THE IMPACT OF REGULAR PHYSICAL ACTIVITY ON DELAYING THE ONSET OF ALZHEIMER’S DISEASE: A REVIEW OF NEUROPROTECTIVE MECHANISMS
DOI:
https://doi.org/10.31435/ijitss.1(49).2026.4942Keywords:
Alzheimer's Disease, Physical Activity, Exercise, Neuroprotection, BDNF, Cognitive Decline, Amyloid-Beta, Tau ProteinAbstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by memory impairment, cognitive deterioration, and neurobiological changes, notably the accumulation of amyloid-beta (Aβ) and tau pathology. Recent data suggests that consistent physical activity (PA) may delay the onset and progression of Alzheimer's disease (AD) through various neuroprotective mechanisms. This research synthesizes results from 31 contemporary investigations encompassing both human and animal subjects. The focus is on the impact of physical activity on brain-derived neurotrophic factor (BDNF) expression, cerebral blood flow, inflammation reduction, and proteinopathy management. Brain-Derived Neurotrophic Factor (BDNF) is crucial for maintaining synaptic plasticity and promoting neurogenesis in the hippocampus, both of which are significantly compromised in Alzheimer's Disease (AD). PA-induced elevations in BDNF enhance cognitive resilience and neuronal integrity. Furthermore, exercise has been shown to enhance cerebral perfusion, so improving the delivery of oxygen and nutrients while promoting the disposal of waste, including glymphatic flow. The anti-inflammatory effects of PA entail the downregulation of pro-inflammatory cytokines (e.g., IL-6, TNF-α) and the upregulation of anti-inflammatory mediators, which alleviate chronic neuroinflammation commonly seen in Alzheimer's disease. Furthermore, PA appears to reduce oxidative stress by enhancing innate antioxidant systems, including superoxide dismutase and glutathione peroxidase. PA may significantly affect essential pathophysiological features of AD, such as amyloid-beta buildup and tau hyperphosphorylation, by promoting proteostasis and stimulating autophagy. Research from both preclinical and clinical studies repeatedly reveals associations between regular physical activity and improved cognitive function, augmented brain structural integrity, and less neurodegeneration. The data indicate that physical activity serves as a cost-effective, accessible, and non-pharmacological intervention with significant neuroprotective potential to reduce the risk of Alzheimer's disease and delay its development.
References
Cutuli, D., Decandia, D., Giacovazzo, G., & Coccurello, R. (2023). Physical exercise as disease-modifying alternative against Alzheimer's disease: A gut-muscle-brain partnership. International Journal of Molecular Sciences, 24(19), 14686. https://doi.org/10.3390/ijms241914686
Khemka, S., Reddy, A., Garcia, R. I., Jacobs, M., Reddy, R. P., Roghani, A. K., Pattoor, V., Basu, T., Sehar, U., & Reddy, P. H. (2023). Role of diet and exercise in aging, Alzheimer's disease, and other chronic diseases. Ageing Research Reviews, 91, 102091. https://doi.org/10.1016/j.arr.2023.102091
López-Ortiz, S., Pinto-Fraga, J., Valenzuela, P. L., Martín-Hernández, J., Seisdedos, M. M., García-López, O., Toschi, N., Di Giuliano, F., Garaci, F., Mercuri, N. B., Nisticò, R., Emanuele, E., Lista, S., Lucia, A., & Santos-Lozano, A. (2021). Physical exercise and Alzheimer's disease: Effects on pathophysiological molecular pathways of the disease. International Journal of Molecular Sciences, 22(6), 2897. https://doi.org/10.3390/ijms22062897
Radić, B., Blažeković, A., Duraković, D., Jurišić-Kvesić, A., Bilić, E., & Borovečki, F. (2021). Could mental and physical exercise alleviate Alzheimer's disease? Psychiatria Danubina, 33(Suppl. 4), 1267–1273.
