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