Understanding the contribution of toxicant exposures to Alzheimer's disease and related dementias.

Alzheimer's disease and related dementias (AD/ADRD) are modulated by gene-environment (GxE) interactions across the lifespan. Variants of specific genes increase AD risk and synergize with exposures to environmental toxicants ("exposome"), including neurotoxic metals and metalloids such as lead (Pb), cadmium (Cd), and arsenic (As). These neurotoxicants enter the body (via drinking water, contaminated food, and airborne particulates), transit in blood, cross the blood-brain barrier, and distribute in brain where the retained toxicant disrupts central nervous system development, structure, and function. Chronic exposure to these ubiquitous toxicants is common in disadvantaged communities, raising concerns about health risk disparities linked to geographic, socioeconomic, and racial demographics. While Pb, Cd, and As are established human neurotoxicants with suspected linkage to AD/ADRDs, the mechanisms underpinning AD/ADRD-related GxE interactions specific to metal-metalloid toxicant exposures are largely unknown and potentially modifiable. Preclinical models and resources are needed to facilitate research into the underlying mechanisms by which AD genetics and exposome affect brain health, aging, and AD/ADRD pathobiology.