Article type: Research Article

Authors: Calderón-Garcidueñas, Liliana; b; * | Mukherjee, Partha S.c | Waniek, Katharinad | Holzer, Maxe | Chao, Chih-kaia | Thompson, Charlesa | Ruiz-Ramos, Rubénf | Calderón-Garcidueñas, Anaf | Franco-Lira, Maricelag | Reynoso-Robles, Rafaelh | Gónzalez-Maciel, Angélicah | Lachmann, Ingolfd

Affiliations: [a] The University of Montana, Missoula, MT, USA | [b] Universidad del Valle de México, Mexico | [c] Department of Mathematics, Boise State University, Boise, ID, USA | [d] AJ Roboscreen GmbH, Leipzig, Germany | [e] Paul-Flechsig-Institute for Brain Research, Leipzig, Germany | [f] Instituto de Medicina Forense, Universidad Veracruzana, Boca del Rio, Mexico | [g] Neurofisiología Clínica, Hospital Español, Ciudad de México, Mexico | [h] Instituto Nacional de Pediatría, Mexico

Correspondence: [*] Correspondence to: Lilian Calderón-Garcidueñas, MA, MD, PhD, University of Montana, 32 Campus Drive, 287 Skaggs Building, Missoula, MT 59812, USA. Tel.: +1 406 243 4785; Fax: +1 406 243 5228; E-mail: [email protected].

Abstract: Long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above USEPA standards is associated with Alzheimer’s disease (AD) risk. Metropolitan Mexico City (MMC) children exhibit subcortical pretangles in infancy and cortical tau pre-tangles, NFTs, and amyloid phases 1-2 by the 2nd decade. Given their AD continuum, we measured in 507 normal cerebrospinal fluid (CSF) samples (MMC 354, controls 153, 12.82±6.73 y), a high affinity monoclonal non-phosphorylated tau antibody (non-P-Tau), as a potential biomarker of AD and axonal damage. In 81 samples, we also measured total tau (T-Tau), tau phosphorylated at threonine 181 (P-Tau), amyloid-β1-42, BDNF, and vitamin D. We documented by electron microscopy myelinated axonal size and the pathology associated with combustion-derived nanoparticles (CDNPs) in anterior cingulate cortex white matter in 6 young residents (16.25±3.34 y). Non-P-Tau showed a strong increase with age significantly faster among MMC versus controls (p = 0.0055). Aβ1 - 42 and BDNF concentrations were lower in MMC children (p = 0.002 and 0.03, respectively). Anterior cingulate cortex showed a significant decrease (p = <0.0001) in the average axonal size and CDNPs were associated with organelle pathology. Significant age increases in non-P-Tau support tau changes early in a population with axonal pathology and evolving AD hallmarks in the first two decades of life. Non-P-Tau is an early biomarker of axonal damage and potentially valuable to monitor progressive longitudinal changes along with AD multianalyte classical CSF markers. Neuroprotection of young urbanites with PM2.5 and CDNPs exposures ought to be a public health priority to halt the development of AD in the first two decades of life.

Keywords: Aβ 1-42 , air pollution, Alzheimer’s disease, axonal damage, BDNF, cerebrospinal fluid, children, combustion-derived nanoparticles, insulin, leptin, Mexico City, non-phosphorylated tau, PM 2.5 , PrPC , vitamin D, Wallerian degeneration, white matter

DOI: 10.3233/JAD-180853

Journal: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1437-1451, 2018