Cholesterol in amyotrophic lateral sclerosis: a bystander, a biomarker, or a target?

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss. In addition to the different pathogenic mechanisms, in recent years, increasing attention has been directed toward the role of lipid metabolism in ALS pathogenesis, although the clinical relevance of lipid alterations in ALS may differ from their well-established role in cardiovascular disease. This review critically examines the multifactorial relationship between cholesterol and ALS through three perspectives: (1) as a risk factor for disease onset, (2) as a prognostic biomarker of disease progression, and (3) as a potential therapeutic target. Epidemiological and genetic studies suggest a complex and sometimes contradictory association between lipid profile and ALS risk. Elevated LDL-cholesterol and total cholesterol have been linked to increased disease susceptibility in some cohorts, with Mendelian randomization studies supporting a potential causal role. Conversely, evidence regarding HDL-cholesterol remains conflicting and may be influenced by sex-specific and metabolic factors. As a prognostic biomarker, hyperlipidemia has been variably associated with prolonged survival in ALS patients; however, these findings often lose significance after adjusting for body mass index and nutritional status, suggesting that lipid levels may reflect systemic metabolic reserve rather than directly modulating disease progression. Pharmacological modulation of cholesterol reveals further complexity. While statins are generally not associated with increased ALS risk in clinical studies, preclinical models show divergent effects: some statins accelerate disease progression, while others like lovastatin may be protective. Other lipidlowering drugs, including fibrates and PCSK9 inhibitors, may also influence ALS-related pathways beyond cholesterol lowering, although their potential role remains to be clarified.