Alzheimer disease starts in childhood in polluted Metropolitan Mexico City. A major health crisis in progress.

Exposures to fine particulate matter (PM2.5) and ozone (O3) above USEPA standards are associated with Alzheimer's disease (AD) risk. Metropolitan Mexico City (MMC) youth have life time exposures to PM2.5 and O3 above standards. We focused on MMC residents ≤30 years and reviewed 134 consecutive autopsies of subjects age 20.03 ± 6.38 y (range 11 months to 30 y), the staging of Htau and ß amyloid, the lifetime cumulative PM2.5 (CPM 2.5) and the impact of the Apolipoprotein E (APOE) 4 allele, the most prevalent genetic risk for AD. We also reviewed the results of the Montreal Cognitive Assessment (MoCA) and the brainstem auditory evoked potentials (BAEPs) in clinically healthy young cohorts. Mobile sources, particularly from non-regulated diesel vehicles dominate the MMC pollutant emissions exposing the population to PM2.5 concentrations above WHO and EPA standards. Iron-rich,magnetic, highly oxidative, combustion and friction-derived nanoparticles (CFDNPs) are measured in the brain of every MMC resident. Progressive development of Alzheimer starts in childhood and in 99.25% of 134 consecutive autopsies ≤30 years we can stage the disease and its progression; 66% of ≤30 years urbanites have cognitive impairment and involvement of the brainstem is reflected by auditory central dysfunction in every subject studied. The average age for dementia using MoCA is 20.6 ± 3.4 y. APOE4 vs 3 carriers have 1.26 higher odds of committing suicide. PM2.5 and CFDNPs play a key role in the development of neuroinflammation and neurodegeneration in young urbanites. A serious health crisis is in progress with social, educational, judicial, economic and overall negative health impact for 25 million residents. Understanding the neural circuitry associated with the earliest cognitive and behavioral manifestations of AD is needed. Air pollution control should be prioritised-including the regulation of diesel vehicles- and the first two decades of life ought to be targeted for neuroprotective interventions. Defining paediatric environmental, nutritional, metabolic and genetic risk factor interactions is a multidisciplinary task of paramount importance to prevent Alzheimer's disease. Current and future generations are at risk.

Gait and balance disturbances are common in young urbanites and associated with cognitive impairment. Air pollution and the historical development of Alzheimer's disease in the young.

To determine whether gait and balance dysfunction are present in young urbanites exposed to fine particular matter PM2.5 ≥ annual USEPA standard, we tested gait and balance with Tinetti and Berg tests in 575 clinically healthy subjects, age 21.0 ±â€¯5.7 y who were residents in Metropolitan Mexico City, Villahermosa and Reynosa. The Montreal Cognitive Assessment was also applied to an independent cohort n:76, age 23.3 ±â€¯9.1 y. In the 575 cohort, 75.4% and 34.4% had abnormal total Tinetti and Berg scores and high risk of falls in 17.2% and 5.7% respectively. BMI impacted negatively Tinetti and Berg performance. Gait dysfunction worsen with age and males performed worse than females. Gait and balance dysfunction were associated with mild cognitive impairment MCI (19.73%) and dementia (55.26%) in 57/76 and 19 cognitively intact subjects had gait and balance dysfunction. Seventy-five percent of urbanites exposed to PM2.5 had gait and balance dysfunction. For MMC residents-with historical documented Alzheimer disease (AD) and CSF abnormalities, these findings suggest Alzheimer Continuum is in progress. Early development of a Motoric Cognitive Risk Syndrome ought to be considered in city dwellers with normal cognition and gait dysfunction. The AD research frame in PM2.5 exposed young urbanites should include gait and balance measurements. Multicity teens and young adult cohorts are warranted for quantitative gait and balance measurements and neuropsychological and brain imaging studies in high vs low PM2.5 exposures. Early identification of gait and balance impairment in young air pollution-exposed urbanites would facilitate multidisciplinary prevention efforts for modifying the course of AD.

Exposure to severe urban air pollution influences cognitive outcomes, brain volume and systemic inflammation in clinically healthy children.

Exposure to severe air pollution produces neuroinflammation and structural brain alterations in children. We tested whether patterns of brain growth, cognitive deficits and white matter hyperintensities (WMH) are associated with exposures to severe air pollution. Baseline and 1 year follow-up measurements of global and regional brain MRI volumes, cognitive abilities (Wechsler Intelligence Scale for Children-Revised, WISC-R), and serum inflammatory mediators were collected in 20 Mexico City (MC) children (10 with white matter hyperintensities, WMH(+), and 10 without, WMH(-)) and 10 matched controls (CTL) from a low polluted city. There were significant differences in white matter volumes between CTL and MC children - both WMH(+) and WMH(-) - in right parietal and bilateral temporal areas. Both WMH(-) and WMH(+) MC children showed progressive deficits, compared to CTL children, on the WISC-R Vocabulary and Digit Span subtests. The cognitive deficits in highly exposed children match the localization of the volumetric differences detected over the 1 year follow-up, since the deficits observed are consistent with impairment of parietal and temporal lobe functions. Regardless of the presence of prefrontal WMH, Mexico City children performed more poorly across a variety of cognitive tests, compared to CTL children, thus WMH(+) is likely only partially identifying underlying white matter pathology. Together these findings reveal that exposure to air pollution may perturb the trajectory of cerebral development and result in cognitive deficits during childhood.

