ALS diagnosis and survival linked to metals in blood, urine

People with higher levels of metals found in their blood and urine may be more likely to be diagnosed with — and die from — amyotrophic lateral sclerosis, or ALS, a University of Michigan-led study suggests.

Researchers have known that ALS, a rare but fatal neurodegenerative condition, is influenced by genetic and environmental factors, including exposure to pesticides and metals.

This latest study examined the levels of metals in the blood and urine of people with and without ALS, finding that exposure to individual and mixtures of metals is associated with a greater risk for ALS and shorter survival.

The results are published in the Journal of Neurology, Neurosurgery, and Psychiatry.

“Strengthening our understanding of the importance of exposure to metals as a risk factor for ALS is essential for future targeted prevention of the disease and improved therapeutic strategies,” said senior author Stephen Goutman, M.D., M.S., director of the Pranger ALS Clinic and associate director of the ALS Center of Excellence at University of Michigan.

“Several epidemiologic studies have linked metal exposure to ALS risk. Nonetheless, it remains critical for us to understand how these metal mixtures associate with ALS risk and survival and to identify who is at greatest risk of exposure or who is most susceptible to the exposure.”

Goutman’s team measured metal levels in plasma and urine samples from over 450 people with ALS and nearly 300 people without the condition.

They found that elevated levels of individual metals, including copper, selenium and zinc, significantly associated with higher ALS risk and earlier death.

They then used these results to create environmental ALS risk scores, similar to the polygenic risk scores previously developed at U-M. The environmental risk scores indicated that mixtures of metals in plasma and urine are linked to around a three-times greater risk for the disease.

In this study, the inclusion of an ALS polygenic risk score to assess a potential moderating effect of underlying genetic factors did not alter the association between metal exposure and disease risk or survival.

“While several studies suggest that environmental factors like metals interact with genetic variants to influence the onset, progression and severity of ALS, our study found that accounting for ALS polygenic risk scores did not influence the relationship between metal exposure and ALS,” said co-author Kelly Bakulski, Ph.D., associate professor of epidemiology at the University of Michigan School of Public Health.  

“The relationships between genes and the environment on disease risk are complex, and future insights into other genetic factors or pathways that may be involved in ALS risk and metabolism of metals could enhance our understanding.”

Investigators also discovered that participants working in occupations with a higher likelihood of metal exposure had increased levels of metal mixtures in their blood and urine.

This echoes a previous study from the research team which found that people with ALS reported higher occupational exposure to metals prior to diagnosis.

“These findings emphasize the necessity of accounting for occupational and environmental factors when evaluating a person’s overall exposure risk,” said first author Dae Gyu Jang, Ph.D., postdoctoral fellow in the U-M Health Department of Neurology.

By avoiding high risk activities associated with metal exposures, Goutman says, individuals might lower their overall exposure and potentially mitigate risk.

“Our future research will further focus on what exposures have the strongest associations and their implications on the disease,” he said.

Additional authors: John Dou, M.P.H., Emily J. Koubek, Ph.D., Samuel Teener, Bhramar Mukherjee, Ph.D., Stuart A. Batterman, Ph.D., and Eva L. Feldman, M.D., Ph.D., all of University of Michigan, and Lili Zhao, Ph.D., of Corewell Health.

Funding for this study was provided in part by the National Institute of Neurological Disorders and Stroke (R01NS127188), the National Institute of Environmental Health Sciences (K23ES027221, R01ES030049), the Centers for Disease Control and Prevention (R01TS000344) and the ALS Association (20-IIA-532, 20-PP-661).

Paper Cited: “Multiple metal exposures associate with higher amyotrophic lateral sclerosis risk and mortality independent of genetic risk and correlate to self-reported exposures: a case-control study,” Journal of Neurology, Neurosurgery, and Psychiatry: DOI: 10.1136/jnnp-2024-333978