Age and genetic variables represent nonmodifiable risk factors for cognitive decline, but accumulating research suggests that modifiable risk factors such as gene-environment interactions may also contribute to changes in cognitive function. Among these factors, studies have demonstrated that excess exposure to certain heavy metals is associated with neurotoxicity that may be attributed to inflammatory processes and oxidative stress.1

With cadmium, for example, acute “high-level exposure or long-term persistent low-level exposure… interferes with the antioxidant defense system and leads to oxidative stress in neuronal cells and brain endothelial cells,” according to a recent study published in Environmental Epidemiology.1 Elevated metal exposures have been linked to cognitive impairment in children, and 2 recent studies add to the growing body of research showing a similar risk among older adults in the US.1,2

“There is strong evidence that metals shown to cause neurotoxic effects in children also have the same effect in older adults,” said David O. Carpenter, MD, professor of environmental health sciences and director of the Institute for Health and the Environment at the University at Albany in Rensselaer, New York.2 “This includes lead, cadmium, arsenic, and probably other metals which haven’t been studied in detail,” Dr Carpenter said.


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Humans are commonly exposed to metals through emissions from diesel and gasoline fuels, wildfire smoke, waste recycling facilities, and contaminated soil, water, and food, among other sources.3

In a February 2022 cross-sectional study published in the International Journal of Environmental Research and Public Health, Dr Carpenter and PhD candidate Nozomi Sasaki, MPH, analyzed associations between cognitive test scores and concentrations of various metals in 3042 adults aged 60 years and older from the National Health and Nutrition Examination Survey (NHANES). After adjusting for demographic and clinical factors, they found that higher blood selenium levels were associated with better performance on tests of immediate, delayed, and working memory.2

For example, the beta coefficient (β) for the association between selenium levels and immediate recall scores was 2.62 (95% CI, 0.22-5.03; P =.03) for participants in their 60s and 3.44 (95% CI, 0.68-6.21; P =.01) for those aged 70 years and older. Analyses also revealed negative associations between cadmium and lead levels and test performance. In addition, some urinary metabolites of cadmium, lead, arsenic, and tungsten demonstrated significant associations with lower scores on tests of cognitive performance.

The positive association between selenium and cognitive function was a surprising result, Dr Carpenter stated. “The other surprise was the finding that mercury compounds, especially methyl mercury, well-known to cause neurotoxicity in children, was not associated with poor performance on the 3 cognitive tests we used,” he explained.

Researchers of another recent cross-sectional study analyzed NHANES data to explore associations between dietary factors, measures of cognitive performance, and combined blood levels of lead, cadmium, and manganese in 1777 adults aged 60 years and older.1 The results showed that a 1-quartile increase in metal concentrations was associated with reductions in overall cognitive performance (β=0.04; 95% CI, –0.09, 0.02) as well as scores on the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word Learning subtest (β=–0.04; 95% CI, –0.12, 0.03), the animal fluency test (β=–0.02; 95% CI, –0.11, 0.06), and the Digit Symbol Substitution Test (β=–0.05; 95% CI, –0.11, 0.02).

However, in sex-stratified analyses, the inverse associations between metal concentrations and cognitive performance were found in male participants only. Associations were especially robust among participants with high pro-inflammatory diets or low-quality diets, as assessed by the Adapted Dietary Inflammatory Index (ADII) and the Healthy Eating Index 2015 (HEI-2015), respectively. These observations indicate that an antioxidant, anti-inflammatory diet may protect against the neurotoxicity associated with blood levels of heavy metals in older adults.

“If confirmed, strategies based on diet could provide a potential complementary and efficient approach to counteract effects of environmental pollutants,” the researchers concluded.1 Foods and nutrients that may reduce oxidative stress and inflammation include fruits and vegetables, folic acid, and omega-3 polyunsaturated fatty acids present in fish and other sources.

In a 2022 preprinted article, Dr Carpenter and colleagues reported that regular consumption of fish, as well as higher blood selenium levels, were closely associated with higher scores on tests of recall and executive function in 2146 NHANES participants aged 60 years and older. The results further suggest that fish consumption and selenium may help to counterbalance the cognitive impairment associated with elevated blood concentrations of lead, cadmium, and mercury.4

These findings warrant additional investigation into the possible preventive and therapeutic effects of fish and selenium for this purpose. “Both have this balance between beneficial and toxic effects, and our preliminary evidence suggests that the situation in older adults is not the same as with young children,” Dr Carpenter noted.

With appropriate caution, selenium supplementation and increased fish consumption may ultimately represent important interventions for metal-related neurotoxicity in older adults. “However, there is long literature showing that selenium is toxic at high concentrations, so supplementation should only be done under careful medical supervision,” Dr Carpenter added.

There is also a need for ongoing research on general associations5,6 between metal exposures and cognitive function, implications for testing and treatment, and the sex-specific variations7,8 observed in multiple studies. 

References

1. Laouali N, Benmarhnia T, Lanphear BP, et al. Association between blood metals mixtures concentrations and cognitive performance, and effect modification by diet in older US adults. Environ Epidemiol. Published online January 25, 2022. doi:10.1097/EE9.0000000000000192

2. Sasaki N, Carpenter DO. Associations between metal exposures and cognitive function in American older adults. Int J Environ Res Public Health. Published online February 17, 2022. doi:10.3390/ijerph19042327

3. Calderón-Garcidueñas L, Chávez-Franco DA, Luévano-Castro SC, et al. Metals, Nanoparticles, Particulate Matter, and Cognitive Decline. Front Neurol. Published online January 21, 2022. doi:10.3389/fneur.2021.794071

4. Sasaki N, Jones LE, Carpenter D. Fish consumption and dietary selenium may reduce adverse effects of heavy metal exposures on cognitive function in older adults. SSRN. doi:10.2139/ssrn.4062581

5. Genuis SJ, Kelln KL. Toxicant Exposure and Bioaccumulation: A Common and Potentially Reversible Cause of Cognitive Dysfunction and Dementia. Behav Neurol. Published online February 4, 2015. doi:10.1155/2015/620143

6. Bakulski KM, Seo YA, Hickman RC, et al. Heavy metals exposure and Alzheimer’s disease and related dementias. J Alzheimers Dis. Published online August 18, 2020. doi:10.3233/JAD-200282

7. Zhou T, Guo J, Zhang J, et al. Sex-specific differences in cognitive abilities associated with childhood cadmium and manganese exposures in school-age children: A prospective cohort study. Biol Trace Elem Res. April 11, 2019. doi:10.1007/s12011-019-01703-9

8. R Cardoso B, Hare DJ, Macpherson H. Sex-dependent association between selenium status and cognitive performance in older adults. Eur J Nutr. Published online September 12, 2020. doi:10.1007/s00394-020-02384-0