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

Air pollution represents a serious environmental health risk worldwide, and it is therefore the subject of growing global public health concern [1]. Air pollution—commonly described as divided in two categories, indoor (household) air pollution and outdoor (ambient) air pollution—emerges from a combination of natural and artificial substances in the air [2]. Indoor air pollution includes the exposure to particulates, carbon oxides, and other pollutants carried by indoor air or dust [2]. Ambient air pollution is associated to exposures that take place outside of the built atmosphere (i.e., the air outside buildings, from ground level to several miles above the Earth’s surface). It can result from both natural and especially human introduction into the Earth’s atmosphere of substances that could have a hostile impact on the ecosystem and humans, including harmful gases (sulfur dioxide, nitrogen oxides, carbon monoxide, chemical vapors), ozone, and other toxic pollutants generated by the burning of fossil fuels (e.g., black carbon, polycyclic aromatic hydrocarbons, mercury, lead) [1, 2]. The term particulate matter is used to describe a complex mix of particles of organic and inorganic substances suspended in the air, whose major constituents are sulfate, nitrates, ammonia, sodium chloride, black carbon, heavy metals, mineral dust and water. Since particulate matter is the most direct and dangerous air pollutant to humans (because it is the most abundant and because its soluble fraction and ultra-fine particles are the ones more efficiently adsorbed by the human body), it is a common proxy measure for air pollution [1].

Ambient and household air pollution provoke combined noxious effects, causing about 7 million premature deaths every year, mainly by provoking increased mortality from chronic obstructive pulmonary disease, lung cancer, acute infectious diseases of the respiratory tract, stroke and coronary artery disease [3]. In particular, World Health Organization (WHO) data shows that ambient air pollution caused 4.2 million premature deaths worldwide in 2016. In that same year of 2016, roughly nine out of ten people worldwide were living in places where the WHO Air Quality Guidelines levels were not observed. The WHO Guidelines give an estimation of health impacts of air pollution and offer global guidance on limits of pollution levels that are harmful for health. The Guidelines are based on expert analyses of current scientific data for particulate matter, ozone, nitrogen dioxide and sulphur dioxide, in all WHO regions [1].

As reported above, chronic exposures to air pollutants have been linked to a heightened risk of cardiovascular and respiratory diseases, and with other health issues including several cancer types [1]. More recently, increasing studies have also shown that the central nervous system is attacked by air pollution [4, 5]. Therefore, air pollution appears to be significantly associated with an elevated risk of general poor mental health and cognitive defects [6], anxiety, depression and suicide [7], neurodevelopmental (e.g., schizophrenia) [8] and neurodegenerative (e.g., Alzheimer’s disease) disorders [9].

It is generally acknowledged that schizophrenia has a multifactorial etiology in which genetic risk factors and early-life environmental brain insults interact to cause neurodevelopmental impairment predisposing an individual to the disorder [10, 11]. Schizophrenia is in fact a complex neurodevelopmental syndrome, clinically heterogenous, and characterized by different degrees of severity in terms of social, emotional, perceptual, and cognitive impairments [12]. This syndrome is clinically characterized by psychotic symptoms such as hallucinations, delusions, and disorganized speech. It also can produce negative symptoms (e.g., lower motivation levels, diminished capacity to express one’s thoughts and feelings) and by cognitive alterations or deficits in different domains, including memory, executive functions, and mental processing speed. Affecting around 1% of the world population, schizophrenia is among the top ten leading causes of disability globally [13].

The concept of dementia clinically refers to a syndrome of acquired intellectual disturbances caused by brain dysfunction [14]. Also referred to as major neurocognitive disorder in DSM-5 [15], dementia is defined by evidence of critical impairments of memory, judgment, orientation, and cognition (e.g., language, executive functioning) [16]. Cognitive deficits cause significant impairment in social and occupational functioning. Although dementia may result from a wide variety of disorders, the most prevalent cause is Alzheimer’s disease (accounting for 60–80% of dementia cases). This latter is a common neurodegenerative disease in the elderly which is characterized by progressive cognitive impairment [17]. The global prevalence of Alzheimer’s disease is estimated to be 6% in people aged over 65 [18], with a growing trend worldwide, therefore representing one of the greatest healthcare challenges of our time [19].

Scientists have discussed for over a century whether there is a biological correlation between schizophrenia and dementia, in particular since Emil Kraepelin conceptualized schizophrenia as “dementia praecox” (premature dementia) [20]. Kraepelin noted that patients with dementia praecox were usually affected by an early onset of symptoms, accompanied by a progressive course which ended up in dementia. Later he observed that not all forms of dementia praecox progressed in dementia and that these patients often developed a withdrawn state, accompanied by perceptual disturbances or delusional psychotic symptoms, and without alterations of cognitive functions.

