BACKGROUND: Central lipid dysregulation is implicated in spinocerebellar ataxia type 3 (SCA3), but peripheral lipid profiles remain poorly understood. Disease-associated low body mass index (BMI) may confound interpretation. OBJECTIVE: The aim was to characterize peripheral lipid profiles across SCA3 disease stages and unmask intrinsic metabolic alterations. METHODS: This cross-sectional study analyzed the lipid profiles of 37 preataxic carriers, 229 ataxic patients, and 316 controls using BMI-adjusted analysis of covariance (ANCOVA), mediation analysis, hierarchical regression, and receiver operating characteristic (ROC) analysis. RESULTS: After adjustment, ataxic patients exhibited elevated low-density lipoprotein cholesterol (LDL-C) and reduced high-density lipoprotein cholesterol (HDL-C). Mediation analysis revealed these alterations were substantially masked by BMI. HDL-C exhibited a stage-dependent pattern-elevated in preataxic carriers but depleted in ataxic patients. Lower HDL-C independently predicted higher Scale for the Assessment and Rating of Ataxia (SARA) (β = -2.881, P = 0.006). HDL-C improved ataxic-preataxic discrimination, achieving an area under the curve (AUC) of 0.837. CONCLUSIONS: SCA3 exhibits dyslipidemia with elevated LDL-C and reduced HDL-C, partially masked by BMI. HDL-C depletion accompanies phenoconversion and correlates with severity, representing a candidate peripheral biomarker. © 2026 International Parkinson and Movement Disorder Society.
Wan et al. (2026) studied this question.