Autio, J., Stenbäck, V., Gagnon, D. D., Leppäluoto, J., & Herzig, K.-H. (2020). (Neuro) peptides, physical activity, and cognition. Journal of Clinical Medicine, 9(8), 2592. https://doi.org/10.3390/jcm9082592
Cutuli, D., Decandia, D., Giacovazzo, G., & Coccurello, R. (2023). Physical exercise as disease-modifying alternative against Alzheimer's disease: A gut-muscle-brain partnership. International Journal of Molecular Sciences, 24(19), 14686. https://doi.org/10.3390/ijms241914686
Gaitán, J. M., Moon, H. Y., Stremlau, M., Dubal, D. B., Cook, D. B., Okonkwo, O. C., & van Praag, H. (2021). Effects of aerobic exercise training on systemic biomarkers and cognition in late middle-aged adults at risk for Alzheimer's disease. Frontiers in Endocrinology, 12, 660181. https://doi.org/10.3389/fendo.2021.660181
Quan, H., Koltai, E., Suzuki, K., Aguiar, A. S., Jr., Pinho, R., Boldogh, I., Berkes, I., & Radak, Z. (2020). Exercise, redox system and neurodegenerative diseases. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1866(10), 165778. https://doi.org/10.1016/j.bbadis.2020.165778
Belaya, I., Kucháriková, N., Górová, V., Kysenius, K., Hare, D. J., Crouch, P. J., Malm, T., Atalay, M., White, A. R., Liddell, J. R., & Kanninen, K. M. (2021). Regular physical exercise modulates iron homeostasis in the 5xFAD mouse model of Alzheimer's disease. International Journal of Molecular Sciences, 22(16), 8715. https://doi.org/10.3390/ijms22168715
Zhao, R. (2024). Exercise mimetics: A novel strategy to combat neuroinflammation and Alzheimer's disease. Journal of Neuroinflammation, 21(1), 40. https://doi.org/10.1186/s12974-024-03031-9
Pape, S. E., Baksh, R. A., Startin, C., Hamburg, S., Hithersay, R., & Strydom, A. (2021). The association between physical activity and CAMDEX-DS changes prior to the onset of Alzheimer's disease in Down syndrome. Journal of Clinical Medicine, 10(9), 1882. https://doi.org/10.3390/jcm10091882
Ren, J., & Xiao, H. (2023). Exercise intervention for Alzheimer's disease: Unraveling neurobiological mechanisms and assessing effects. Life, 13(12), 2285. https://doi.org/10.3390/life13122285
Pinho, R. A., Muller, A. P., Marqueze, L. F., Radak, Z., & Arida, R. M. (2024). Physical exercise-mediated neuroprotective mechanisms in Parkinson's disease, Alzheimer's disease, and epilepsy. Brazilian Journal of Medical and Biological Research, 57, e14094. https://doi.org/10.1590/1414-431X2024e14094
Devanand, D. P., Masurkar, A. V., & Wisniewski, T. (2023). Vigorous, regular physical exercise may slow disease progression in Alzheimer's disease. Alzheimer's & Dementia, 19(4), 1592–1597. https://doi.org/10.1002/alz.12946
Xu, L., Liu, R., Qin, Y., & Wang, T. (2023). Brain metabolism in Alzheimer's disease: Biological mechanisms of exercise. Translational Neurodegeneration, 12(1), 33. https://doi.org/10.1186/s40035-023-00364-y
Ribarič, S. (2022). Physical exercise, a potential non-pharmacological intervention for attenuating neuroinflammation and cognitive decline in Alzheimer's disease patients. International Journal of Molecular Sciences, 23(6), 3245. https://doi.org/10.3390/ijms23063245
Clemente-Suárez, V. J., Rubio-Zarapuz, A., Belinchón-deMiguel, P., Beltrán-Velasco, A. I., Martín-Rodríguez, A., & Tornero-Aguilera, J. F. (2024). Impact of physical activity on cellular metabolism across both neurodegenerative and general neurological conditions: A narrative review. Cells, 13(23), 1940. https://doi.org/10.3390/cells13231940
Ruiz-González, D., Hernández-Martínez, A., Valenzuela, P. L., Morales, J. S., & Soriano-Maldonado, A. (2021). Effects of physical exercise on plasma brain-derived neurotrophic factor in neurodegenerative disorders: A systematic review and meta-analysis of randomized controlled trials. Neuroscience & Biobehavioral Reviews, 128, 394–405. https://doi.org/10.1016/j.neubiorev.2021.05.025
Cantón-Suárez, A., Sánchez-Valdeón, L., Bello-Corral, L., Cuevas, M. J., & Estébanez, B. (2024). Understanding the molecular impact of physical exercise on Alzheimer's disease. International Journal of Molecular Sciences, 25(24), 13576. https://doi.org/10.3390/ijms252413576