There is no doubt that subjects with schizophrenia experience a variety of neuropsychological deficits and cognitive impairments, which have negative effects on social and professional skills and contribute significantly to the long-term disease burden [11, 20]. Nevertheless, this question remains unanswered: is cognitive dysfunction a key feature of schizophrenia? Subjects affected by schizophrenia often show to have dysfunctions in different cognitive domains like working memory, executive function, attention/vigilance, processing speed, social cognition and visuospatial orientation [11, 20–22]. Furthermore, subjects with schizophrenia show various degrees of cognitive deterioration, and generally have lower functioning than healthy subjects. Cognition abnormalities typically begin before the onset of the first episode of psychosis, and cognitive deficits usually remain chronic [11, 12].

Schizophrenia and dementia seem to share some larger anatomical abnormalities that exhibit an underlying cellular modification, such as increased ventricles size, widened sulci and reduced hippocampal size, but evidence of more specific brain pathological alterations is harder to come by [23]. Studies on common cerebral pathophysiology and neurochemistry suggest a limbic involvement—especially for what concerns structural and atrophic changes of the medial temporal region—and the central role of modifications of the dopaminergic/cholinergic axis [24]. As evidence of this involvement, the fact that roughly 50% of subjects with Alzheimer’s disease experience positive psychotic symptoms (in particular delusions and hallucinations) and negative psychotic symptoms (such as apathy), frequently treated with atypical antipsychotics, originally developed for schizophrenia. The fact that physio-pathological alterations related to schizophrenia could contribute to the elevated mortality of affected subjects has contributed to advance the hypothesis that schizophrenia may be a syndrome of accelerated aging [25]. Furthermore, subjects with schizophrenia present a higher risk of dementia not fully explained by recognized underlying conditions of risk of dementia [21]. In this line of thought, a thorough hypothetical explanation may be the presence of a gradual, neurodegenerative process in addition to a neurodevelopmental component in individuals with schizophrenia [12].

Although the specific pathophysiologic aspects of the connection between schizophrenia and dementia are still uncertain, some hypothetical models have been recently proposed to clarify this issue. One of these models identifies a common brain network that connects development, aging, and vulnerability to disease, and shows that the degeneration of a healthy brain and the developmental process mirror one another in specific brain areas [26]. This network is mostly composed by interconnected transmodal regions (heteromodal cortex, limbic and paralimbic regions). It matures during adolescence, presents accelerated degeneration in old age, and characterizes regions of increased susceptibility to unhealthy or disturbed developmental (e.g., schizophrenia) and aging (e.g., Alzheimer’s disease) processes. This network obtained, in particular, from healthy subjects, structurally reflects the pattern of brain anomalies found in both schizophrenia and Alzheimer’s disease, and is associated with intellectual ability and episodic memory. Indeed, dysfunctions in verbal comprehension, perceptual speed, inductive and deductive reasoning, and memory, are important for the expression of key features of both the disorders. Another hypothetical, fascinating model to explain the relationship between schizophrenia and Alzheimer’s disease is based on the transgenerational interaction of both disorders through amyloid evolvability [27]. According to this model, parental Alzheimer’s disease and schizophrenia in offspring may transgenerationally interplay with each other. This fact may elucidate why the two disorders have not been selected out through natural selection of evolution. This hypothesis suggests a role of the protofibrils of amyloidogenic proteins in evolvability.

The causal association between schizophrenia and Alzheimer’s disease has not yet been proven till now, anyway.

In recent years, the topic of urbanicity (being born or raised in cities) and mental health has become increasingly important. Specifically, diverse urban social, economic and environmental stressors such as migration, ethnic density, social environment, economic deprivation, infections, and air pollution [8, 28–31], are currently described as reliable risk factors for schizophrenia and other psychoses, but with considerable international geographic variation [32]. As for the association between pollution exposure (e.g., exposure to xenobiotic heavy metals such as lead and cadmium, to air pollution components such as particulate matter and nitrogen and sulfur oxides, organic solvents, and to other environmental pollutants) and the risk of developing psychosis, a recent review indicates that pollution might probably intervene in the association between urbanicity and increased risk of psychosis, at least partially [8]. It has been suggested that prenatal and early childhood pollution exposures (i.e., exposures during periods of rapid neurogenesis and gliogenesis) may be significant risk factors for neurodevelopmental disorders that share features with autism-spectrum disorders, such as schizophrenia. Recents studies indicate that air pollution exposure, particularly to nitrogen oxides, produces a higher likelihood of adolescent psychotic experiences, which relatively explained the link between urban residency and adolescent psychotic experiences [33]. They also demonstrated that exposure during childhood is associated with an increased risk for subsequently developing schizophrenia [34]. Conversely, early life rural living seems to be related to an increase in the risk of Alzheimer’s disease but, in this case as well, with substantial geographical variation [35]. And yet, urban residents, especially subjects living close to heavy traffic roads, appear to have an increased incidence of dementia [36]. Furthermore, although urban environmental exposures seem to be not linked to cognitive performance, evidence exists that air pollution can affect cerebral cortical thickness of areas related to Alzheimer’s disease vulnerability, thus suggesting an association between environmental hazards and brain’s vulnerability to Alzheimer’s disease [37].

