Cognitive Performance Falls as Metal Exposure Rises

Traces of nine essential metals and non-essential metals in urine were linked with lower cognitive performance and the risk of future dementia, a large prospective study showed.

The study assessed concentrations of the essential metals cobalt, copper, manganese, and zinc, and the non-essential metals arsenic, cadmium, lead, tungsten, and uranium.

Comparing the top and bottom percentiles of exposure to all nine metals, the HR of dementia was 1.71 (95% CI 1.24-3.89), reported Arce Domingo-Relloso, PhD, of the Columbia University Mailman School of Public Health in New York City, in JAMA Network Open.

Scores on the Digit Symbol Coding (DSC) test -- which measured how fast simple mental operations could be performed -- were inversely associated with metal levels. DSC scores range from 0-133, and the median score at baseline was 51.

Mean differences in DSC z scores per IQR of log-transformed metal levels were -0.05 for cobalt, -0.05 for copper, -0.04 for uranium, -0.03 for arsenic, and -0.03 for zinc.

Comparing the bottom and top percentiles of exposure of all nine metals, the mean difference of DSC scores was -0.30 for APOE4 carriers and -0.10 for noncarriers.

Identifying modifiable risk factors and groups at higher risk for Alzheimer's and dementia is crucial, Domingo-Relloso observed.

"This study not only shows that exposure to metals is associated with cognitive decline, but more importantly, carrying at least one copy of the APOE4 allele could modify this association, which opens the door to the creation of early risk assessment tools based on individuals' genetic and environmental exposure profiles," she told MedPage Today.

"Experimental studies had already shown that ApoE4 could be interacting with metals in the brain, but showing this potential effect modification in humans for urinary metals in a diverse and multi-ethnic population sets the basis for further exploration of the role of interactions between genetic and environmental factors in dementia and Alzheimer's risk," Domingo-Relloso continued.

"An important finding is that not only toxic metals, but also essential metals -- which are needed for key biological processes -- were associated with cognitive decline," she added. "Elevated levels of these metals in urine might reflect loss of body reserves of these elements due to dysregulated biological processes, which warrants further investigation."

The analysis used data from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, which started in 2000. Earlier MESA research showed that metals detected in urine were associated with an increased risk of cardiovascular disease and all-cause mortality.

Domingo-Relloso and colleagues followed 6,303 MESA participants for a dementia diagnosis through 2018. Median baseline age was 60 and 52% of the sample were women. Overall, 559 participants were diagnosed with dementia during a median follow-up of 11.7 years.

Urine samples were collected at baseline from 2000-2002 and stored. In 2020-2022, metals in urine were analyzed individually and as a nine-metal mixture. To correct for diluted urine, the researchers divided metal concentrations by creatinine concentrations.

Cognitive tests were administered in 2010-2012. Besides the DSC, these included the Cognitive Abilities Screening Instrument (CASI) and the Digit Span (DS) tests. There were no associations with CASI and DS for more than one metal, the researchers noted.

In APOE4 carriers, the association of DSC scores with increased exposure to the nine-metal mixture was comparable to a 6-year increase in age, the researchers noted. In non-APOE4 carriers, the relationship with DSC was significant only in the highest range of exposure.

The study had several limitations, Domingo-Relloso and co-authors said. Information about patients with dementia who were never hospitalized, died, or were lost to follow-up without a diagnosis was likely not captured. In addition, dementia diagnoses in MESA included nonspecific ICD codes like memory loss, which may have led to false-positive reports.

"Future research is needed to develop statistical models to better quantify the potential biases derived from competing risks in aging research," the researchers wrote.

"In addition, although this was a relatively large study of the cognitive outcomes associated with metals exposure, the sample size was insufficient to evaluate the associations between metals and cognitive test scores for carriers of two APOE4 alleles."

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