day in and day out to air pollutants. Along with a number of environmental, vascular, metabolic, and genetic factors playing a role in the highly heterogeneous disease in terms of clinical presentation and their neuropathological features mixing several abnormal folding proteins, the situation is dire.

Alzheimer’s disease is indeed one of the many neurodegenerative diseases we are detecting across the world as multiple proteinopathies, involving different types of neurons and anatomical regions. The question is: what could be the common denominator for Alzheimer’s disease, frontotemporal lobar degeneration, Lewy body disease, Parkinson’s disease, and amyotrophic lateral sclerosis?

Neuropathologists are used to seeing an overlap of “hallmarks” in older brains, as well as the co-existence of pathologies associated with every one of the chronic-degenerative diseases killing people in this century. The missing link is still missing, except for the fact that in populations highly exposed to air pollutants, we are seeing the early stages of fatal neurodegenerative diseases in toddlers and teens and are thus witnessing their development and progression from pediatric ages. Moreover, we are also documenting cognitive, gait/equilibrium, auditory, and olfactory changes in young people, some of whom already have brain imaging abnormalities.

This handbook is a remarkable compilation of researchers’ work, pursuing the goal of establishing plausible links between air pollution and neurodegeneration. Six sections have been put together that include works from epidemiological studies establishing a strong link between dementia and particulate matter and ozone; particles and nanoparticle papers describing the properties of pollution; and works describing the intricate pathways which take normal neurons to ghost tangles surrounded by a devastated brain. A section on how neuroinflammation, traffic air pollution, and tobacco smoke damage the brain and why the years of education matter when we see the brain impact of environmental pollutants is also included.

Everyone thinks air pollution is not complicated, but indeed it is, and how pollutants play different roles in their capacity to damage neural tissue is illustrated when we read about ozone and nanoparticles with magnetic properties and E-waste titanium nanorods in Section 1. Pollution is much more than smog and hazy summer days, and we ought to be aware that the source of pollutants and their portals of entry play a role in the brain pathology we are documenting from childhood. Air pollution is now a focus of attention and if we could modify people’s exposures and decrease their risk for Alzheimer’s and other neurodegenerative diseases that could be a major advance in a field of diseases for which we still do not have a cure.

Section 2 covers the neurobiology and neuropathology associated with particulate matter and the role of neuroinflammation and specifically inflammasomes as potential therapeutic targets. The impact of tobacco smoke—the perfect generator of millions of nanoparticles—upon insulin/IGF signaling is key in neurodegeneration.

Cognitive decline has been associated with hyperphosphorylated tau and synaptic dysfunction and is a marker of neurodegenerative processes representing a non-invasive and comprehensible way to detect changes in longitudinal follow-up studies. Although most studies are focused on elderly populations, children and young adults are experiencing cognitive deficits altering their academic and daily activity performance.

Section 3 discusses cognitive performance and the fact that levels of air pollutants, accumulated lifetime exposures, and certainly the specific characteristics of pollutants, all play a role in neural effects. People residing in low pollution places have the best chances of minimal brain impact and, key for our readers, carriers of an APOE4 allele living in clean places likely do not increase their chances of developing Alzheimer’s disease.

The U.S. Environmental Protection Agency (EPA) has strengthened as of October 1, 2015, the National Ambient Air Quality Standards (NAAQS) for ground-level ozone (O₃) to an eight-hour average exposure of 70 parts per billion (ppb). Ozone is a photochemical secondary air pollutant and currently, 137 million Americans live in an area with unhealthy levels of O₃. Ozone is likely a hidden player in neurodegeneration, a subject discussed in Section 4.

We have come a long way to reduce major air pollutants in the United States and to protect public health and welfare; however, it should be clear that everyone, regardless of age, gender, or socio-economic status, is at risk of brain effects associated with air pollutants. It is true that populations with morbidities have higher vulnerability, but the presence of multiple proteinopathies in children and young adults with absolutely no extraneural pathology, underlines the intrinsic high vulnerability of the brain under conditions of air pollutants above the current EPA standards.

Early diagnosis of Alzheimer’s disease is key if we are to identify young people at risk and neuroprotect them. Section 5 is dedicated to the application of non-invasive tests that give us a glimpse of what is going on in the brain of seemingly healthy children and young adults.

SARS-CoV-2 has caused havoc around the world and we are aware of the neuropsychiatric complications and the fact the RNA virus uses the same portals of entry as nanoparticles with the advantage that these barriers are already severely damaged. In the setting of neuroinflammation and progression of neurodegeneration, SARS-CoV-19 is likely a factor to accelerate the progression of neurodegenerative processes, increased risk of suicide, and mental disease worsening, issues discussed in Section 6.