Evidence has been emerging about the fact that greater exposure to air pollutants such as particulate matter, and nitrogen and carbon oxides, is associated with an enhanced risk of dementia [38], and the results from epidemiological researches reveal that exposure to ambient air pollution can also have adverse impacts on cognition, possibly leading to impairment and decline [39].

There are various, multiple and complex pathways through which air pollution can arrive at the central nervous system and impair it, resulting in an increased risk for developing schizophrenia and Alzheimer’s disease. Specifically, brain is a target of air pollutants: through the nasal pathway, pollutants can enter the brain after reaching the bulbus olfactorius and the fifth cranial nerve; through respiratory intake, pollutants can enter the brain after reaching the systemic circulation, the hematoencephalic barrier, and the vagal nerves [40]. Once they have reached the central nervous system, pollutants can activate immune inflammatory reactions. The central nervous system can consequently be injured by systemic inflammation originating from the respiratory and cardiovascular systems. Oxidative stress, microglial activation, increased lipid peroxidation, protein aggregation, disturbed glutamatergic and GABAergic neurotransmission, neuroinflammation, subclinical damages of cerebral circulation, and dysfunction of the hematoencephalic barrier, are all pathological mechanisms by which air pollutants can affect central nervous system health hypothetically, contributing to an increased risk of developing neurodevelopmental and neurodegenerative disorders [4, 40–42]. Central nervous system development and neurogenesis are deeply influenced by pollution exposure during each stage of lifecycle, possibly leading to substantial behavioral and cognitive disturbances [6]. In fact, recent evidence suggests that gestational pollution exposure affects embryonic neurodevelopment, postnatal brain growth and maturation, by interfering with neurogenesis, gliogenesis, myelination and synaptogenesis. Adult neurogenesis could also be influenced at different stages or levels, including neural stem cell amplification, maturation and integration. Microglia activation, neuroinflammation, and epigenetic mechanisms such as DNA methylation and aberrant microRNA expression, could all have a role in the pollution-induced pathogenesis [6]. Cognitive functions could be affected by air pollution also through other different biological pathways, including Tau and beta-amyloid brain deposition (with cardiovascular and respiratory diseases and stroke intervening as possible mediators), increased cerebral beta-amyloid production, specific neuronal alterations in hippocampus and molecular alterations in glutamate receptors [39, 43]. Also the role of heavy metals deserves mention for their ability to directly reach and harm the central nervous system tissue. For example, the presence of magnetite (the most stable iron oxide) particles, released into the air by burning fuel, found inside amyloid plaques in Alzheimer’s disease brains suggests their contribution to plaque formation by mechanisms of abnormal accumulation [44]. Exposures to heavy metals such as lead and cadmium may have a role in the hypothesized altered ratio of glutamate and GABA in subjects with schizophrenia. By accessing to the body via contaminated air, water, or food, heavy metals can induce neurotransmitter dysfunction and cause hypofunction of the NMDA subtype of glutamate receptors (a mechanism involved in psychosis pathophysiology) [8]. In conclusion, it has been revealed that environmental pollution, especially air pollution, is a common risk factor for both schizophrenia and Alzheimer’s disease. Public health concerns for air pollution have certainly grown over the years, especially as more countries develop and as accompanied by an increasing concern for climate change. However, the debate of whether air pollution is causing specific health effects, especially regarding mental disorders, is still ongoing. Epidemiological studies’ results suggest potential associations, but they are still insufficient to confirm causality [45]. Further researches are obviously, strongly recommended in order to verify this hypothesis. If confirmed, the clinical relevance for public and mental health would be substantial. In particular, future studies have to investigate the impacts of specific constituents of air pollution on increased risk for mental, neurodevelopmental, and neurodegenerative disorders in humans through large population-based studies, and the results should be carefully analyzed by experts to plan prevention programs/strategies possibly [28]. Establishing critical periods (especially for schizophrenia) and identification of at-risk subjects (in particular for Alzheimer’s disease) are necessary, too. Health consequences determined by the duration of exposure to pollutants as well as pollutant concentration deserve to be investigated more systematically [46]. International policy efforts, regulatory measures, and strong management plans will have to be undertaken in order to improve environmental quality, minimize current air pollution levels and lessen the associated disease burden; in this way, the health benefits would be significant [47]. Finally, a combined approach—epidemiological, neuroscientific, experimental, and computational model-based—may improve our knowledge about the effects of the urbanicity on mental health, and it would eventually allow to plan evidence-based actions towards a healthy environment and a sustainable ecosystem [46].