Apolipoprotein E4, Gender, Body Mass Index, Inflammation, Insulin Resistance, and Air Pollution Interactions: Recipe for Alzheimer's Disease Development in Mexico City Young Females

Abstract

Given the epidemiological trends of increasing Alzheimer's disease (AD) and growing evidence that exposure and lifestyle factors contribute to AD risk and pathogenesis, attention should be paid to variables such as air pollution, in order to reduce rates of cognitive decline and dementia. Exposure to fine particulate matter (PM2.5) and ozone (O3) above the US EPA standards is associated with AD risk. Mexico City children experienced pre- and postnatal high exposures to PM2.5, O3, combustion-derived iron-rich nanoparticles, metals, polycyclic aromatic hydrocarbons, and endotoxins. Exposures are associated with early brain gene imbalance in oxidative stress, inflammation, innate and adaptive immune responses, along with epigenetic changes, accumulation of misfolded proteins, cognitive deficits, and brain structural and metabolic changes. The Apolipoprotein E (APOE) 4 allele, the most prevalent genetic risk for AD, plays a key role in the response to air pollution in young girls. APOE 4 heterozygous females with >75% to <94% BMI percentiles are at the highest risk of severe cognitive deficits (1.5-2 SD from average IQ). This review focused on the relationships between gender, BMI, systemic and neural inflammation, insulin resistance, hyperleptinemia, dyslipidemia, vascular risk factors, and central nervous system involvement in APOE4 urbanites exposed to PM2.5 and magnetite combustion-derived iron-rich nanoparticles that can reach the brain. APOE4 young female heterozygous carriers constitute a high-risk group for a fatal disease: AD. Multidisciplinary intervention strategies could be critical for prevention or amelioration of cognitive deficits and long-term AD progression in young individuals at high risk.

Keywords: APOE; Alzheimer’s disease; Mexico City; PM 2.5; body mass index; children; cognition; dementia; diabetes; female gender; glucose; insulin resistance; leptin; metabolic syndrome; nanoparticles.

Fig. 1.

Conceptual framework of how air pollution interacts with apolipoprotein E (APOE) ε4 genotype, female gender, and obesity to drive metabolic syndrome (MetS), cognitive decline and Alzheimer’s disease (AD). In the setting of chronic high-level exposures to PM_2.5 and significantly high concentrations of iron-rich combustion-derived magnetite nanoparticles, present in Mexico City’s polluted air, individuals carrying an APOE ε4 allele, particularly girls, are predisposed to develop insulin resistance and metabolic dysfunction which drive obesity. Having a single risk factor (APOE ε4, increased BMI, or female sex) increases the likelihood of developing mild insulin resistance, Type 2 diabetes mellitus (T2DM), and mild cognitive impairment (MCI). Dual risk factors are more precarious and promote moderate insulin resistance, MetS, and cognitive decline. Finally, having three risk factors is the most serious as that state predisposes children to developing obesity, severe systemic insulin resistance (IR), MetS, and brain IR, and ultimately dementia due to AD.