Awareness of air pollutants playing a critical role on molecular neurodegenerative pathomechanisms is a very good step, and given the fact the most important neurodegenerative diseases are indeed fatal and we currently do not have a cure for them, this Handbook brings to light our only hope: prevention is at hand and if we can protect millions of people exposed to air pollutants and ameliorate their brain effects, we will be in the right path to have a clean planet free of Alzheimer’s disease.

Lilian Calderón-Garcidueñas

Several studies with animal research associate air pollution in Alzheimer’s disease (AD) neuropathology, but the actual impact of air pollution on the risk of AD is unknown. Here, this study investigates the association between long-term exposure to ozone (O₃) and particulate matter (PM) with an aerodynamic diameter equal to or less than 2.5 μm (PM_2.5), and newly diagnosed AD in Taiwan. We conducted a cohort study of 95,690 individuals’ age ≥ 65 during 2001–2010. We obtained PM₁₀ and O₃ data from Taiwan Environmental Protection Agency during 2000–2010. Since PM_2.5 data is only accessible entirely after 2006, we used the mean ratio between PM_2.5 and PM₁₀ during 2006–2010 (0.57) to estimate the PM_2.5 concentrations from 2000 to 2005. A Cox proportional hazards model was used to evaluate the associations between O₃ and PM_2.5 at baseline and changes of O₃ and PM_2.5 during the follow-up period and AD. The adjusted HR for AD was weakly associated with a raised concentration in O₃ at baseline per increase of 9.63 ppb (adjusted HR 1.06, 95% confidence interval (CI) 1.00–1.12). Further, we estimated a 211% risk of increase of AD per increase of 10.91 ppb in O₃ over the follow-up period (95% CI 2.92–3.33). We found a 138% risk of increase of AD per increase of 4.34 μg/m³ in PM_2.5 over the follow-up period (95% CI 2.21–2.56). These findings suggest long-term exposure to O₃ and PM_2.5 above the current US EPA standards are associated with increased the risk of AD.

This paper presents an overview of the literature studies on the sources of ultrafine particles (UFPs), nanomaterials (NMs), and nanoparticles (NPs) occurring in indoor (occupational and residential) and outdoor environments. Information on the relevant emission factors, particle concentrations, size, and compositions is provided, and health relevance of UFPs and NPs is discussed. Particular attention is focused on the fraction of particles that upon inhalation deposit on the olfactory bulb, because these particles can possibly translocate to brain and their possible role in neurodegenerative diseases is an important issue emerging in the recent literature.

Atmospheric nanoparticles can be formed either via nucleation in atmosphere or be directly emitted to the atmosphere. In urban areas, several combustion sources (engines, biomass burning, power generation plants) are directly emitting nanoparticles to the atmosphere and, in addition, the gaseous emissions from the same sources can participate to atmospheric nanoparticle formation. This article focuses on the sources and formation of nanoparticles in traffic-influenced environments and reviews current knowledge on composition and characteristics of these nanoparticles. In general, elevated number concentrations of nanoparticles are very typically observed in traffic-influenced environments. Traffic related nanoparticles can originate from combustion process or from non-exhaust related sources such as brake wear. Particles originating from combustion process can be divided to three different sources; 1) primary nanoparticles formed in high temperature, 2) delayed primary particles formed as gaseous compounds nucleate during the cooling and dilution process and 3) secondary nanoparticles formed from gaseous precursors via the atmospheric photochemistry. The nanoparticles observed in roadside environment are a complex mixture of particles from several sources affected by atmospheric processing, local co-pollutants and meteorology.

Millions of children and young adults are exposed to fine particulate matter (PM_2.5) and ozone, associated with Alzheimer’s disease (AD) risk. Mexico City (MC) children exhibit systemic and brain inflammation, low cerebrospinal fluid (CSF) Aβ_1-42, breakdown of nasal, olfactory, alveolar-capillary, duodenal, and blood-brain barriers, volumetric and metabolic brain changes, attention and short-term memory deficits, and hallmarks of AD and Parkinson’s disease. Airborne iron-rich strongly magnetic combustion-derived nanoparticles (CDNPs) are present in young urbanites’ brains. Using transmission electron microscopy, we documented CDNPs in neurons, glia, choroid plexus, and neurovascular units of young MC residents versus matched clean air controls. CDNPs are associated with pathology in mitochondria, endoplasmic reticulum (ER), mitochondria-ER contacts (MERCs), axons,and dendrites. There is a significant difference in size and numbers between spherical CDNPs (>85%) and the angular, euhedral endogenous NPs (<15%). Spherical CDNPs (dogs 21.2 ± 7.1 nm in diameter versus humans 29.1 ± 11.2 nm, p = 0.002) are present in neurons, glia, choroid plexus, endothelium, nasal and olfactory epithelium, and in CSF at significantly higher in numbers in MC residents (p < 0.0001). Degenerated MERCs, abnormal mitochondria, and dilated ER are widespread, and CDNPs in close contact with neurofilaments, glial fibers, and chromatin are a potential source for altered microtubule dynamics, mitochondrial dysfunction, accumulation and aggregation of unfolded proteins, abnormal endosomal systems, altered insulin signaling, calcium homeostasis, apoptotic signaling, autophagy, and epigenetic changes. Highly oxidative, ubiquitous CDNPs constitute a novel path into AD pathogenesis. Exposed children and young adults need early neuroprotection and multidisciplinary prevention efforts to modify the course of AD at early stages.