Auditory Brainstem Dysfunction, Non-Invasive Biomarkers for Early Diagnosis and Monitoring of Alzheimer's Disease in Young Urban Residents Exposed to Air Pollution.

Alzheimer's disease (AD) is a biological construct defined by abnormal deposits of hyperphosphorylated tau and amyloid-ß. The 2050 projection for AD in the USA is 14 million. There is a strong association between AD, air pollution, and traffic. Early diagnosis is imperative for intervention in the initial disease stages. Hearing and, specifically, the ability to encode complex sounds are impaired in AD. Nuclei in the auditory brainstem appear to be sensitive to neurodevelopmental and neurodegenerative disorders. Specifically, sustained exposure to air pollution is harmful to the brainstem; young residents of Metropolitan Mexico City (MMC) exposed to fine particulate matter and combustion-derived nanoparticles develop AD pathology in infancy. MMC clinically healthy children and teens have significant central delays in brainstem auditory evoked potentials (BAEPs). Herein, we review evidence that the auditory pathway is a key site of AD early pathology associated with air pollution and is significantly involved in AD patients. We strongly suggest electrophysiological screening, including BAEPs, be employed to screen individuals for early delays and to monitor progressive decline in patients diagnosed with mild cognitive impairment and AD. Understanding auditory dysfunction in early AD in pediatric and young adult populations may clarify mechanisms of disease progression. Air pollution is a risk factor for the development of AD and as the number of Americans with AD continues to grow without a cure, we need to focus on preventable, early causes of this fatal disease and intervene appropriately.

Increased Gain in the Auditory Pathway, Alzheimer's Disease Continuum, and Air Pollution: Peripheral and Central Auditory System Dysfunction Evolves Across Pediatric and Adult Urbanites.

A major impediment in early diagnosis of Alzheimer's disease (AD) is the lack of robust non-invasive biomarkers of early brain dysfunction. Metropolitan Mexico City (MMC) children and young adults show hyperphosphorylated tau, amyloid-ß, and α-synuclein within auditory and vestibular nuclei and marked dysmorphology in the ventral cochlear nucleus and superior olivary complex. Based on early involvement of auditory brainstem centers, we believe brainstem auditory evoked potentials can provide early AD biomarkers in MMC young residents. We measured brainstem auditory evoked potentials in MMC clinically healthy children (8.52±3.3 years) and adults (21.08±3.0 years, 42.48±8.5 years, and 71.2±6.4 years) compared to clean air controls (6.5±0.7 years) and used multivariate analysis adjusting for age, gender, and residency. MMC children had decreased latency to wave I, delays in waves III and V, and longer latencies for interwave intervals, consistent with delayed central conduction time of brainstem neural transmission. In sharp contrast, young adults have significantly shortened interwave intervals I-III and I-V. By the 5th decade, wave V and interval I-V were significantly shorter, while the elderly cohort had significant delay in mean latencies and interwave intervals. Compensatory plasticity, increased auditory gain, cochlear synaptopathy, neuroinflammation, and AD continuum likely play a role in the evolving distinct auditory pathology in megacity urbanites. Understanding auditory central and peripheral dysfunction in the AD continuum evolving and progressing in pediatric and young adult populations may shed light on the complex mechanisms of AD development and help identify strong noninvasive biomarkers. AD evolving from childhood in air pollution environments ought to be preventable.

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 ɛ4 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.

Air pollution is associated with brainstem auditory nuclei pathology and delayed brainstem auditory evoked potentials.

We assessed brainstem inflammation in children exposed to air pollutants by comparing brainstem auditory evoked potentials (BAEPs) and blood inflammatory markers in children age 96.3±8.5 months from highly polluted (n=34) versus a low polluted city (n=17). The brainstems of nine children with accidental deaths were also examined. Children from the highly polluted environment had significant delays in wave III (t(50)=17.038; p<0.0001) and wave V (t(50)=19.730; p<0.0001) but no delay in wave I (p=0.548). They also had significantly longer latencies than controls for interwave intervals I-III, III-V, and I-V (all t(50)>7.501; p<0.0001), consisting with delayed central conduction time of brainstem neural transmission. Highly exposed children showed significant evidence of inflammatory markers and their auditory and vestibular nuclei accumulated α synuclein and/or ß amyloid(1-42). Medial superior olive neurons, critically involved in BAEPs, displayed significant pathology. Children's exposure to urban air pollution increases their risk for auditory and vestibular impairment.