Exploring Early Neurodegeneration Through Fasting-Induced Metabolic Signatures and High-Sensitivity Biomarkers
Abstract
1. Introduction
2. Metabolic Foundations of Intermittent Fasting
3. Metabolic Signatures of Fasting as Modulators of Early Neurodegenerative Biomarkers
4. Metabolic and Neuroinflammatory Pathways in Early Neurodegeneration
5. Plasma and CSF Biomarkers for Early Neurodegeneration
6. Do Fasting-Induced Metabolic Mediators Measurably Modify Plasma/CSF Biomarkers?
7. Metabolic, Molecular, and Clinical Effects of IF
8. Future Directions in IF: Biomarkers and Precision Neuro-Nutrition
9. IF Clinical Considerations: Safety and Contraindications
10. Limitations and Evidence Gaps
11. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
| AD | Alzheimer’s disease |
| ADF | Alternate-Day Fasting |
| AI | Artificial Intelligence |
| Aβ | Amyloid-beta |
| Aβ42/Aβ40 | Amyloid-beta 42/amyloid-beta 40 ratio |
| AMPK | AMP-activated protein kinase |
| AT(N) | Amyloid/tau/neurodegeneration framework |
| BDNF | Brain-derived Neurotrophic Factor |
| BHB | β-hydroxybutyrate |
| CSF | Cerebrospinal Fluid |
| DALYs | Disability-adjusted life years |
| GABA | Gamma-aminobutyric acid |
| GAP-43 | Growth-associated protein 43 |
| GFAP | Glial Fibrillary Acidic Protein |
| GH | Growth hormone |
| hFABP | Heart-type fatty acid-binding protein |
| IF | Intermittent Fasting |
| IGF-1 | Insulin-like Growth Factor 1 |
| IL-6 | Interleukin-6 |
| MAPK | Mitogen-activated protein kinase |
| MCP-1 | Monocyte chemoattractant protein-1 |
| MCI | Mild Cognitive Impairment |
| mTOR | Mechanistic Target of Rapamycin |
| NDs | Neurodegenerative diseases |
| NF-κB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
| NfL | Neurofilament light chain |
| PD | Parkinson’s disease |
| PI3K/Akt | Phosphoinositide 3-kinase/protein kinase B |
| p-Tau | Phosphorylated tau |
| p-Tau181 | Phosphorylated tau at threonine 181 |
| p-Tau217 | Phosphorylated tau at threonine 217 |
| p-Tau231 | Phosphorylated tau at threonine 231 |
| RCTs | Randomised controlled trials |
| ROS | Reactive oxygen species |
| SCFAs | Short-Chain Fatty Acids |
| S100B | S100 calcium-binding protein B |
| SIRT1 | Sirtuin 1 |
| SIRT3 | Sirtuin 3 |
| SNAP-25 | Synaptosomal-Associated Protein 25 |
| sTREM2 | Soluble triggering receptor expressed on myeloid cells 2 |
| TDP-43 | TAR DNA-binding protein 43 |
| t-Tau | Total tau |
| TREM2 | Triggering receptor expressed on myeloid cells 2 |
| TRF | Time-restricted Feeding |
| UCH-L1 | Ubiquitin C-terminal hydrolase L1 |
| VRF | Visceral fat ratio |
| VILIP-1 | Visinin-like protein 1 |
| YKL-40 | Chitinase-3-like protein 1 |
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| Pathological Domain | Biomarker(s) | Biofluid(s) | Main Pathological Process Captured | Clinical/Research Use in Early Disease |
|---|---|---|---|---|
| Amyloid pathology | Aβ42 Aβ42/Aβ40 ratio | CSF, plasma | Amyloid-β production/clearance imbalance | Identification of amyloidosis; inclusion in multimarker panels for early AD diagnosis |
| Tau pathology | p-Tau181 p-Tau217 p-Tau231 | CSF, plasma | Tau phosphorylation, tangle formation, neuronal injury | Discrimination of AD vs. controls and non-AD dementias; staging along AT(N) framework |
| t-Tau | CSF | Neurodegeneration | Marker of neuronal injury and disease severity | |
| Neurodegeneration | NfL hFABP | CSF, plasma | Axonal injury and neurodegeneration | Sensitive markers of neuronal damage; prognosis and disease monitoring across AD and non-AD dementias |
| VILIP-1 | CSF | Neuronal calcium-mediated injury | Marker associated with neuronal damage and disease progression | |