Fewer than 5% of Alzheimer’s disease (AD) cases are demonstrably directly inherited, indicating that environmental factors may be important in initiating and/or promoting the disease. Excess iron is toxic to cells; iron overload in the AD brain may aggressively accelerate AD. Magnetite nanoparticles, capable of catalyzing formation of reactive oxygen species, occur in AD plaques and tangles; they are thought to form in situ, from pathological iron dysfunction. A recent study has identified in frontal cortex samples the abundant presence of magnetite nanoparticles consistent with high-temperature formation; identifying therefore their external, not internal source. These magnetite particles range from ∼10 to 150 nm in size, and are often associated with other, non-endogenous metals (including platinum, cadmium, cerium). Some display rounded crystal morphologies and fused surface textures, reflecting cooling and crystallization from an initially heated, iron-bearing source material. Precisely-matching magnetite ‘nanospheres’ occur abundantly in roadside air pollution, arising from vehicle combustion and, especially, frictional brake-wear. Airborne magnetite pollution particles <∼200 nm in size can access the brain directly via the olfactory and/or trigeminal nerves, bypassing the blood-brain barrier. Given their toxicity, abundance in roadside air, and nanoscale dimensions, traffic-derived magnetite pollution nanoparticles may constitute a chronic and pernicious neurotoxicant, and hence an environmental risk factor for AD, for large population numbers globally. Olfactory nerve damage displays strong association with AD development. Reported links between AD and occupational magnetic fields (e.g., affecting welders, machinists) may instead reflect inhalation exposure to airborne magnetic nanoparticles.

Exposures to fine particulate matter (PM_2.5) and ozone (O₃)≥US EPA standards are associated with Alzheimer’s disease (AD) risk. The projection of 13.8 million AD cases in the US by the year 2050 obligate us to explore early environmental exposures as contributors to AD risk and pathogenesis. Metropolitan Mexico City children and young adults have lifetime exposures to PM_2.5 and O₃, and AD starting in the brainstem and olfactory bulb is relentlessly progressing in the first two decades of life. Magnetite combustion and friction-derived nanoparticles reach the brain and are associated with early and progressive damage to the neurovascular unit and to brain cells. In this review: 1) we highlight the interplay environment/genetics in the AD development in young populations; 2) comment upon ApoE ε4 and the rapid progression of neurofibrillary tangle stages and higher suicide risk in youth; and 3) discuss the role of combustion-derived nanoparticles and brain damage. A key aspect of this review is to show the reader that air pollution is complex and that profiles change from city to city with common denominators across countries. We explore and compare particulate matter profiles in Mexico City, Paris, and Santiago in Chile and make the point of why we should invest in decreasing PM_2.5 to at least our current US EPA standard. Multidisciplinary intervention strategies are critical for prevention or amelioration of cognitive deficits and AD progression and risk of suicide in young individuals. AD pathology evolving from childhood is threating the wellbeing of future generations.

Background:

Ambient air pollution exposure has been associated with dementia. Additionally, epidemiologic evidence supports associations between air pollution and diabetes as well as diabetes and dementia. Thus, an indirect pathway between air pollution and dementia may exist through metabolic dysfunction.

Objective:

To investigate whether local traffic-related air pollution (TRAP) influences incident dementia and cognitive impairment, non-dementia (CIND) in a cohort of older Mexican Americans. We also assess how much of this estimated effect might be mediated through type 2 diabetes (T2DM).

Methods:

In a 10-year, prospective study of Latinos (n = 1,564), we generated TRAP-NO_x as a surrogate for pollution from local traffic sources at participants’ residences during the year prior to enrollment. We used Cox proportional hazards modeling and mediation analysis to estimate the effects of TRAP-NO_x on dementia and/or CIND and indirect pathways operating through T2DM.

