Ketogenic Metabolism in Neurodegenerative Diseases: Mechanisms of Action and Therapeutic Potential
Abstract
1. Introduction
1.1. Neurodegenerative Disorders: Shared Mechanisms
1.2. Ketogenic Metabolism and Neuroprotection
1.3. Aims of the Review
2. Ketone Bodies and Brain Metabolism
2.1. Ketogenesis and Ketone Bodies
2.2. Energy Utilization in the Brain
2.3. Metabolic and Epigenetic Effects
3. Mechanisms of Neuroprotection
3.1. Mitochondrial Enhancement and Oxidative Stress Reduction
3.2. Anti-Inflammatory and Immunomodulatory Effects
3.3. Effects on Neurotransmission and Synaptic Plasticity
3.4. Limitations of Animal Models in Translational Research
4. Clinical and Experimental Evidence
4.1. Experimental Evidence on Ketogenic Interventions in Alzheimer’s Disease
4.2. Clinical Studies on the Ketogenic Diet in Alzheimer’s Disease
4.3. Experimental Evidence on Ketogenic Interventions in Parkinson’s Disease
4.4. Clinical Studies on the Ketogenic Diet in Parkinson’s Disease
4.5. Ketogenic Strategies in Amyotrophic Lateral Sclerosis: Preclinical and Clinical Evidence
Disorders | Study Groups | Intervention | Results | Study |
---|---|---|---|---|
Alzheimer’s disease | 152 mild-to-moderate AD patients | oral ketogenic compound AC-1202 | improved cognitive outcomes in APOE4 patients; no benefit in APOE4+ carriers | Henderson et al. [105] |
Alzheimer’s disease | 26 patients with probable AD | modified ketogenic diet vs. usual diet (crossover design) | improved daily function and quality of life; no significant cognitive improvement; mild adverse effects | Phillips et al. [97] |
Alzheimer’s disease | 83 patients with mild-to-moderate AD | ketogenic MCT drink vs. placebo | significant improvements in verbal fluency, naming, and executive function tests | Fortier et al. [135] |
Alzheimer’s disease | MCI or early-stage AD | Modified Atkins Diet | improved episodic memory (Memory Composite Score) in participants achieving ketosis; increased energy levels; feasibility limited by adherence challenges | Brandt et al. [100] |
Alzheimer’s disease | 413 patients with Mild-to-Moderate AD | AC-1204 | no improvement in cognitive and functional abilities in people with mild to moderate AD | Henderson et al. [96] |
Parkinson’s disease | 14 PD patients | ketogenic diet vs. high-carbohydrate diet | enhanced cognitive performance | Krikorian et al. [116] |
Parkinson’s disease | 7 PD patients | low-carbohydrate vs. healthy fat vs. ketogenic diet | enhanced cognition, mood, motor and nonmotor symptoms, and reduced pain and anxiety | Tidman et al. [118] |
Parkinson’s disease | 16 PD patients | LCHF diet | improved scores on the PAS anxiety scale, no improvements on the CESD-R-20 scale for symptoms of depression in the 12 weeks, positive trends for reducing overall PD symptoms, improving biomarkers of chronic disease, and reducing anxiety in persons with PD | Tidman et al. [117] |
Parkinson’s disease | 16 PD patients | medium-chain triglyceride-supplemented ketogenic diet | no significant improvement in motor and mobility results compared to the standard diet | Choi et al. [111] |
Parkinson’s disease | 68 PD patients | ketogenic diet | improved VHI parameters | Koyuncu et al. [119] |
Parkinson’s disease | 47 PD patients | modified ketogenic diet | improved non-motor symptoms (especially urinary problems, pain, fatigue, daytime sleepiness), improved cognitive impairment | Phillips et al. [115] |
Parkinson’s disease | 7 PD patients | ketogenic diet | improved motor scores | VanItallie et al. [136] |
Amyotrophic Lateral Sclerosis | 40 ALS patients | Mediterranean diet + coconut oil | benefits at the anthropometric level: increased percentage of muscle mass and decreased percentage of fat mass and abdominal skin folds compared to the control diet | Carrera-Juliá et al. [131] |
Mild Cognitive Impairment | 23 older adults with MCI | ketogenic diet | improved verbal memory performance | Krikorian et al. [137] |
