ORIGINAL RESEARCH article
Front. Hum. Neurosci.
Sec. Brain Health and Clinical Neuroscience
Volume 19 - 2025 | doi: 10.3389/fnhum.2025.1598495
Serum Lipidomic Analysis Identifies Potential Therapeutic Targets for Neurodegeneration
Provisionally accepted
- 1Wenzhou Hospital of Traditional Chinese Medicine, Wenzhou, Zhejiang Province, China
- 2Zhejiang University, Hangzhou, Zhejiang Province, China
- 3First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
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Serum lipidomic profiles may offer insights into potential therapeutic targets for neurodegeneration prevention, yet specific lipid species with neuroprotective properties remain incompletely characterized. This cross-sectional investigation examined associations between circulating fatty acid profiles, with particular emphasis on very-long-chain saturated fatty acids (VLSFAs), and neurodegeneration (assessed by serum neurofilament light chain, NfL) in 1677 US adults from NHANES 2013-2014. Mixture modeling and mediation analyses including weighted quantile sum regression, Bayesian kernel machine regression, quantile g-computation, and mediation analyses were employed to elucidate these relationships. Lipidomic analysis identified VLSFAs as demonstrating significant inverse associations with serum NfL (β=-0.044, 95%CI:-0.076,-0.011) and hypertension (OR=0.788, 95%CI:0.672,0.923). The inverse association between VLSFAs and NfL exhibited non-linearity, with more pronounced effects observed at lower VLSFA concentrations, suggesting a potential threshold effect relevant for targeted interventions. Higher VLSFA concentrations were significantly associated with better cognitive performance, particularly in processing speed (Digit-Symbol Substitution Test, DSST) and memory (delayed recall) domains. Hypertension was positively associated with NfL (β=4.133, 95%CI:1.705,6.562), with systolic blood pressure demonstrating a stronger relationship than diastolic blood pressure. Mediation analysis revealed that hypertension mediated approximately 15-20% of the indirect effects between VLSFAs and NfL. These findings identify circulating VLSFAs as potential therapeutic targets for neurodegeneration, demonstrating inverse associations with the neurodegenerative biomarker NfL and positive correlations with cognitive performance. The neuroprotective associations of VLSFAs may be partially mediated through blood pressure regulation pathways, highlighting a potential mechanism through which these lipid species may influence neurological health.
Keywords: VLSFA, NFL, neurodegeneration, Hypertension, NHANES
Received: 23 Mar 2025; Accepted: 02 Jun 2025.
Copyright: © 2025 Zhang, Li, Zhao and Peng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Lumi Zhang, Wenzhou Hospital of Traditional Chinese Medicine, Wenzhou, Zhejiang Province, China
Na Zhao, Wenzhou Hospital of Traditional Chinese Medicine, Wenzhou, Zhejiang Province, China
Guoping Peng, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang Province, China
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