Leveraging the large European EPIC cohort with extended follow-up, high-resolution proteomic profiling, and independent indirect validation in prevalent ALS, we identified the plasma protein biomarkers SECTM1, CA3, THAP4, KLHL41, and SLC26A7 as associated with ALS up to 15–25 years before ALS-related death (or 10–20 years or more before diagnosis). This evidence concerns the gene CA3 and amyotrophic lateral sclerosis.