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This study aimed to investigate how genetic predisposition to adiposity might influence ALS through specific lipid metabolic pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted mass spectrometry\u2013based quantitative lipidomics on plasma from 104 ALS patients and 78 age\u2010 and sex\u2010matched controls. Life\u2010course adiposity polygenic risk scores (PRS) for birth weight, body fat percentage, appendicular lean mass and whole\u2010body fat\u2010free mass were constructed. Associations and PRS\u2010by\u2010disease interaction effects on the lipidome were evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared to controls, ALS patients exhibited widespread lipid dysregulation. Seventy\u2010eight lipid species were significantly altered (FDR \u2009&lt;\u20090.05, |Cohen's\n                      <jats:italic>d<\/jats:italic>\n                      |\u2009&gt;\u20091.0), characterized by a predominant decrease in acylcarnitines (75% of species) and distinct shifts within sphingolipid and glycerophospholipid subclasses. A three\u2010acylcarnitine candidate panel (C10:0, C12:0 and C18:2) using fivefold analysis with feature selection repeated within each training fold yielded an overall out\u2010of\u2010fold AUC of 0.958. Exploratory PRS\u2010by\u2010disease\u2010status analyses identified 16 nominal interaction signals, including 13 acylcarnitines; no significant mediation effect of lipids between PRS and ALS risk was detected.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings identify robust ALS\u2010associated plasma lipid alterations, and our exploratory findings suggest that genetic predisposition to adiposity may shape the pattern of lipid metabolic disruption in ALS, offering new insights into the disease's metabolic pathophysiology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70410","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T12:51:18Z","timestamp":1792587078000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Plasma Lipidome Is Dysregulated in Amyotrophic Lateral Sclerosis and Associated With Life\u2010Course Adiposity Polygenic Risk"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1087-2619","authenticated-orcid":false,"given":"Linjing","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5445-9554","authenticated-orcid":false,"given":"Leyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Developmental Biology Chinese Academy of Sciences  Beijing China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1162-5186","authenticated-orcid":false,"given":"Yongping","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhuang","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Institute of Vascular Medicine Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3589-6287","authenticated-orcid":false,"given":"Lu","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Neurology Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Neurology Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kailin","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Neurology Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Neurology Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tielun","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Neurology Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0328-1368","authenticated-orcid":false,"given":"Tao","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology Peking University Third Hospital  Beijing China"},{"name":"Department of Nutrition and Food Hygiene, School of Public Health Peking University  Beijing China"},{"name":"State Key Laboratory of General Artificial Intelligence Peking University  Beijing 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