Results:

Higher TRAP-NO_x was associated with incident dementia (HR = 1.55 for the highest versus lower tertiles, 95% CI = 1.04, 2.55). Higher TRAP-NO_x was also associated with T2DM (OR = 1.62, 95% CI = 1.27, 2.05); furthermore, T2DM was associated with dementia (HR = 1.94, 95% CI = 1.42, 2.66). Mediation analysis indicated that 20% of the estimated effect of TRAP-NO_x on dementia/CIND was mediated through T2DM.

Conclusion:

Our results suggest that exposure to local traffic-related air pollution is associated with incident dementia. We also estimated that 20% of this effect is mediated through T2DM. Thus, ambient air pollution might affect brain health via direct damage as well as through indirect pathways related to diabetes and metabolic dysfunction.

Background:

Iron nanoparticles, mainly in magnetite phase (Fe₃O₄ NPs), are released to the environment in areas with high traffic density and braking frequency. Fe₃O₄ NPs were found in postmortem human brains and are assumed to get directly into the brain through the olfactory nerve. However, these pollution-derived NPs may also translocate from the lungs to the bloodstream and then, through the blood-brain barrier (BBB), into the brain inducing oxidative and inflammatory responses that contribute to neurodegeneration.

Objective:

To describe the interaction and toxicity of pollution-derived Fe₃O₄ NPs on primary rat brain microvascular endothelial cells (rBMECs), main constituents of in vitro BBB models.

Methods:

Synthetic bare Fe₃O₄ NPs that mimic the environmental ones (miFe₃O₄) were synthesized by co-precipitation and characterized using complementary techniques. The rBMECs were cultured in Transwell^® plates. The NPs-cell interaction was evaluated through transmission electron microscopy and standard colorimetric in vitro assays.

Results:

The miFe₃O₄ NPs, with a mean diameter of 8.45 ± 0.14 nm, presented both magnetite and maghemite phases, and showed super-paramagnetic properties. Results suggest that miFe₃O₄ NPs are internalized by rBMECs through endocytosis and that they are able to cross the cells monolayer. The lowest miFe₃O₄ NPs concentration tested induced mid cytotoxicity in terms of 1) membrane integrity (LDH release) and 2) metabolic activity (MTS transformation).

Conclusion:

Pollution-derived Fe₃O₄ NPs may interact and cross the microvascular endothelial cells forming the BBB and cause biological damage.

Background:

Cerebrovascular diseases play an important role in dementia. Air pollution is associated with cardiovascular disease, with growing links to neurodegeneration. Prior studies demonstrate associations between fine particulate matter (PM_2.5) and biomarkers of endothelial injury in the blood; however, no studies have evaluated these biomarkers in cerebrospinal fluid (CSF).

Objective:

We evaluate associations between short-term and long-term PM_2.5 exposure with CSF vascular cell adhesion molecule-1 (VCAM-1) and e-selectin in cognitively normal and mild cognitive impairment (MCI)/Alzheimer’s disease (AD) individuals.

Methods:

We collected CSF from 133 community volunteers at VA Puget Sound between 2001–2012. We assigned short-term PM_2.5 from central monitors and long-term PM_2.5 based on annual average exposure predictions linked to participant addresses. We performed analyses stratified by cognitive status and adjusted for key covariates with tiered models. Our primary exposure windows for the short-term and long-term analyses were 7-day and 1-year averages, respectively.

Results:

Among cognitively normal individuals, a 5 μg/m³ increase in 7-day and 1-year average PM_2.5 was associated with elevated VCAM-1 (7-day: 35.4 (9.7, 61.1) ng/ml; 1-year: 51.8 (6.5, 97.1) ng/ml). A 5 μg/m³ increase in 1-year average PM_2.5, but not 7-day average, was associated with elevated e-selectin (53.3 (11.0, 95.5) pg/ml). We found no consistent associations among MCI/AD individuals.

Conclusions:

We report associations between short-term and long term PM_2.5 and CSF biomarkers of vascular damage in cognitively normal adults. These results are aligned with prior research linking PM_2.5 to vascular damage in other biofluids as well as emerging evidence of the role of PM_2.5 in neurodegeneration.

Background:

Previous studies indicated an association between Alzheimer’s disease (AD) dementia and air particulate matter (PM) with aerodynamic diameter <10 μm (PM10), as well as smaller PM. Limited information, however, is available for the neuropathological links underlying such association.

Objective:

This study aimed to investigate the relationship between long-term PM10 exposure and in vivo pathologies of AD using multimodal neuroimaging.

