Iron and Ferritin Dyshomeostasis Intersect with Sex, Age, and Disease Severity in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by progressive loss of motor neurons. Due to heterogeneity in both cause and clinical phenotype, accuracy of diagnosis and efficacy of treatment remain challenging. An evolving body of evidence point to the importance of the "gene-time-environment" hypothesis in ALS onset and progression. Despite extensive research, understanding of the complex environmental risk factors remains fragmented. In this study, we comprehensively analyzed the associations between trace elements, biochemical signatures, and modifiable risk factors among ALS patients stratified by age, sex, type of onset, disease severity, and progression. Specifically, we investigated blood concentrations of cadmium (Cd), lead (Pb), copper (Cu), zinc (Zn), calcium (Ca), magnesium (Mg), and iron (Fe) levels in 121 participants. Moreover, we examined the associations between trace metals, biochemical indicators including serum ferritin (SF), blood glucose, cholesterol (CHOL), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), cerebrospinal fluid (CSF) cell count, CSF total protein, as well as history of hypertension, hazardous chemical exposure, drinking, and smoking in ALS patients. Specifically, we report that high Fe levels were found in male and spinal-onset patients. Moreover, high serum ferritin was positively associated with age of onset, blood iron and glucose, as well as high disease severity. Results from this study highlight the complex characteristics of ALS and provide new insight for understanding the intricate relationship between disease phenotype, metal homeostasis, and modifiable risk factors.