The use of creatine as a neuroprotective agent in Alzheimer’s disease
DOI:
https://doi.org/10.33448/rsd-v14i12.50322Keywords:
Creatine, Neuroprotection, Alzheimer’s disease, Brain bioenergetics, Nutritional supplementation.Abstract
Alzheimer’s disease is a progressive neurodegenerative condition marked by cognitive decline, synaptic loss, and biochemical disturbances associated with beta-amyloid deposition, tau aggregation, and mitochondrial dysfunction. This study aimed to examine, through a narrative literature review, the biochemical mechanisms underlying the use of creatine as an adjunct intervention in the management of Alzheimer’s disease, as well as to evaluate the existing clinical evidence, its methodological limitations, and future research directions. The methodology involved a structured search in the PubMed, SciELO, and ScienceDirect databases for articles published between 2008 and 2025, focusing on experimental studies in animal models and human clinical trials assessing the effects of creatine supplementation in Alzheimer’s disease or related at-risk conditions, such as mild cognitive impairment. The findings indicate that preclinical research reports improvements in mitochondrial function, increased cellular energy stores, reduced excitotoxicity, and modulation of neurotrophic factors following supplementation. Pilot clinical studies suggest feasibility, safety, and potential cognitive benefits in early disease stages, although limitations persist regarding dose standardization, intervention duration, and sample size. Overall, creatine appears to be a promising nutritional intervention with potential to enhance cerebral bioenergetics; however, available evidence remains inconclusive, and rigorous, long-term randomized trials are required to confirm its therapeutic effectiveness.
References
Adhihetty, P. J., & Beal, M. F. (2008). Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseases. NeuroMolecular Medicine, 10(4), 275–290. https://doi.org/10.1007/s12017-008-8034-x
Alzheimer’s Association. (2024). Alzheimer’s disease facts and figures 2024. Alzheimer’s & Dementia. https://www.alz.org
Alzheimer’s Drug Discovery Foundation. (2024). Creatine for Alzheimer’s disease: Clinical evidence update. ADDF.
Bender, A., et al. (2007). Creatine supplementation in Parkinson disease: A randomized controlled trial. Neurology, 67(7), 1262–1264. https://doi.org/10.1212/01.wnl.0000238508.52739.b0
Braak, H., & Braak, E. (1991). Neuropathological stageing of Alzheimer-related changes. Acta Neuropathologica, 82, 239–259. https://doi.org/10.1007/BF00308809
Brasil. Agência Nacional de Vigilância Sanitária. (2018). Resolução RDC nº 243, de 26 de julho de 2018: Requisitos sanitários dos suplementos alimentares. Diário Oficial da União.
Cipriani, G., Dichiarlantonio, L., & Borio, E. (2011). Alzheimer’s disease and neurodegenerative disorders: Historical aspects and new perspectives. Journal of Alzheimer’s Disease, 26(1), 3–12.
Consensus Group on Nutrition and Dementia. (2023). Dietary interventions for cognitive decline: Expert consensus recommendations. Journal of Nutrition and Aging, 27(4), 345–358.
Cummings, J., et al. (2023). Advances in therapeutic development for neurodegenerative diseases. Nature Reviews Drug Discovery, 22, 41–58. https://doi.org/10.1038/s41573-022-00643-0
De Wilde, M. C., et al. (2017). The role and bioavailability of nutrients in the prevention and treatment of Alzheimer’s disease: A systematic review. Journal of Alzheimer’s Disease, 55(4), 1493–1508. https://doi.org/10.3233/JAD-160766
DeTure, M. A., & Dickson, D. W. (2019). The neuropathological diagnosis of Alzheimer’s disease. Molecular Neurodegeneration, 14, 32. https://doi.org/10.1186/s13024-019-0333-5
El Gaamouch, F., et al. (2022). Polyphenols in neurodegenerative diseases: Molecular targets and clinical evidence. Antioxidants, 11(6), 1150. https://doi.org/10.3390/antiox11061150
Ellouze, M., Hamden, K., & Ben Amor, H. (2023). Effects of dietary antioxidants on neurodegenerative diseases: Molecular mechanisms and therapeutic perspectives. Journal of Functional Foods, 99, 105–113.
Gadhave, K., Patil, P., & Bhosale, S. (2024). Possible etiological factors of Alzheimer’s disease: An updated review. Neuroscience Letters, 818, 137–145. https://doi.org/10.1016/j.neulet.2023.137145
Gordji-Nejad, A., et al. (2024). Creatine as a therapeutic target for neurodegenerative diseases: Evidence and challenges. Brain Sciences, 14(1), 91–103.
Insausti, R., & Amaral, D. G. (2004). Hippocampal formation. In G. Paxinos (Ed.), The human nervous system (2nd ed., pp. 871–914). Elsevier Academic Press.
Jack, C. R., Jr., et al. (2018). NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimer’s & Dementia, 14(4), 535–562. https://doi.org/10.1016/j.jalz.2018.02.018
Kovacs, G. G. (2016). Molecular pathological classification of neurodegenerative diseases: Turning towards precision medicine. Acta Neuropathologica, 129(3), 389–408. https://doi.org/10.1007/s00401-016-1605-7
Kreider, R. B., et al. (2017). International Society of Sports Nutrition position stand: Safety and efficacy of creatine supplementation in exercise, sport, and medicine. Journal of the International Society of Sports Nutrition, 14, 18.