Methods:

The study population consisted of 309 older adults without dementia (191 cognitively normal and 118 mild cognitive impairment individuals), who lived in Republic of Korea. Participants underwent comprehensive clinical assessments, ¹¹C-Pittsburg compound B (PiB) positron emission tomography (PET), and magnetic resonance imaging scans. A subset of 78 participants also underwent ¹⁸F-AV-1451 tau PET evaluation. The mean concentration of PM with aerodynamic diameter <10 μm over the past 5 years (PM10_mean) collected from air pollution surveillance stations were matched to each participant’s residence.

Results:

In this non-demented study population, of which 62% were cognitively normal and 38% were in mild cognitive impairment state, exposure to the highest tertile of PM10_mean was associated with increased risk of amyloid-β (Aβ) positivity (odds ratio 2.19, 95% confidence interval 1.13 to 4.26) even after controlling all potential confounders. In contrast, there was no significant associations between PM10_mean exposure and tau accumulation. AD signature cortical thickness and white matter hyperintensity volume were also not associated with PM10_mean exposure.

Conclusion:

The findings suggest that long-term exposure to PM10 may contribute to pathological Aβ deposition.

Background:

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, neuroinflammation, and neuronal death. There are several well-established genetic and environmental factors hypothesized to contribute to AD progression including air pollution. However, the molecular mechanisms by which air pollution exacerbates AD are unclear.

Objective:

This study explored the effects of particulate matter exposure on AD-related brain changes using the APP/PS1 transgenic model of disease.

Methods:

Male C57BL/6;C3H wild type and APP/PS1 mice were exposed to either filtered air (FA) or particulate matter sized under 2.5 μm (PM_2.5) for 6 h/day, 5 days/week for 3 months and brains were collected. Immunohistochemistry for Aβ, GFAP, Iba1, and CD68 and western blot analysis for PS1, BACE, APP, GFAP, and Iba1 were performed. Aβ ELISAs and cytokine arrays were performed on frozen hippocampal and cortical lysates, respectively.

Results:

The Aβ plaque load was significantly increased in the hippocampus of PM_2.5-exposed APP/PS1 mice compared to their respective FA controls. Additionally, in the PM_2.5-exposed APP/PS1 group, increased astrocytosis and microgliosis were observed as indicated by elevated GFAP, Iba1, and CD68 immunoreactivities. PM_2.5 exposure also led to an elevation in the levels of PS1 and BACE in APP/PS1 mice. The cytokines TNF-α, IL-6, IL-1β, IFN-γ, and MIP-3α were also elevated in the cortices of PM_2.5-exposed APP/PS1 mice compared to FA controls.

Conclusion:

Our data suggest that chronic particulate matter exposure exacerbates AD by increasing Aβ plaque load, gliosis, and the brain inflammatory status.

As one of the most harmful air pollutants, fine particulate matter (PM2.5) has been implicated as a risk factor for multiple diseases, which has generated widespread public concern. Accordingly, a growing literature links PM2.5 exposure with Alzheimer’s disease (AD). A critical gap in our understanding of the adverse effects of PM2.5 on AD is the mechanism triggered by PM2.5 that contributes to disease progression. Recent evidence has demonstrated that PM2.5 can activate NLRP3 inflammasome-mediated neuroinflammation. In this review, we highlight the novel evidence between PM2.5 exposure and AD incidence, which is collected and summarized from neuropathological, epidemiological, and neuroimaging studies to in-depth deciphering molecular mechanisms. First, neuropathological, epidemiological, and neuroimaging studies will be summarized. Then, the transport pathway for central nervous system delivery of PM2.5 will be presented. Finally, the role of NLRP3 inflammasome-mediated neuroinflammation in PM2.5 induced-effects on AD will be recapitulated.

Background:

Human studies suggest tobacco smoking is a risk factor for cognitive impairment and neurodegeneration, including Alzheimer’s disease (AD). However, experimental data linking tobacco smoke exposures to underlying mediators of neurodegeneration, including impairments in brain insulin and insulin-like growth factor (IGF) signaling in AD are lacking.

Objective:

This study tests the hypothesis that cigarette smoke (CS) exposures can impair brain insulin/IGF signaling and alter expression of AD-associated proteins.

Methods:

Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 or 8 weeks (CS4, CS8), or CS8 followed by 2 weeks recovery (CS8+R). Gene expression was measured by qRT-PCR analysis and proteins were measured by multiplex bead-based or direct binding duplex ELISAs.

