Atherosclerotic Cardiovascular Diseases Increase ALS Risk by 82% While Optimal Cardiovascular Health Halves It: A 0.5‐Million Prospective Cohort Study

OBJECTIVE: The objective of this study was to determine whether prevalent atherosclerotic cardiovascular diseases (ASCVDs) increase the risk of amyotrophic lateral sclerosis (ALS) and whether high cardiovascular health (CVH) can offset this risk. METHODS: We prospectively analyzed 502,279 UK Biobank participants (37-73 years) with linked electronic health records. Prevalent ASCVD (coronary artery disease [CAD], ischemic stroke [IS], and peripheral artery disease [PAD]) was ascertained at baseline. CVH was quantified using Life's Essential 8 and categorized as low, moderate, or high. Cox models, joint analyses, and Mendelian randomization were applied. RESULTS: Over a median follow-up of 13.74 years, 675 incident ALS cases were documented. A history of ASCVD was associated with a 43% higher risk of ALS (hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.16-1.78, p = 0.001), primarily driven by CAD and IS. Conversely, high CVH was associated with a lower risk of ALS compared with low CVH (HR = 0.52, 95% CI = 0.33-0.81, p = 0.004). Joint analysis revealed that individuals with low CVH and pre-existing ASCVD exhibited the highest ALS risk. Mendelian randomization analyses provided supportive evidence consistent with the observational associations among CAD, IS, and ALS. The inverse association between CVH and ALS risk was most pronounced among participants aged ≤65 years. INTERPRETATION: Prevalent ASCVD was associated with a higher risk of ALS, whereas high CVH was associated with a lower risk of ALS. These findings support a potential link between CVH and ALS susceptibility, particularly among individuals aged ≤65 years. ANN NEUROL 2026.