Role of the Exposome in Neurodegenerative Disease: Recent Insights and Future Directions

Abstract

Neurodegenerative diseases are increasing in prevalence and place a significant burden on society. The causes are multifactorial and complex, and increasing evidence suggests a dynamic interplay between genes and the environment, emphasizing the importance of identifying and understanding the role of lifelong exposures, known as the exposome, on the nervous system. This review provides an overview of recent advances toward defining neurodegenerative disease exposomes, focusing on Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. We present the current state of the field based on emerging data, elaborate on key themes and potential mechanisms, and conclude with limitations and future directions. ANN NEUROL 2024;95:635-652.

Figure 1.. The neural exposome.

The cumulative external and internal factors individuals are exposed to over the course of their lifetime. Exposures may interact with underlying genetic background (risk-modifying single-nucleotide polymorphisms represented by red shaded circles) to influence risk of neurodegenerative disease. Image created using BioRender.com.

Figure 2.. Potential mechanisms by which air pollution influences risk of neurodegenerative disease.

Inhaled air pollution components access the brain directly through the olfactory system or indirectly through the blood stream and cause neurotoxicity and neuroinflammation. Airway epithelial cells trigger a systemic inflammatory response, which compromises the BBB. In the brain, components of air pollution induce oxidative stress, accumulation of proteins, e.g., β-amyloid and phosphorylated tau, and activates the hypothalamus-pituitary-adrenal axis. In the gut, air pollution changes the gut microbiome. Image created using BioRender.com.

Figure 3.. Potential mechanisms by which OCPs influence risk of neurodegenerative disease.

OCPs cross the BBB and accumulate in lipid-rich brain tissue where they can affect neuronal function and survival through mitochondrial dysfunction, reactive oxygen species (ROS) production, oxidative stress, and microglial activation. OCP-induced histone hyperacetylation and genome-wide DNA methylation can also induce epigenetic dysregulation of gene expression. In AD, OCPs promote aggregation of β-amyloid and phosphorylated tau. In PD, OCPs disrupt dopamine synthesis, inhibit dopamine reuptake, and impact dopamine receptors and transporters. Image created using BioRender.com.

Figure 4.. Potential mechanisms by which metal overexposure influences risk of neurodegenerative disease.

Essential metal dyshomeostasis or toxic metal accumulation induces reactive oxygen species (ROS) generation, which increases oxidative stress and impairs mitochondrial function. Dyshomeostasis of essential metals disrupts cellular processes. In addition, metal binding or metal-induced alterations in protein expression and activity facilitates accumulation of β-amyloid, phosphorylated tau, and α-synuclein. Metal overload promotes neural inflammation through microglial activation and production of proinflammatory cytokines. Image created using BioRender.com.