Stojanovic, M., Jin, Y., Fagan, A. M., Benzinger, T. L., Hassenstab, J., Cruchaga, C., Morris, J. C., & Head, D. (2020). Physical exercise and longitudinal trajectories in Alzheimer disease biomarkers and cognitive functioning. Alzheimer Disease & Associated Disorders, 34(3), 212–219. https://doi.org/10.1097/WAD.0000000000000385
Sanchez-Martinez, J., Solis-Urra, P., Olivares-Arancibia, J., & Plaza-Diaz, J. (2024). Physical exercise and mechanism related to Alzheimer's disease: Is gut-brain axis involved? Brain Sciences, 14(10), 974. https://doi.org/10.3390/brainsci14100974
Bagit, A., Hayward, G. C., & MacPherson, R. E. K. (2021). Exercise and estrogen: Common pathways in Alzheimer's disease pathology. American Journal of Physiology-Endocrinology and Metabolism, 321(1), E164–E168. https://doi.org/10.1152/ajpendo.00008.2021
Jaberi, S., & Fahnestock, M. (2023). Mechanisms of the beneficial effects of exercise on brain-derived neurotrophic factor expression in Alzheimer's disease. Biomolecules, 13(11), 1577. https://doi.org/10.3390/biom13111577
Mahalakshmi, B., Maurya, N., Lee, S. D., & Bharath Kumar, V. (2020). Possible neuroprotective mechanisms of physical exercise in neurodegeneration. International Journal of Molecular Sciences, 21(16), 5895. https://doi.org/10.3390/ijms21165895
Arciero, P. J., Grasso, P., Anderson-Hanley, C., & Zimmerman, E. (2023). Editorial: How does exercise modify the course of Alzheimer's disease? Frontiers in Aging Neuroscience, 15, 1127747. https://doi.org/10.3389/fnagi.2023.1127747
Baranowski, B. J., Mohammad, A., Finch, M. S., Brown, A., Dhaliwal, R., Marko, D. M., LeBlanc, P. J., McCormick, C. M., Fajardo, V. A., & MacPherson, R. E. K. (2023). Exercise training and BDNF injections alter amyloid precursor protein (APP) processing enzymes and improve cognition. Journal of Applied Physiology, 135(1), 121–135. https://doi.org/10.1152/japplphysiol.00114.2023
Baranowski, B. J., Marko, D. M., Fenech, R. K., Yang, A. J. T., & MacPherson, R. E. K. (2020). Healthy brain, healthy life: A review of diet and exercise interventions to promote brain health and reduce Alzheimer's disease risk. Applied Physiology, Nutrition, and Metabolism, 45(10), 1055–1065. https://doi.org/10.1139/apnm-2019-0910
Zhao, N., Xia, J., & Xu, B. (2021). Physical exercise may exert its therapeutic influence on Alzheimer's disease through the reversal of mitochondrial dysfunction via SIRT1-FOXO1/3-PINK1-Parkin-mediated mitophagy. Journal of Sport and Health Science, 10(1), 1–3. https://doi.org/10.1016/j.jshs.2020.08.009
Barros-Aragão, F. G. Q., Januszkiewicz, E., Hunter, T., Lyra e Silva, N. M., & De Felice, F. G. (2025). Physical activity in Alzheimer's disease prevention: Sex differences and the roles of BDNF and irisin. Frontiers in Neuroendocrinology, 77, 101189. https://doi.org/10.1016/j.yfrne.2025.101189
Jodeiri Farshbaf, M., & Alviña, K. (2021). Multiple roles in neuroprotection for the exercise derived myokine irisin. Frontiers in Aging Neuroscience, 13, 649929. https://doi.org/10.3389/fnagi.2021.649929
Qi, J. Y., Yang, L. K., Wang, X. S., Wang, M., Li, X. B., Feng, B., Wu, Y. M., Zhang, K., & Liu, S. B. (2022). Irisin: A promising treatment for neurodegenerative diseases. Neuroscience, 498, 289–299. https://doi.org/10.1016/j.neuroscience.2022.07.018
Scheltens, P., De Strooper, B., Kivipelto, M., Holstege, H., Chételat, G., Teunissen, C. E., Cummings, J., & van der Flier, W. M. (2021). Alzheimer's disease. The Lancet, 397(10284), 1577–1590. https://doi.org/10.1016/S0140-6736(20)32205-4
Breijyeh, Z., & Karaman, R. (2020). Comprehensive review on Alzheimer's disease: Causes and treatment. Molecules, 25(24), 5789. https://doi.org/10.3390/molecules25245789
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Luiza Łabuzińska, Laura Magdalena Sikorska, Paulina Pudło, Anna Koman, Martyna Bukowiec, Karolina Szałata, Mikołaj Asztabski
This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.
How to Cite
