Blood Metal Levels and Amyotrophic Lateral Sclerosis Risk: A Prospective Cohort

Abstract

Objective Metals have been suggested as a risk factor for amyotrophic lateral sclerosis (ALS), but only retrospective studies are available to date. We compared metal levels in prospectively collected blood samples from ALS patients and controls, to explore whether metals are associated with ALS mortality. Methods A nested ALS case–control study was conducted within the prospective EPIC (European Prospective Investigation into Cancer and Nutrition) cohort. Cases were identified through death certificates. We analyzed metal levels in erythrocyte samples obtained at recruitment, as a biomarker for metal exposure from any source. Arsenic, cadmium, copper, lead, manganese, mercury, selenium, and zinc concentrations were measured by inductively coupled plasma–mass spectrometry. To estimate ALS risk, we applied conditional logistic regression models. Results The study population comprised 107 cases (65% female) and 319 controls matched for age, sex, and study center. Median time between blood collection and ALS death was 8 years (range = 1–15). Comparing the highest with the lowest tertile, cadmium (odds ratio [OR] = 2.04, 95% confidence interval [CI] = 1.08–3.87) and lead (OR = 1.89, 95% CI = 0.97–3.67) concentrations suggest associations with increased ALS risk. Zinc was associated with a decreased risk (OR = 0.50, 95% CI = 0.27–0.94). Associations for cadmium and lead remained when limiting analyses to noncurrent smokers. Interpretation This is the first study to compare metal levels before disease onset, minimizing reverse causation. The observed associations suggest that cadmium, lead, and zinc may play a role in ALS etiology. Cadmium and lead possibly act as intermediates on the pathway from smoking to ALS. ANN NEUROL 20209999:n/a–n/a

Assessing the Causal Role of Selenium in Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

“…The results of these sensitivity analyses were in accordance with the IVW result. Therefore, the present study did not find evidence supporting any causal relationship between ALS and selenium, which is in accordance with the null association found between ALS and erythrocyte-bound selenium level in a recent prospective case-control study (Peters et al, 2020).…”

“…The questionnaire-based observational studies, which rely on self-reported information for the assessment of exposures, are subject to recall and selection biases (Filippini et al, 2020). The prospective case-control study design, on the other hand, is usually restricted by the modest number of cases enrolled, partly due to the low prevalence of ALS in the general population (Peters et al, 2020). Therefore, given the rarity of the disease and ethical issues, it is difficult to conduct unbiased association studies of ALS and selenium in practice.…”

Assessing the Causal Role of Selenium in Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

“…Here we leveraged the summary statistics from recent largescale GWAS datasets to probe the association between selenium exposure and the risk for ALS. The current evidence did not support any causal relationship between the two, which is in accordance with the null association found between ALS and erythrocyte-bound selenium level in a recent prospective casecontrol study [18]. However, given the modest number of valid IVs available for this analysis and the relatively low percentage of variance in selenium level explained by these IVs, the statistical power to detect any postulated causal association might be limited.…”

“…In addition, the questionnaire-based observational studies relying on self-reported information for the assessment of exposures are also subject to recall and selection biases [14]. The prospective case-control study design, on the other hand, is usually restricted by the modest number of cases enrolled, partly due to the low prevalence of ALS in general population [18]. Therefore, given the rarity of the disease and ethical issues, it is di cult to conduct unbiased environmental studies of ALS.…”

Amyotrophic Lateral Sclerosis: A Diet Review

“…In particular, exposure to metals has been suggested to be a possible risk factor for ALS, but results are not conclusive. Studies show that cadmium and lead may be associated with an increased risk of developing ALS and zinc with a decreased risk based on pre-disease metal levels in blood, with lead having the strongest a priori connection [ 133 , 134 , 135 ].…”