Mild Cognitive Impairment | 39 participants with MCI completed | 6-month ketogenic medium-chain triglyceride supplement | minimal effects on circulating cardiometabolic and inflammatory markers, aside from a significant increase in plasma IL-8 levels of unclear clinical significance | Myette-Côté et al. [101] |
5. Therapeutic Approaches and Translational Potential
5.1. Ketogenic Diet vs. Exogenous Ketone Supplements
5.2. Potential for Combined Interventions
5.3. Barriers to Implementation
5.4. Interpretation Challenges Due to Protocol Heterogeneity
6. Limitations and Future Directions
6.1. Evidence Gaps and Methodological Issues
6.2. Personalized Approaches
6.3. Suggested Future Research
6.4. Safety Considerations and Population-Specific Risk
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
6-OHDA | 6-hydroxydopamine |
Aβ | amyloid β |
AC-1202 | medium-chain triglyceride composed of glycerin and caprylic acid |
AC-1204 | caprylic triglyceride |
AcAc | acetoacetate |
AD | Alzheimer’s disease |
ALS | amyotrophic lateral sclerosis |
APOE4 | epsilon 4 variant of the apolipoprotein E gene |
BBB | blood–brain barrier |
BDH1 | β-hydroxybutyrate dehydrogenase 1 |
BH4 | tetrahydrobiopterin-4 |
BHB | β-hydroxybutyrate |
BMI | body mass index |
CESD-R-20 | The Centre for Epidemiological Studies Depression Scale |
COX-2 | cyclooxygenase-2 |
DP | the Deanna Protocol |
ETC | electron transport chain |
FA | fatty acid |
GABA | gamma-aminobutyric acid |
GFAP | glial fibrillary acidic protein |
HMG-CoA | hydroxymethylglutaryl-CoA |
HMGCS2 | 3-hydroxy-3-methylglutaryl-CoA synthase 2 |
HNE | 4-hydroxy-2,3-nonenal |
Iba1 | ionized calcium-binding adaptor molecule 1 |
IGF-1 | insulin-like growth factor 1 |
KBs | ketone bodies |
KD | ketogenic diet |
KEED | ketone ester-enriched diet |
LCFA | long-chain fatty acid |
LCHF diet | low-carb, high-fat diet |
MCI | mild cognitive impairment |
MCT | a ketogenic drink containing medium-chain triglycerides |
MMKD | modified Mediterranean-ketogenic diet |
MDS-UPDRS | Movement Disorder Society Unified Parkinson’s Disease Rating Scale |
mPT | mitochondrial permeability complex |
MT2 | metallothionein 2 |
NF-κB | nuclear factor kappa-light-chain-enhancer of activated B cells |
NM | Nishimura Geriatric Rating Scale for Mental Status |
NLRP3 | nucleotide-binding domain, leucine-rich repeat, and pyrin domain containing protein 3 (inflammasome) |
OAA | oxaloacetate |
OS | oxidative stress |
PAS | Parkinson Anxiety Scale |
PD | Parkinson’s disease |
PGC-1α | peroxisome proliferator-activated receptor gamma coactivator 1-alpha |
ROS | reactive oxygen species |
RNS | reactive nitrogen species |
rCBF | regional cerebral blood flow |
SCFA | short-chain fatty acid |
SCOT | succinyl-CoA:3-oxoacid CoA transferase |
SOD2 | superoxide dismutase 2 |
TCA | tricarboxylic acid |
TH | tyrosine hydroxylase |
TNF-α | tumor necrosis factor alpha |
Tregs | regulatory T cells |
TUG | Timed Up & Go test |
VHI | Voice Handicap Index |
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Pawłowska, M.; Kruszka, J.; Porzych, M.; Garbarek, J.; Nuszkiewicz, J. Ketogenic Metabolism in Neurodegenerative Diseases: Mechanisms of Action and Therapeutic Potential. Metabolites 2025, 15, 508. https://doi.org/10.3390/metabo15080508
Pawłowska M, Kruszka J, Porzych M, Garbarek J, Nuszkiewicz J. Ketogenic Metabolism in Neurodegenerative Diseases: Mechanisms of Action and Therapeutic Potential. Metabolites. 2025; 15(8):508. https://doi.org/10.3390/metabo15080508
Chicago/Turabian StylePawłowska, Marta, Joanna Kruszka, Marta Porzych, Jakub Garbarek, and Jarosław Nuszkiewicz. 2025. "Ketogenic Metabolism in Neurodegenerative Diseases: Mechanisms of Action and Therapeutic Potential" Metabolites 15, no. 8: 508. https://doi.org/10.3390/metabo15080508
APA StylePawłowska, M., Kruszka, J., Porzych, M., Garbarek, J., & Nuszkiewicz, J. (2025). Ketogenic Metabolism in Neurodegenerative Diseases: Mechanisms of Action and Therapeutic Potential. Metabolites, 15(8), 508. https://doi.org/10.3390/metabo15080508