Blood Lactate as a Prognostic Biomarker for Survival and Weight Loss in Amyotrophic Lateral Sclerosis: An Exploratory–Validation Study

OBJECTIVE: Lactate is increasingly recognized as an energy substrate, but its relevance to amyotrophic lateral sclerosis (ALS) remains unclear. We examined whether blood lactate is associated with survival and weight loss in ALS. METHODS: This retrospective study included an Australian exploratory cohort and a Japanese validation cohort with clinical data matched to measures of blood lactate. The primary outcome was survival from onset to death or tracheostomy. In the exploratory cohort, survival was analyzed using Kaplan-Meier curves stratified by the first quartile (Q1) of lactate and multivariable Cox regression. This cutoff was applied for log-rank analysis in the validation cohort. The secondary outcome was 3-month body mass index (BMI) change (ΔBMI). Associations between baseline lactate and ΔBMI were assessed using multivariable regression in the exploratory cohort, whereas Q1-based stratification was used in the validation cohort. RESULTS: The exploratory cohort included 110 patients with ALS (57 with ΔBMI data) and 86 healthy controls; the validation cohort included 36 patients (17 with ΔBMI data). In the exploratory cohort, lower lactate levels (below Q1; 1.05 mmol/L) were associated with shorter survival (p = 0.031) and remained independently predictive of higher risk for mortality (adjusted hazard ratio [HR] per 1 SD = 0.57, 95% confidence interval [CI] = 0.35-0.91). This association was confirmed in the validation cohort (p = 0.003). Lactate was independently associated with ΔBMI (β = 0.53, p = 0.032), and patients with lower lactate had a greater BMI decline (p = 0.010). INTERPRETATION: Lower blood lactate is associated with increased risk for earlier death and greater weight loss in ALS, suggesting that lactate is a prognostic biomarker of nutritional status. ANN NEUROL 2026;99:1526-1535.