Apolipoprotein E4, Gender, Body Mass Index, Inflammation, Insulin Resistance, and Air Pollution Interactions: Recipe for Alzheimer’s Disease Development in Mexico City Young Females

Given the epidemiological trends of increasing Alzheimer’s disease (AD) and growing evidence that exposure and lifestyle factors contribute to AD risk and pathogenesis, attention should be paid to variables such as air pollution, in order to reduce rates of cognitive decline and dementia. Exposure to fine particulate matter (PM2.5) and ozone (O3) above the US EPA standards is associated with AD risk. Mexico City children experienced pre- and postnatal high exposures to PM2.5, O3, combustion-derived iron-rich nanoparticles, metals, polycyclic aromatic hydrocarbons, and endotoxins. Exposures are associated with early brain gene imbalance in oxidative stress, inflammation, innate and adaptive immune responses, along with epigenetic changes, accumulation of misfolded proteins, cognitive deficits, and brain structural and metabolic changes. The Apolipoprotein E (APOE) 4 allele, the most prevalent genetic risk for AD, plays a key role in the response to air pollution in young girls. APOE 4 heterozygous females with >75% to <94% BMI percentiles are at the highest risk of severe cognitive deficits (1.5–2 SD from average IQ). This review focused on the relationships between gender, BMI, systemic and neural inflammation, insulin resistance, hyperleptinemia, dyslipidemia, vascular risk factors, and central nervous system involvement in APOE4 urbanites exposed to PM2.5 and magnetite combustion-derived iron-rich nanoparticles that can reach the brain. APOE4 young female heterozygous carriers constitute a high-risk group for a fatal disease: AD. Multidisciplinary intervention strategies could be critical for prevention or amelioration of cognitive deficits and long-term AD progression in young individuals at high risk.

A Critical Proton MR Spectroscopy Marker of Alzheimer’s Disease Early Neurodegenerative Change: Low Hippocampal NAA/Cr Ratio Impacts APOE ε4 Mexico City Children and Their Parents

Severe air pollution exposures produce systemic, respiratory, myocardial, and brain inflammation and Alzheimer’s disease (AD) hallmarks in clinically healthy children. We tested whether hippocampal metabolite ratios are associated with contrasting levels of air pollution, APOE, and body mass index (BMI) in paired healthy children and one parent sharing the same APOE alleles. We used 1H-MRS to interrogate bilateral hippocampal single-voxel in 57 children (12.45 ± 3.4 years) and their 48 parents (37.5 ± 6.78 years) from a low pollution city versus Mexico City (MC). NAA/Cr, Cho/Cr, and mI/Cr metabolite ratios were analyzed. The right hippocampus NAA/Cr ratio was significantly different between cohorts (p = 0.007). The NAA/Cr ratio in right hippocampus in controls versus APOE ε4 MC children and in left hippocampus in MC APOE ε4 parents versus their children was significantly different after adjusting for age, gender, and BMI (p = 0.027 and 0.01, respectively). The NAA/Cr ratio is considered reflective of neuronal density/functional integrity/loss of synapses/higher pTau burden, thus a significant decrease in hippocampal NAA/Cr ratios may constitute a spectral marker of early neurodegeneration in young urbanites. Decreases in NAA/Cr correlate well with cognitive function, behavioral symptoms, and dementia severity; thus, since the progression of AD starts decades before clinical diagnosis, our findings support the hypothesis that under chronic exposures to fine particulate matter and ozone above the standards, neurodegenerative processes start in childhood and APOE ε4 carriers are at higher risk. Gene and environmental factors are critical in the development of AD and the identification and neuroprotection of young urbanites at high risk must become a public health priority.

Air Pollution as Risk Factor for Mental Disorders: In Search for a Possible Link with Alzheimer’s Disease and Schizophrenia

As a global problem that has increasingly been causing worldwide concern, air pollution poses a significant and serious environmental risk to health. Risks of cardiovascular and respiratory diseases, as well as various types of cancer, have been consistently associated with the exposure to air pollutants. More recently, various studies have also shown that the central nervous system is also attacked by air pollution. Air pollution appears to be strongly associated with a higher risk of cognitive defects, neurodevelopmental (e.g., schizophrenia) and neurodegenerative (e.g., Alzheimer’s disease) disorders. Subjects with schizophrenia, as well as subjects with Alzheimer’s disease, experience a variety of neuropsychological deficits and cognitive impairments. This determines an adverse effect on social and professional functioning, and it contributes to the long-term disease burden. However, no final conclusions have been drawn on the matter of the direct relationship between schizophrenia and Alzheimer’s disease. In recent years, the topic of urbanicity and mental health has become increasingly important. Urban exposure to environmental toxins and pollution is currently described as a reliable risk factor for schizophrenia and other psychoses, and it has been demonstrated more and more how exposure to air pollutants is associated with increased risk of dementia. Pathways by which air pollution can target and damage the brain, leading to an increased risk for developing schizophrenia and Alzheimer’s disease, are multiple and complex. Results from epidemiological studies suggest potential associations, but are still insufficient to confirm causality. Further studies are needed in order to verify this hypothesis. And if confirmed, the clinical implications could be of substantial relevance for both public and mental health.

