LIPIDIC PROFILING AND IMMUNE-RELATED PATHWAYS IN AMYOTROPHIC LATERAL SCLEROSIS: A REAL-WORLD COHORT STUDY

ALS is a neurodegenerative disorder characterized by the progressive degeneration of UMN and LMN, leading to respiratory failure and death, typically within 2 to 5 years from symptom onset. To date, no effective disease-modifying treatment is available. The heterogeneity in the clinical presentation of the different phenotypes suggests that ALS may be a syndromic disorder with multifactorial causes. Lipid metabolism and immune system dysfunctions, that are now regarded as systemic players contributing to non-cell autonomous toxicity, may impact on disease progression and on responses to treatments. Consequently, increasing attention has been directed toward the identification of clinical “endophenotypes” capable of stratifying patients into more homogeneous subgroups with potentially different therapeutic responses to treatments in clinical trials. This study aimed to stratify ALS patients into clinically and biologically homogeneous groups. Specifically, we studied the lipid profile of a real-world ALS cohort and investigated its correlation with immune-related inflammatory pathways, nutritional status, clinical phenotypes and whether these associations carry prognostic relevance in this patient population. This observational study was conducted in a single MND centre in Northern Italy and included ALS patients regardless of their disease stage. Clinical and laboratory data, including lipid species, inflammatory (CRP, NLR) and nutritional biomarkers (albumin, creatinine, uric acid) were reported at the time point closest to biobanking. Preliminary associations between lipid profile, nutritional status and inflammatory biomarkers were assessed through Spearman's correlation tests or regression analyses. LCA based on generalized structural equation modelling was performed to identify immune-metabolic patients clusters. Survival from symptom onset to death or IV was evaluated using Kaplan-Meier and Cox regression models. Hypercholesterolemic ALS patients showed better functional status, lower inflammatory burden and greater survival estimates, especially in female patients. Albumin emerged as the strongest nutritional correlate of circulating cholesterol species, whereas higher BMI did not correlate with hypercholesterolemia. Weight loss was significantly associated with both inflammatory markers and lipid profiles. Higher total, HDL and LDL cholesterol levels were associated with lower peripheral inflammatory markers such as neutrophils, NLR and CRP, while LDL/HDL ratio showed a positive association. LCA identified distinct immune-metabolic endophenotypes that predicted disease severity and survival. A hyperinflammatory and catabolic biotype characterized by severe weight loss and low cholesterol levels was associated with greater impairment, respiratory dysfunction and nutritional compromise whereas a metabolically preserved, hypercholesterolemic and low-inflammatory biotype showed a significantly lower disease burden. These findings suggest that cholesterol metabolism, nutritional status and systemic inflammation are tightly interconnected in ALS. Hypercholesterolemia was associated with a more favourable clinical and inflammatory profile and with improved survival in female patients, suggesting a sex-specific interplay of cholesterol metabolism. Integrated immune-metabolic clustering identified biologically distinct patient subgroups associated with disease severity and survival, capturing ALS biological heterogeneity.