Metabolome informs about the chemical exposome and links to brain health.

The metabolome is an intermediate phenotype, summarizing the profile of all small molecules (<1.5 kDa) in biospecimens. The metabolome provides a readout for the net influence of the chemical exposome, diet, gut microbiome, and genome on human health. Metabolic changes observed in exposome studies may thus provide clues about adverse outcome pathways related to cancer, diabetes, heart disease, cognitive impairment and other neurological conditions such as Alzheimer's disease (AD). Whilst the number of human cohort studies including both metabolomic and exposomic profiles is increasing, they are particularly limited in the domain of neurological conditions. Environmental exposures and chemical toxicants are known to have significant effects on the brain, gut microbiome, and gut-brain axis. Environmental chemicals of greatest interest include bisphenols, phthalates, persistent organic pollutants such as polychlorinated biphenyls (PCBs) and per- and poly-fluoroalkyl substances (PFAS), heavy metals, chemicals from household products and pesticides/herbicides; all of which may increase the risk of AD as they impact relevant biochemical mechanisms, especially with chronic exposure. In this review we describe how the chemical exposome can be assessed, including the approach our consortium is taking in the context of AD. Further, we review the current evidence about the impact of the chemical exposome on cognition as well as its influence on the risk and pathogenesis of AD. Finally, we highlight our approach to study the exposome in AD as part of large national and international collaborative efforts on the topic.