| Astroglial activation | GFAP | CSF, plasma | Astrocyte reactivity and astrogliosis | Early marker of amyloid-driven astroglial response; prediction of progression in preclinical and prodromal AD |
| Synaptic dysfunction | SNAP-25 Neurogranin Progranulin GAP-43 | CSF | Synaptic loss and dysfunction | Early indication of synaptic damage; improved discrimination between controls and preclinical AD when combined with tau markers |
| BDNF | CSF, plasma | Neurotrophic signalling and synaptic plasticity | Exploratory marker of synaptic plasticity and neurotrophic support; currently less established than SNAP-25 and neurogranin | |
| Neuroinflammation | YKL-40 sTREM2 S100B | CSF | Microglial and astroglial activation, inflammatory signalling | Association with imaging measures of neurodegeneration; under evaluation for routine diagnostic use |
| IL-6 MCP-1 | CSF, plasma | Cytokine-mediated inflammatory signalling | Investigational markers of neuroinflammatory activation | |
| Proteinopathy (non-AT(N) axis) | TDP-43 | CSF (experimental) | TDP-43 protein aggregation | Emerging biomarker of TDP-43 proteinopathy; CSF detection remains experimental and assays are not yet standardised |
| Reference | Intermittent Fasting Protocol | Main Outcomes | Molecular/Biological Mechanisms |
|---|---|---|---|
| Brocchi et al., 2022 [33] | Various IF regimens (TRF, ADF) | Improved insulin sensitivity, lipid metabolism and body composition | Improved insulin signalling and mitochondrial efficiency, associated with brain energy metabolism and neuroprotection |
| Brandhorst et al., 2015 [34] | Periodic fasting-mimicking cycles | Reduced IGF-1 levels, improved metabolic markers | Enhanced cellular stress resistance, regeneration and improved cognitive performance |
| Joaquim et al., 2022 [35] | IF strategies | Improved glycaemic control and metabolic flexibility | Reduced inflammatory markers and improved metabolic regulation |
| Silva et al., 2023 [36] | Different IF regimens | Body weight reduction and improved metabolic homeostasis | Regulation of metabolic pathways associated with glucose metabolism and insulin signalling |
| Punyatoya et al., 2025 [77] | Various IF regimens | Improved glycaemic control, reduced HbA1c, weight loss and improved insulin sensitivity | Enhanced insulin signalling, reduced oxidative stress, circadian rhythm regulation and improved metabolic flexibility |
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Cacciabaudo, F.; Agnello, L.; Gambino, C.M.; Accardi, G.; Masucci, A.; Tamburello, M.; Vassallo, R.; Ciaccio, M. Exploring Early Neurodegeneration Through Fasting-Induced Metabolic Signatures and High-Sensitivity Biomarkers. Curr. Issues Mol. Biol. 2026, 48, 358. https://doi.org/10.3390/cimb48040358
Cacciabaudo F, Agnello L, Gambino CM, Accardi G, Masucci A, Tamburello M, Vassallo R, Ciaccio M. Exploring Early Neurodegeneration Through Fasting-Induced Metabolic Signatures and High-Sensitivity Biomarkers. Current Issues in Molecular Biology. 2026; 48(4):358. https://doi.org/10.3390/cimb48040358
Chicago/Turabian StyleCacciabaudo, Francesco, Luisa Agnello, Caterina Maria Gambino, Giulia Accardi, Anna Masucci, Martina Tamburello, Roberta Vassallo, and Marcello Ciaccio. 2026. "Exploring Early Neurodegeneration Through Fasting-Induced Metabolic Signatures and High-Sensitivity Biomarkers" Current Issues in Molecular Biology 48, no. 4: 358. https://doi.org/10.3390/cimb48040358
APA StyleCacciabaudo, F., Agnello, L., Gambino, C. M., Accardi, G., Masucci, A., Tamburello, M., Vassallo, R., & Ciaccio, M. (2026). Exploring Early Neurodegeneration Through Fasting-Induced Metabolic Signatures and High-Sensitivity Biomarkers. Current Issues in Molecular Biology, 48(4), 358. https://doi.org/10.3390/cimb48040358