Results:

CS exposure effects on insulin/IGF and insulin receptor substrate (IRS) proteins and phosphorylated proteins were striking compared with the mRNA. The main consequences of CS4 or CS8 exposures were to significantly reduce insulin R, IGF-1R, IRS-1, and tyrosine phosphorylated insulin R and IGF-1R proteins. Paradoxically, these effects were even greater in the CS8+R group. In addition, relative levels of ^S312-IRS-1, which inhibits downstream signaling, were increased in the CS4, CS8, and CS8+R groups. Correspondingly, CS and CS8+R exposures inhibited expression of proteins and phosphoproteins required for signaling through Akt, PRAS40, and/or p70S6K, increased AβPP-Aβ, and reduced ASPH protein, which is a target of insulin/IGF-1 signaling.

Conclusion:

Secondhand CS exposures caused molecular and biochemical abnormalities in brain that overlap with the findings in AD, and many of these effects were sustained or worsened despite short-term CS withdrawal.

Background:

Ambient air pollution has been associated with Alzheimer’s disease (AD) in the elderly. However, its effects on AD have not been meta-analyzed comprehensively.

Objective:

We conducted a systematic review and meta-analysis to assess the associations between air pollution and AD incidence.

Methods:

We searched PubMed and Web of Science for indexed publications up to March 2020. Odds risk (OR) and confidence intervals (CI) were estimated for particulate matter (PM)10 (PM₁₀), PM_2.5, ozone (O₃), nitrogen dioxide (NO₂), sulfur dioxide (SO₂), and carbon monoxide (CO). The subgroup analysis was conducted based on the pollution levels.

Results:

Nine studies were included in the meta-analysis and review. The OR per 10 μg/m³ increase of PM_2.5 was 1.95 (95% CI: 0.88–4.30). The corresponding values per 10 μg/m3 increment of other pollutants were 1.03 (95% CI: 0.68–1.57) for O₃, 1.00 (95% CI: 0.89–1.13) for NO₂, and 0.95 (95% CI: 0.91–0.99) for PM₁₀ (only one study), respectively. Overall OR of the five air pollutants above with AD was 1.32 (95% CI: 1.09–1.61), suggesting a positive association between ambient air pollution and AD incidence. The sub-analysis indicated that the OR (2.20) in heavily polluted regions was notably higher than that in lightly polluted regions (1.06). Although AD risk rate data related to SO₂ or CO exposure are still limited, the epidemiologic and toxicological evidence indicated that higher concentration of SO₂ or CO exposure increased risks of dementia, implying that SO₂ or CO might have a potential impact on AD.

Conclusion:

Air pollution exposure may exacerbate AD development.

Background:

Multiple studies report a strong correlation between traffic-generated air pollution-exposure and detrimental outcomes in the central nervous system (CNS), including Alzheimer’s disease (AD). Incidence of AD is rapidly increasing and, worldwide, many live in regions where pollutants exceed regulatory standards. Thus, it is imperative to identify environmental pollutants that contribute to AD, and the mechanisms involved.

Objective:

We investigated the effects of mixed gasoline and diesel engine emissions (MVE) on the expression of factors involved in progression of AD in the hippocampus and cerebrum in a young versus aged mouse model.

Methods:

Young (2 months old) and aged (18 months old) male C57BL/6 mice were exposed to either MVE (300 μg/m³ PM) or filtered air (FA) for 6 h/d, 7 d/wk, for 50 d. Immunofluorescence and RT-qPCR were used to quantify oxidative stress (8-OHdG) and expression of amyloid-β protein precursor (AβPP), β secretase (BACE1), amyloid-β (Aβ), aryl hydrocarbon receptor (AhR), cytochrome P450 (CYP) 1B1, angiotensin-converting enzyme (ACE1), and angiotensin II type 1 (AT1) receptor in the cerebrum and hippocampus, in addition to cerebral microvascular tight junction (TJ) protein expression.

Results:

We observed age-related increases in oxidative stress, AhR, CYP1B1, Aβ, BACE1, and AT1 receptor in the CA1 region of the hippocampus, and elevation of cerebral AβPP, AhR, and CYP1B1 mRNA, associated with decreased cerebral microvascular TJ protein claudin-5. MVE-exposure resulted in further promotion of oxidative stress, and significant increases in AhR, CYP1B1, BACE1, ACE1, and Aβ, compared to the young and aged FA-exposed mice.

Conclusion:

Such findings suggest that MVE-exposure exacerbates the expression of factors in the CNS associated with AD pathogenesis in aged populations.

