Background: Amyotrophic lateral sclerosis (ALS) is highly heterogeneous with survival rate ranging from months to decades. Approximately 10-20% of patients develop a rapidly progressive disease and may die within the first year. Therefore, there is an increasing need for an early detection of unique molecular signatures associated with more aggressive forms of disease as it may help identify therapeutic targets. Methods: To identify a unique molecular signature in fast progressing patients, we recruited 45 sporadic ALS (sALS) patients and 35 age-matched healthy controls and measured 62 immune markers in plasma using cytokines array. Results: We found that leptin was significantly downregulated in plasma of sALS patients and more importantly in fast progressing disease. Immune markers CCL16 and sTNF-RII were significantly increased in rapidly progressing disease. We also found that leptin was significantly downregulated in plasma of SOD1G93A mice across disease stage. This was caused by an increased in levels of phospho-AMPK in mice adipocytes and in adipocytes exposed to fast sALS patients’ plasma. Conclusions: We propose that the combination of decreased plasma leptin levels and up-regulation in CCL16/sTNF-RII may be used as a prognostic biomarker to identify fast progressing ALS patients. This unique immune/metabolic profile may cause dysfunction in metabolic homeostasis.