Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of upper and lower motor neurons, leading to muscle weakness, atrophy, and paralysis. As the disease progresses, patients experience impairments in speech, swallowing, respiration, and limb function, with most succumbing to respiratory failure within 3-5 years of symptom onset (1,2). Clinical heterogeneity is a hallmark of ALS, with bulbar- and limb-onset ALS being the two predominant subtypes. Bulbar-onset ALS manifests with dysarthria and dysphagia due to degeneration in the bulbar regions, while limb-onset ALS is characterized by weakness and fasciculations in the extremities (3-7). These phenotypes differ not only in clinical manifestations but also in prognosis; although less common, bulbar-onset ALS typically exhibits rapid disease progression and is associated with shorter survival (3-5). Emerging evidence further suggests that subtype-specific pathophysiological features involve distinct neural pathways and genetic risk factors (8-11). However, therapeutic strategies still primarily target ALS as a single entity (12,13), overlooking potential subtype-specific targets.

Dyslipidemia in ALS, characterized by altered cholesterol and triglyceride levels, has been associated with both neuroprotective and deleterious effects, suggesting a multifaceted and context-dependent role in disease pathogenesis (14-18). Some studies report that hyperlipidemia and a higher body mass index may slow disease progression and improve survival (16,19), whereas others associate lipid abnormalities with worse prognosis (20-22). These inconsistencies likely stem from variations in study design, evaluated lipid markers, and patient cohorts. Notably, most studies have treated ALS as a uniform disease, with limited consideration of heterogeneity across clinical subtypes. This gap is significant as bulbar- and limb-onset ALS exhibit distinct clinical trajectories, and emerging evidence indicates potential differences in metabolic mechanisms.

Most existing studies have been conducted in Western populations (14-21), raising uncertainties about the generalizability of the findings to other regions. The regional and ethnic differences in both ALS epidemiology and metabolic risk factors highlight the importance of investigating non-Western cohorts (23-25). While some studies have explored the lipid profiles in Chinese patients with ALS, systematic analyses focusing on subtype-specific associations remain scarce.

In this study, we investigated serum lipid profiles in a Chinese ALS cohort, specifically exploring whether the association with disease severity varied between bulbar- and limb-onset subtypes. Through correlation analyses and multivariable interaction models, our objective was to determine if lipid parameters have subtype-specific effects on functional impairment. These analyses provide new insights into the metabolic heterogeneity of ALS and may contribute to the development of more tailored prognostic assessments and management strategies across clinical subtypes.

This study demonstrates dyslipidemia in a Chinese ALS cohort and reveals that the associations between lipid levels and functional severity are modified by clinical subtype. In bulbar-onset ALS, higher sdLDL-c levels and TG/HDL ratios were associated with better functional status, whereas higher HDL and ApoA1 levels tended to correlate with worse outcomes. In contrast, in limb-onset ALS, higher sdLDL-c and ApoB levels were associated with greater functional impairment, whereas other lipid measures showed no significant association. These findings extend the observations from Western cohorts and underscore the importance of accounting for clinical heterogeneity when investigating metabolic alterations in ALS.

Altered lipid metabolism has long been recognized as a feature of ALS, reflecting the high energy demands of denervated and atrophic muscle tissues (28). Lipids serve as major energy substrates, and their imbalance may influence both systemic metabolism and neuronal vulnerability (29). Previous studies in Western populations have reported inconsistent results regarding dyslipidemia in patients with ALS. Some studies have linked elevated lipid levels, particularly triglycerides, to improved survival and slower progression, whereas others have found no significant association or even adverse effects (21,22,30-32). These inconsistencies may arise from methodological differences, variation in disease stage, and unaccounted phenotypic diversity. Evidence from Asian cohorts provides additional context for these discrepancies. Early studies from southwestern China have reported no significant lipid differences between patients with ALS and controls (33). However, more recent Chinese studies have observed negative correlations between total cholesterol or LDL-c levels and ALSFRS-R scores, and between ApoB or Lp(a) levels and respiratory function, suggesting that lipid imbalance accompanies disease severity (34). Another large Chinese cohort found lower HDL and total cholesterol levels but higher LDL/HDL ratios, consistent with stage-related metabolic shifts (35). Our findings partially align with these results but further reveal subtype-specific lipid signatures, indicating that metabolic adaptations differ between bulbar- and limb-onset ALS. Similar heterogeneity has been observed in non-Western populations. In Japanese cohorts, higher total cholesterol, LDL, and triglyceride levels were associated with slower disease progression (36), supporting our observation that elevated lipid levels may reflect compensatory metabolic responses. Conversely, Nakamura et al (25) reported that high HDL levels predict poor prognosis, paralleling our finding of a negative association between HDL and functional status. In South Korea, lipid depletion, especially in men, suggests accelerated lipid consumption (37), and CT-based analyses have demonstrated that fat depletion (adipopenia) independently predicts poor survival (38). Collectively, these findings, together with our data, indicate that dyslipidemia is a shared metabolic feature of ALS; however, its clinical implications vary by ethnicity, sex, and phenotype, reflecting diverse adaptive responses to neurodegeneration.