Children’s urban air pollution exposures result in systemic and brain inflammation and the early hallmarks of Alzheimer’s disease (AD). The apolipoprotein E (APOE) ε4 allele is the most prevalent genetic risk for AD. We assessed whether APOE in healthy children modulates cognition, olfaction, and metabolic brain indices. The Wechsler Intelligence Scale for Children (WISC-R) and the University of Pennsylvania Smell Identification Test were administered to 50 Mexico City Metropolitan Area children (13.4 ± 4.8 years, 28 APOE ε3 and 22 APOE ε4). N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, myo-inositol (mI)/Cr, and NAA/mI were calculated using proton magnetic resonance spectroscopy in the white matter of the frontal and parietal lobes, hippocampus, and pons. APOE ε4 versus ε3 children had a reduced NAA/Cr ratio in the right frontal white matter and decrements on attention, short-term memory, and below-average scores in Verbal and Full Scale IQ (>10 points). APOE modulated the group effects between WISC-R and left frontal and parietal white matter, and hippocampus metabolites. Soap was the predominantly failed odor in urban children and, in APOE ε4 versus ε3 carriers, strongly correlated with left hippocampus mI/Cr ratio. APOE modulates responses to air pollution in the developing brain. APOE ε4 carriers could have a higher risk of developing early AD if they reside in a polluted environment. APOE, cognition, and olfaction testing and targeted magnetic resonance spectroscopy may contribute to the assessment of urban children and their results could provide new paths toward the unprecedented opportunity for early neuroprotection and AD prevention.

Exposures to fine particulate matter PM_2.5 and ozone O₃ are associated with Alzheimer’s disease (AD) risk. Mexico City residents have lifetime exposures to PM_2.5 and O₃ above annual USEPA standards and their brains contain high redox, combustion, and friction-derived magnetite nanoparticles. AD pathological changes with subcortical pre-tangle stages in infancy and cortical tau pre-tangles, NFT Stages I-II, and amyloid phases 1–2 are identified by the 2nd decade. Given their AD continuum, a reliable identification of cognitive impairment is of utmost importance. The Montreal Cognitive Assessment (MoCA) was administered to 517 urbanites, age 21.60 ± 5.88 years, with 13.69 ± 1.28 formal education years, in Mexican PM_2.5 polluted cities. MoCA score was 23.92 ± 2.82, and 24.7% and 30.3% scored ≤24 and ≤22, respectively (MCI ≤ 24, AD ≤ 22). Cognitive deficits progressively targeted Visuospatial, Executive, Language, and Memory domains, body mass index (BMI) impacting total scores negatively (p = 0.0008), aging driving down Executive, Visuospatial, and Language index scores (p < 0.0001, 0.0037, and 0.0045), and males performing better in Executive tasks. Average age for AD MoCA scores was 22.38 ± 7.7 years. Residency in polluted cities is associated with progression of multi-domain cognitive impairment affecting 55% of Mexican seemingly healthy youth. Normal BMI ought to be a neuroprotection goal. MoCA provides guidance for further mandatory neuropsychological testing in young populations. Identifying and lowering key neurotoxicants impacting neural risk trajectories in the developing brain and monitoring cognitive performance would greatly facilitate multidisciplinary early diagnosis and prevention of AD in high risk young populations. Cognitive deficits hinder development of those representing the force moving the country in future years.

Background:

The impact of air pollution on cognitive impairment in older people has not been fully understood. It is unclear which air pollutants are the culprit.

Objective:

We assessed the associations of six air pollutants and air quality index (AQI) with cognitive impairment.

Methods:

We examined 7,311 participants aged ≥60 years from the ZJMPHS cohort in China. They were interviewed for baseline socio-demographic and disease risk factors in 2014, and re-interviewed in 2015 and 2016, respectively. The presence of cognitive impairment was determined by the Chinese version of the Mini-Mental State Examination. Daily area-level data monitored for air pollution during 2013–2015 was then examined for associations with cognitive impairment in logistic regression models.

Results:

Over the two years follow-up, 1,652 participants developed cognitive impairment, of which 917 were severe cases. Continuous air pollution data showed the risk of cognitive impairment increased with exposure to PM_2.5 (fully adjusted odds ratio [aOR] 1.04, 95%CI 1.01–1.08), PM₁₀ (1.03, 1.001–1.06), and SO₂ (1.04, 1.01–1.08), but not with NO₂, CO, O₃, and AQI. Categorized data analysis for low, middle, and high level exposure demonstrated that the aOR increased with PM_2.5 and AQI, somehow with PM₁₀ and CO, but not significantly with SO₂ and NO₂, and decreased with O₃. The patterns for these associations with severe cognitive impairment were stronger.

Conclusion:

Lowering PM_2.5, PM₁₀, SO₂, and CO level could reduce the risk of cognitive impairment in older Chinese. Strategies to target most important air pollutants should be an integral component of cognitive interventions.

Background:

Previous studies have assessed limited cognitive domains with relatively short exposure to air pollutants, and studies in Asia are limited.