Association of Low-Level Ozone with Cognitive Decline in Older Adults

Increasing evidence points to an association of airborne pollutant exposure with respiratory, cardiovascular, and neurological pathology. We examined whether or not ground-level ozone or fine particulate matter ≤ 2.5 μm in diameter (PM2.5) was associated with accelerated cognitive decline. Using repeated measures mixed regression modeling, we analyzed cognitive performance of a geographically diverse sampling of individuals from the National Alzheimer’s Coordinating Center between 2004–2008. Ambient air concentrations of ozone and PM2.5 were established using a space-time Hierarchical Bayesian Model that statistically merged air monitor data and modeled air quality estimates. We then compared the ambient regional concentrations of ozone and PM2.5 with the rate of cognitive decline in residents within those regions. Increased levels of ozone correlated with an increased rate of cognitive decline, following adjustment for key individual and community-level risk factors. Furthermore, individuals harboring one or more APOE4 alleles exhibited a faster rate of cognitive decline. The deleterious association of ozone was confined to individuals with normal cognition who eventually became cognitively impaired as opposed to those who entered the study with baseline impairment. In contrast to ozone, we did not observe any correlation between ambient PM2.5 and cognitive decline at regulatory limits set by the Environmental Protection Agency. Our findings suggest that prolonged exposure to ground-level ozone may accelerate cognitive decline during the initial stages of dementia development.

Anthropogenic Iron Oxide Nanoparticles Induce Damage to Brain Microvascular Endothelial Cells Forming the Blood-Brain Barrier

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.

Air Pollution, Combustion and Friction Derived Nanoparticles, and Alzheimer’s Disease in Urban Children and Young Adults

Exposures to fine particulate matter (PM2.5) 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 PM2.5 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 PM2.5 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.

Where Do Ultrafine Particles and Nano-Sized Particles Come From?

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.

Long-Term Exposure to Ambient Air Pollution and Cognitive Function Among Hispanic/Latino Adults in San Diego, California

Background: Hispanics/Latinos in the United States are more likely to live in neighborhoods with greater exposure to air pollution and are projected to have the largest increase in dementia among race/ethnic minority groups. Objective: We examined the associations of air pollution with performance on cognitive function tests in Hispanic/Latino adults. Methods: We used data from the San Diego site of the Hispanic Community Health Study/Study of Latinos, an ongoing cohort of Hispanics/Latinos. This analysis focused on individuals ≥45 years of age who completed a neurocognitive battery examining overall mental status, verbal learning, memory, verbal fluency, and executive function (n = 2,089). Air pollution (PM2.5 and O3) before study baseline was assigned to participants’ zip code. Logistic and linear regression were used to estimate the associations of air pollution on overall mental status and domain-specific standardized test scores. Models accounted for complex survey design, demographic, and socioeconomic characteristics. Results: We found that for every 10 μg/m3 increase in PM2.5, verbal fluency worsened (β: −0.21 [95% CI: −0.68, 0.25]). For every 10 ppb increase in O3, verbal fluency and executive function worsened (β: −0.19 [95% CI: −0.34, −0.03]; β: −0.01 [95% CI: −0.01, 0.09], respectively). We did not identify any detrimental effect of pollutants on other domains. Conclusion: Although we found suggestions that air pollution may impact verbal fluency and executive function, we observed no consistent or precise evidence to suggest an adverse impact of air pollution on cognitive level among this cohort of Hispanic/Latino adults.

Ozone, Particulate Matter, and Newly Diagnosed Alzheimer’s Disease: A Population-Based Cohort Study in Taiwan

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 (PM2.5), 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 PM2.5 data is only accessible entirely after 2006, we used the mean ratio between PM2.5 and PM10 during 2006–2010 (0.57) to estimate the PM2.5 concentrations from 2000 to 2005. A Cox proportional hazards model was used to evaluate the associations between O3 and PM2.5 at baseline and changes of O3 and PM2.5 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 PM2.5 over the follow-up period (95% CI 2.21–2.56). These findings suggest long-term exposure to O3 and PM2.5 above the current US EPA standards are associated with increased the risk of AD.

Long-Term Exposure to Air Pollutants and Cognitive Function in Taiwanese Community-Dwelling Older Adults: A Four-Year Cohort Study

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 PM2.5 (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 PM2.5 (>29.98 μg/m3) was associated with an increased risk of global cognitive impairment (adjusted odds ratio = 4.56; β = −0.60). High-level PMcoarse 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 PM2.5, PMcoarse or PM10 and high concentration of NO2 were associated with poor verbal fluency (PM2.5 and NO2: β = −0.17; PMcoarse 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 PM2.5 (higher than TEPA guidelines), PM10 (lower than TEPA guidelines) or co-exposure to PMx and NO2 were associated with poor global, verbal fluency, and executive function over 4 years.