A new study in mice finds that cadmium exposure, combined with a genetic predisposition to Alzheimer disease, can trigger symptoms of cognitive decline.

The so-called human apolipoprotein E (APOE) gene encodes instructions for creating the homonymous protein.

Typically, the APOE gene combines with fats to create lipoproteins—proteins that, in turn, carry cholesterol and other liquids through the bloodstream.

There are three variants, or alleles, of this gene. The E3 variant, for instance, is widespread, with half of the population carrying it.

The variant E4 of the APOE gene significantly raises a person's risk of developing Alzheimer disease.

New research in mice suggests that people who already have a copy of the APOE4 gene and are thus at risk of Alzheimer may experience cognitive decline as a result of exposure to cadmium—a neurotoxic heavy metal.

Cadmium occurs naturally in the earth, and "it is extracted during the production of copper, lead, and zinc." Foods such as shellfish, some leafy green vegetables, or grain cereals may contain cadmium; cigarette smoke and polluted air can also contain the metal.

Zhengui Xia, professor of environmental and occupational health sciences at the University of Washington School of Public Health, is the last and corresponding author of the new study, which appears in the journal Toxicological Sciences.

Studying cadmium and the APOE4 gene

In the new study, the scientists used mouse models of Alzheimer disease with an activated version of the E4 or E3 variant of the APOE gene. Then, the researchers added low doses of cadmium to the drinking water, which the mice drank for 14 weeks.

The maximum amount of cadmium that the mice ingested was the equivalent to the amount that humans in the United States have in their blood, including people who have never smoked.

The researchers examined the rats' cognitive abilities through standard novel objection location tests and T-maze tests.

The cognitive skills that the scientists chose to focus on rely on the hippocampus—a brain area crucial for learning and memory. It is also one of the brain regions that gets most damaged in the early stages of Alzheimer.

Cadmium accelerates cognitive impairment

The mice that had ingested cadmium performed less well in the novel object location tests, indicating a poorer short-term spatial working memory.

These symptoms occurred earlier in mice with the APOE4 gene than those with APOE3.

Male mice experienced an earlier onset than females with the same genetic makeup.

Later in life, mice with the APOE4 gene performed worse in the T-maze test than those with APOE3.

The authors conclude that exposure to cadmium "impaired neuronal differentiation of adult-born neurons" in the hippocampus of male mice with the APOE4 gene.

Overall, conclude the researchers, the results suggest that an interaction between APOE4 and cadmium exposure "leads to accelerated cognitive impairment and that impaired adult hippocampal neurogenesis may be one of the underlying mechanisms."

Young male mice seemed overall more susceptible to the effects of this interaction than young female rodents.

"This heavy metal is bad for you," says Xia.

"Exposure to cadmium through our daily lives could have a detrimental effect on our cognition. If you have the APOE4 gene, the risk is significantly higher."

—Zhengui Xia

"Our study provides direct evidence for an interaction between this Alzheimer genetic risk gene and environmental exposures on accelerated cognitive impairment."

The author also comments on the potential mechanisms that may explain the findings. "It is possible that APOE4 may cause leakage on the blood-brain barrier and lead to a higher degree of cadmium accumulation in the APOE4 brain."