Examining the impact and role of lipid classes on the risk of amyotrophic lateral sclerosis (ALS) onset: a systematic review and GRADE analysis of the evidence

Background: This study aimed to synthesize existing research on pre-diagnostic blood lipid levels and the risk of amyotrophic lateral sclerosis (ALS) onset in adults, and the quality of this evidence. Methods: A systematic review was conducted (8 March 2024, updated 19 June 2025) across six databases (PubMed, Embase, CINAHL, Scopus, Cochrane Library, and Web of Science) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, identifying adult clinical studies of blood lipids measured prior to ALS onset. Studies with high risk of bias, assessed using the Quality in Prognostic Studies tool, were excluded. Standardized mean difference and 95% confidence intervals were calculated. Study outcomes were categorized by lipid class as indicating reduced, no effect, or increased ALS risk. Certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Results: Of 7222 studies identified, eight (n = 7 sterol lipids, n = 1 fatty acids) met inclusion. No significant differences in sterol lipids were observed between ALS cases and controls (I² = 69.9–77.3%). Most studies reported no association or increased risk between ALS onset and higher total cholesterol, triglycerides, LDL-C, HDL-C, or LDL/HDL ratio. For HDL-C, two studies showed protective associations. A single fatty acid study reported increased disease risk with higher arachidonic acid and reduced risk with higher alpha-linoleic acid. Certainty of evidence was low to very low. Conclusion: Circulating sterol lipid levels were inconsistently associated with ALS risk. The overall low certainty of evidence, and variability of findings across studies call for research using standardized designs, high-resolution lipid profiling, and robust causal inference approaches to clarify the role of lipids in ALS risk.