The inverse relationship between cholesterol and ALSFRS-R scores observed in this study supports growing evidence that cholesterol homeostasis may play a role in disease progression. Cholesterol is a structural component of neuronal membranes and a precursor of signaling molecules such as steroid hormones and oxysterols (39,40). Disturbances in cholesterol regulation have been implicated in ALS through multiple molecular pathways. Dysregulation of the LXR/RXR signaling pathways and polymorphisms in lipid-related genes such as APOE and SREBP2 have been associated with altered lipid metabolism and neuronal stress responses in ALS (41,42). Furthermore, TDP-43, a central protein in ALS pathology, modulates SREBP2-dependent cholesterol metabolism, suggesting a mechanistic link between lipid dysregulation and neurodegeneration (43,44). Large-scale genome-wide association studies have also identified elevated total cholesterol as a potential risk factor for ALS (45), further reinforcing the role of lipid homeostasis in disease susceptibility.

Our subtype-specific analysis provides further insight into metabolic diversity in ALS. In patients with bulbar-onset ALS, we observed that higher levels of sdLDL-c and TG/HDL ratio were associated with better functional status, potentially indicating a compensatory lipid mobilization response to the heightened metabolic stress in this subgroup (46). This observation aligns with the concept that individuals with bulbar-onset ALS, who typically experience faster disease progression, may rely on enhanced lipid utilization to meet elevated energy demands (4,5). Conversely, in limb-onset ALS, elevated levels of sdLDL-c and ApoB were linked to poorer functional status, suggesting that lipid accumulation in this subgroup could contribute to exacerbate the disease burden. These opposing trends underscore the idea that lipid dysregulation in ALS is not uniform, but is likely context-dependent, with the clinical phenotype and metabolic dynamics playing a critical role (46). Similarly, previous reports have noted that elevated triglyceride level or BMI may predict longer survival, whereas high HDL levels have been associated with poorer outcomes (15,16,25). This finding reinforces the notion that lipid dysregulation in ALS is phenotype-specific with distinct metabolic responses to neuronal degeneration in bulbar-onset and limb-onset ALS. Bulbar-onset ALS may rely on lipid mobilization as an adaptive response to rapid degeneration, whereas limb-onset ALS may exhibit lipid accumulation, reflecting a passive metabolic adaptation to impaired muscle function. These contrasting trends highlight the importance of clinical heterogeneity when interpreting lipid alterations in patients with ALS.

These findings emphasize the significance of considering ALS as a metabolically heterogeneous disorder rather than a singular disease entity. Lipid signatures specific to subtypes could potentially function as biomarkers for monitoring disease progression and categorizing patients in clinical studies. Apart from their biomarker potential, lipid changes may hold therapeutic relevance. Increasing evidence indicates that maintaining metabolic balance can influence ALS outcomes. Nutritional and metabolic strategies, such as high-calorie or high-fat diets, have demonstrated positive effects in SOD1(G86R) ALS mouse models and in small clinical trials, improving energy balance, tolerance, and occasionally survival (47-49). Recent reviews highlight that energy deficits and lipid depletion accelerate neurodegeneration, while replenishing lipid availability might offer neuroprotective effects (8,50). Although our study did not establish causation, the identified subtype-specific correlations suggest that personalized metabolic or dietary interventions tailored to specific phenotypes could complement future pharmacological approaches in ALS management.

Despite these insights, this study has several limitations. First, the retrospective, cross-sectional design limits causal inference. Since the data were extracted from existing clinical records, the analysis has been subject to missing information, unrecorded confounders, and potential selection bias. Therefore, our findings should be viewed as hypothesis-generating rather than confirmatory, pending validation in prospective longitudinal cohorts. Second, the relatively small sample size of the bulbar-onset subgroup (n=30) may have affected the statistical stability of the subtype-specific associations. Given this modest number, the observed trends should be interpreted with caution, as they may reflect random variations rather than robust effects. Nonetheless, the internal consistency across analyses and biological plausibility lend support to the reliability of the main findings. Future studies with larger, multicenter cohorts are required to confirm these subtype-specific metabolic patterns and to assess their generalizability across populations. Finally, our study focused on conventional lipid metrics; future research incorporating advanced lipidomics and longitudinal designs is crucial to unravel the precise temporal dynamics and molecular mechanisms of lipid dysregulation across ALS subtypes.

In conclusion, our study identified dyslipidemia as a prevalent feature of ALS and revealed subtype-specific associations between lipid parameters and functional impairment. These findings suggest that the metabolic pathways differ between bulbar- and limb-onset ALS, reflecting distinct pathophysiological mechanisms. Integrating metabolic profiling into ALS research may improve the prognostic accuracy and support the development of personalized management strategies tailored to each clinical phenotype.