Objective:

This study aims to explore the association between long-term exposure to air pollutants and cognition in community-dwelling older adults.

Methods:

This four-year prospective cohort study recruited 605 older adults at baseline (2011–2013) and 360 participants remained at four-year follow-up. Global and domain-specific cognition were assessed biennially. Data on PM_2.5 (particulate matter ≤ 2.5 μm diameter, 2005–2015), PM₁₀ (1993–2015), and nitrogen dioxide (NO₂, 1993–2015) were obtained from Taiwan Environmental Protection Administration (TEPA). Bayesian Maximum Entropy was utilized to estimate the spatiotemporal distribution of levels of these pollutants.

Results:

Exposure to high-level PM_2.5 (>29.98 μg/m³) was associated with an increased risk of global cognitive impairment (adjusted odds ratio = 4.56; β = −0.60). High-level PM_coarse exposure (>26.50 μg/m³) was associated with poor verbal fluency (β = −0.19). High-level PM₁₀ exposure (>51.20 μg/m³) was associated with poor executive function (β = −0.24). Medium-level NO2 exposure (>28.62 ppb) was associated with better verbal fluency (β = 0.12). Co-exposure to high concentrations of PM_2.5, PM_coarse or PM₁₀ and high concentration of NO₂ were associated with poor verbal fluency (PM_2.5 and NO₂: β = −0.17; PM_coarse and NO₂: β = −0.23; PM₁₀ and NO₂: β = −0.21) and poor executive function (PM₁₀ and NO₂: β = −0.16). These associations became more evident in women, apolipoprotein ε4 non-carriers, and those with education > 12 years.

Conclusion:

Long-term exposure to PM_2.5 (higher than TEPA guidelines), PM₁₀ (lower than TEPA guidelines) or co-exposure to PM_x and NO₂ were associated with poor global, verbal fluency, and executive function over 4 years.

Background:

Air pollution is linked to worse cognitive function in older adults, but whether differences in this relationship exist by education, a key risk factor for cognitive decline, remains unknown.

Objective:

To determine if the association between fine particulate matter air pollution (PM2.5) and incident cognitive impairment varies by level of education in two cohorts assessed a decade apart.

Methods:

We used data on adults ages 60 and older from the nationally representative Health and Retirement Study (HRS) linked with tract-level annual average PM_2.5. We used mixed-effects logistic regression models to examine education differences in the association between PM_2.5 and incident cognitive impairment in two cohorts: 2004 (n = 9,970) and 2014 (n = 9,185). Cognitive impairment was determined with tests of memory and processing speed for self-respondents and proxy and interviewer assessments of cognitive functioning in non-self-respondents.

Results:

PM_2.5 was unrelated to incident cognitive impairment among those with 13 or more years of education, but the probability of impairment increased with greater concentrations of PM_2.5 among those with 8 or fewer years of education. The interaction between education and PM_2.5 was only found in 2004, possibly because PM_2.5 concentrations were much lower in 2014.

Conclusion:

Education is a key determinant of cognitive decline and impairment, and in higher pollution contexts may serve as a protective factor against the harms of air pollution on the aging brain. Additionally, because air pollution is ubiquitous, and particularly harmful to vulnerable populations, even small improvements in air quality may have large impacts on population health.

Background:

Air pollution has been consistently linked with dementia and cognitive decline. However, it is unclear whether risk is accumulated through long-term exposure or whether there are sensitive/critical periods. A key barrier to clarifying this relationship is the dearth of historical air pollution data.

Objective:

To demonstrate the feasibility of modelling historical air pollution data and using them in epidemiological models.

Methods:

Using the EMEP4UK atmospheric chemistry transport model, we modelled historical fine particulate matter (PM_2.5) concentrations for the years 1935, 1950, 1970, 1980, and 1990 and combined these with contemporary modelled data from 2001 to estimate life course exposure in 572 participants in the Lothian Birth Cohort 1936 with lifetime residential history recorded. Linear regression and latent growth models were constructed using cognitive ability (IQ) measured by the Moray House Test at the ages of 11, 70, 76, and 79 years to explore the effects of historical air pollution exposure. Covariates included sex, IQ at age 11 years, social class, and smoking.

Results:

Higher air pollution modelled for 1935 (when participants would have been in utero) was associated with worse change in IQ from age 11–70 years (β = −0.006, SE = 0.002, p = 0.03) but not cognitive trajectories from age 70–79 years (p > 0.05). There was no support for other critical/sensitive periods of exposure or an accumulation of risk (all p > 0.05).

Conclusion:

The life course paradigm is essential in understanding cognitive decline and this is the first study to examine life course air pollution exposure in relation to cognitive health.