ArticleNeurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology2025
Two-step Mendelian randomization reveals a lipid-driven protective effect of type 2 diabetes on ALS.
Article in Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed.
- Cholesterol in amyotrophic lateral sclerosis: a bystander, a biomarker, or a target?Atherosclerosis plus · 2026Review
- Biobank-based genetic characterization of neurodegenerative diseases and idiopathic normal pressure hydrocephalus: insights and lessons learned from FinnGen.Molecular psychiatry · 2026Review
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Abstract
backgroundAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with few therapeutic options. Observational data suggest that type 2 diabetes mellitus (T2DM) might protect against ALS, yet the mechanisms are unclear. Clarifying whether glucose or lipid metabolism underpins this protective effect could guide targeted interventions.
objectiveThis study aims to investigate if T2DM reduces ALS risk through glycemic or lipid pathways using a two-step Mendelian Randomization (MR) approach.
methodsSummary-level genetic data were sourced from FinnGen (n = 440,735), MAGIC (n = 200,622), UK Biobank (n = 115,078), and Project MinE (n = 138,086). Two-sample MR assessed T2DM's causal effect on ALS, followed by multivariable MR adjusting for glycemic traits to identify metabolic pathways. A two-step MR analyzed significant blood metabolites contributing to the T2DM-ALS relationship. Sensitivity analyses confirmed the robustness of these findings.
resultsT2DM exhibited a protective causal association with ALS (inverse variance weighting OR = 0.956, 95% CI 0.916-0.997, p = 0.037). Glycemic traits did not mediate this protection; instead, lipid metabolism played a role. Specifically, a 1 SD reduction in LDL diameter was linked to a 16.7% decrease in ALS risk, accounting for 24.4% of T2DM's protective effect. Similarly, a 1 SD decrease in total esterified cholesterol (TEC) reduced ALS risk by about 13.2%, contributing to 13.3% of T2DM's overall protective impact. No evidence of horizontal pleiotropy was observed.
conclusionT2DM's protective influence on ALS primarily involves lipid rather than glucose pathways, highlighting TEC and LDL particle diameter as crucial mediators. Targeting lipid metabolism may offer new therapeutic strategies to reduce ALS risk or progression, potentially leading to focused nutritional interventions and biomarker development.
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