Sex Differences in Amyotrophic Lateral Sclerosis Survival and Progression: A Multidimensional Analysis

Objective: To investigate sex-related differences in amyotrophic lateral sclerosis (ALS) prognosis and their contributing factors. Methods: Our primary cohort was the Piemonte and Aosta Register for ALS (PARALS); the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) and the Answer ALS databases were used for validation. Survival analyses were conducted accounting for age and onset site. The roles of forced vital capacity and weight decline were explored through a causal mediation analysis. Survival and disease progression rates were also evaluated after propensity score matching. Results: The PARALS cohort included 1,890 individuals (44.8% women). Men showed shorter survival when stratified by onset site (spinal onset HR 1.20, 95% CI 1.00–1.44, p = 0.0439; bulbar onset HR 1.36, 95% CI 1.09–1.70, p = 0.006917), although women had a steeper functional decline (+0.10 ALSFRS-R points/month, 95% CI 0.07–0.15, p < 0.00001) regardless of onset site. Instead, men showed worse respiratory decline (−4.2 forced vital capacity%/month, 95% CI −6.3 to −2.2, p < 0.0001) and faster weight loss (−0.15 kg/month, 95% CI −0.25 to −0.05, p = 0.0030). Causal mediation analysis showed that respiratory function and weight loss were pivotal in sex-related survival differences. Analysis of patients from PRO-ACT (n = 1,394, 40.9% women) and Answer ALS (n = 849, 37.2% women) confirmed these trends. Interpretation: The shorter survival in men is linked to worse respiratory function and weight loss rather than a faster disease progression. These findings emphasize the importance of considering sex-specific factors in understanding ALS pathophysiology and designing tailored therapeutic strategies. ANN NEUROL 2024;96:159–169.