Heavy Metals Exposure and Alzheimer's Disease and Related Dementias

Abstract

Alzheimer's disease and related dementias lack effective treatment or cures and are major public health challenges. Risk for Alzheimer's disease and related dementias is partially attributable to environmental factors. The heavy metals lead, cadmium, and manganese are widespread and persistent in our environments. Once persons are exposed to these metals, they are adept at entering cells and reaching the brain. Lead and cadmium are associated with numerous health outcomes even at low levels of exposure. Although manganese is an essential metal, deficiency or environmental exposure or high levels of the metal can be toxic. In cell and animal model systems, lead, cadmium, and manganese are well documented neurotoxicants that contribute to canonical Alzheimer's disease pathologies. Adult human epidemiologic studies have consistently shown lead, cadmium, and manganese are associated with impaired cognitive function and cognitive decline. No longitudinal human epidemiology study has assessed lead or manganese exposure on Alzheimer's disease specifically though two studies have reported a link between cadmium and Alzheimer's disease mortality. More longitudinal epidemiologic studies with high-quality time course exposure data and incident cases of Alzheimer's disease and related dementias are warranted to confirm and estimate the proportion of risk attributable to these exposures. Given the widespread and global exposure to lead, cadmium, and manganese, even small increases in the risks of Alzheimer's disease and related dementias would have a major population impact on the burden on disease. This article reviews the experimental and epidemiologic literature of the associations between lead, cadmium, and manganese on Alzheimer's disease and related dementias and makes recommendations of critical areas of future investment.

Keywords: Cadmium; epidemiology; heavy metal; lead; manganese; toxicant; window of susceptibility.

Fig. 1.

Etiologic window for environmental exposures linked to Alzheimer’s disease and related dementias (ADRD).

Fig. 2.

Transport of lead (Pb), cadmium (Cd) and manganese (Mn) to the brain. Lead, cadmium and manganese enter the body through the gut and lung and are distributed in the bloodstream and transported to the brain. Cadmium and manganese also reach the brain through the olfactory nervous system. Lead crosses the blood-brain barrier and accumulates in the brain. All three metals can accumulate in the choroid plexus, a component of the blood-CSF (cerebrospinal fluid) barrier. The image was created in the Mind the GRAPH (https://mindthegraph.com/).

Fig. 3.

Mechanisms of general neurotoxicity action (yellow) and Alzheimer’s disease specific toxicity (orange) of cadmium, lead, and manganese on Alzheimer’s disease. Possible intervention options (green) and exposure routes and body distribution (light blue) are highlighted. Adapted from [223].