APOE Peripheral and Brain Impact: APOE4 Carriers Accelerate Their Alzheimer Continuum and Have a High Risk of Suicide in PM2.5 Polluted Cities

Ricardo Torres Jardón

ResearchGate  | Biomolecules


Lilian Calderón-Garcidueñas , Jacqueline Hernández-Luna , Mario Aiello-Mora , Rafael Brito-Aguilar , Pablo A. Evelson, Rodolfo Villarreal-Ríos , Ricardo Torres-Jardón*, Alberto Ayala and Partha S. Mukherjee

* Ciencias Ambientales | Fisicoquímica Atmosférica



his Review emphasizes the impact of APOE4—the most significant genetic risk factor for
Alzheimer’s disease (AD)—on peripheral and neural effects starting in childhood. We discuss major
mechanistic players associated with the APOE alleles’ effects in humans to understand their impact
from conception through all life stages and the importance of detrimental, synergistic environmental
exposures. APOE4 influences AD pathogenesis, and exposure to fine particulate matter (PM2.5),
manufactured nanoparticles (NPs), and ultrafine particles (UFPs) associated with combustion and
friction processes appear to be major contributors to cerebrovascular dysfunction, neuroinflammation,
and oxidative stress. In the context of outdoor and indoor PM pollution burden—as well as Fe, Ti,
and Al alloys; Hg, Cu, Ca, Sn, and Si UFPs/NPs—in placenta and fetal brain tissues, urban APOE3
and APOE4 carriers are developing AD biological disease hallmarks (hyperphosphorylated-tau
(P-tau) and amyloid beta 42 plaques (Aβ42)). Strikingly, for Metropolitan Mexico City (MMC) young
residents ≤ 40 y, APOE4 carriers have 4.92 times higher suicide odds and 23.6 times higher odds
of reaching Braak NFT V stage versus APOE4 non-carriers. The National Institute on Aging and
Alzheimer’s Association (NIA-AA) framework could serve to test the hypothesis that UFPs and
NPs are key players for oxidative stress, neuroinflammation, protein aggregation and misfolding,
faulty complex protein quality control, and early damage to cell membranes and organelles of neural
and vascular cells. Noninvasive biomarkers indicative of the P-tau and Aβ42 abnormal protein
deposits are needed across the disease continuum starting in childhood. Among the 21.8 million
MMC residents, we have potentially 4 million APOE4 carriers at accelerated AD progression. These
APOE4 individuals are prime candidates for early neuroprotective interventional trials. APOE4 is
key in the development of AD evolving from childhood in highly polluted urban centers dominated
by anthropogenic and industrial sources of pollution. APOE4 subjects are at higher early risk of AD
development, and neuroprotection ought to be implemented. Effective reductions of PM2.5, UFP, and
NP emissions from all sources are urgently needed. Alzheimer’s Disease prevention ought to be at
the core of the public health response and physicians-scientist minority research be supported