Plasma Lipid Remodeling across Preclinical Burden, Disease Onset, and Early Motor Severity in Huntington's Disease

BACKGROUND AND OBJECTIVES: Huntington's disease (HD) evolves silently for years before motor onset, yet the systemic metabolic alterations accompanying cumulative exposure to mutant huntingtin and disease progression remain poorly understood. We aimed to identify plasma metabolic signatures associated with disease burden, disease onset and motor severity in HD. METHODS: Mutation carriers with 36 or more cytosine-adenine-guanine (CAG) repeats in the HTT gene were prospectively recruited and classified as premanifest or early manifest. Fasting plasma samples were analyzed using targeted metabolomics and lipidomics. Linear models adjusted for covariates were used to investigate associations with CAG-Age Product (CAP) score, disease stage, and motor severity (Unified Huntington's Disease Rating Scale total motor score). Lipid-class enrichment, acyl-chain enrichment and composite lipid score analyses were performed to characterize coordinated metabolic remodeling. RESULTS: Ninety-three mutation carriers (54 premanifest and 39 early manifest individuals) were included. Increasing CAP scores were associated with coordinated enrichment of eicosapentaenoic (20:5) and docosahexaenoic (22:6) acid-containing phospholipids together with depletion of triglycerides. In contrast, disease onset was characterized by enrichment of triglycerides and of lipids containing palmitate, palmitoleate, and arachidonate, accompanied by an increased palmitoleate-to-palmitate ratio of cholesteryl esters. In early manifest individuals, increasing motor severity was associated with depletion of docosahexaenoic acid-containing phospholipids, an increased phosphatidylserine-to-phosphatidylcholine ratio and reduced circulating acylcarnitines. These findings were supported by composite lipid scores and leave-one-subject-out sensitivity analyses. CONCLUSIONS: HD is associated with coordinated plasma lipid remodeling across disease stages. Distinct lipid signatures characterize cumulative mutant huntingtin exposure, disease onset and motor progression, providing insights into the metabolic consequences of HD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.