Lamptey, R. B., et al. (2022). Neurodegenerative diseases: Risk factors, mechanisms and therapeutic strategies. Biomedicine & Pharmacotherapy, 145, 112–124. https://doi.org/10.1016/j.biopha.2021.112124
Lou, Y., et al. (2023). Nutritional interventions and cognitive decline: An updated systematic review. Nutrients, 15(8), 1856. https://doi.org/10.3390/nu15081856
Malek-Ahmadi, M., et al. (2020). Braak staging and cognitive decline in Alzheimer’s disease. Journal of Alzheimer’s Disease, 78(4), 1487–1495.
McGeer, P. L., & McGeer, E. G. (2011). Neuroinflammation in Alzheimer’s disease and mild cognitive impairment: A field in its infancy. Journal of Alzheimer’s Disease, 19(1), 355–361.
McMorris, T. (2024). Creatine supplementation and cognition: Unresolved questions and research gaps. Nutrients, 16(3), 512–528.
Morris, M. C., et al. (2015). MIND diet slows cognitive decline with aging. Alzheimer’s & Dementia, 11(9), 1015–1022. https://doi.org/10.1016/j.jalz.2015.04.011
Moutinho, S. (2025). Women twice as likely to develop Alzheimer’s disease as men — but scientists do not know why. Nature Medicine, 31, 704–707.
Muddapu, V. R., et al. (2020). Neurodegenerative diseases — A mechanistic overview of common pathways. Frontiers in Neuroscience, 14, 213. https://doi.org/10.3389/fnins.2020.00213
Nucci, A., et al. (2024). Mediterranean diet and neurodegeneration: An updated review. Nutrients, 16(11), 2145.
Ostojic, S. M. (2022). Creatine as a brain energy buffer: Targeting bioenergetic failure in neurodegeneration. Aging and Disease, 13(8), 2036–2048.
Pereira, A. S., et al. (2018). Metodologia da pesquisa científica. [free ebook]. Santa Maria. Editora da UFSM.
Pfrieger, F. W. (2021). Neurodegenerative diseases: Common and divergent pathways toward a shared goal of neuronal dysfunction. Frontiers in Aging Neuroscience, 13, 766587. https://doi.org/10.3389/fnagi.2021.766587
Pless, I., et al. (2023). Progression of Alzheimer pathology: From neuropathological stages to clinical symptoms. Brain Pathology, 33(1), e13067. https://doi.org/10.1111/bpa.13067
Rae, C., et al. (2014). Oral creatine monohydrate supplementation improves brain performance: A double-blind, placebo-controlled, cross-over trial. Proceedings of the Royal Society B: Biological Sciences, 281(1780), 2014–2140. https://doi.org/10.1098/rspb.2014.2140
Ramsay, A., et al. (2024). Creatine to augment bioenergetics in Alzheimer’s (CABA): Protocol for a single-arm pilot trial. Alzheimer’s & Dementia: Translational Research & Clinical Interventions, 10(1), e12498. https://doi.org/10.1002/trc2.12498
Rother, E. T. (2007). Revisão sistemática x revisão narrativa. Acta Paulista de Enfermagem, 20(2), 5–6.
Scheltens, P., et al. (2021). Alzheimer’s disease. The Lancet, 397(10284), 1577–1590.
Smith, R. A. (2023). Creatine supplementation and cognitive function: Current evidence and future directions. Journal of Neurochemistry, 166(4), 512–528.
Smith, R. A., et al. (2025). The role of creatine metabolism in neurodegenerative disorders: Translational insights. Nutrients, 17(2), 310–322.
Soininen, H., et al. (2021). Nutritional strategies for Alzheimer’s disease: A comprehensive review. Ageing Research Reviews, 70, 101–124. https://doi.org/10.1016/j.arr.2021.101124
Turner, C. E., Miller, A. L., & Wilson, M. A. (2023). Bioenergetic interventions in Alzheimer’s disease: Evaluating creatine through neuroimaging and metabolic biomarkers. Journal of Neurodegenerative Research, 45(2), 112–128.
Van der Velpen, I., et al. (2018). Systematic review and meta-analysis of circulating inflammatory biomarkers in Alzheimer’s disease. Alzheimer’s & Dementia, 14(8), 993–1011. https://doi.org/10.1016/j.jalz.2018.02.002
Wei, Z., et al. (2023). Dietary patterns and risk of Alzheimer’s disease: A meta-analysis. Nutrition Reviews, 81(6), 701–718.
Wang, X., et al. (2021). Molecular mechanisms underlying Alzheimer’s disease and potential biomarkers. Reviews in the Neurosciences, 32(6), 563–579. https://doi.org/10.1515/revneuro-2021-0030
Xu, Y., et al. (2024). Creatine supplementation as a potential therapeutic strategy in Alzheimer’s disease: Bioenergetic and neuroprotective perspectives. Frontiers in Neuroscience, 18, 145–162.
Yiannopoulou, K. G., & Papageorgiou, S. G. (2023). Current pharmacological treatments for Alzheimer’s disease. Journal of Central Nervous System Disease.
Zhang, C., et al. (2024). New and emerging drug therapies for Alzheimer disease. CNS Drugs, 38, 213–230. https://doi.org/10.1007/s40263-024-01083
Zhang, J., et al. (2024). Recent advances in Alzheimer’s disease: Mechanisms and therapeutic strategies. Signal Transduction and Targeted Therapy.
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