Synergistic Effects of Combined Aerobic and Resistance Exercise on Cognitive Decline and Alzheimer's Disease Biomarkers in Middle-Aged Populations: A Systematic Review

Azadeh Naderi; Peyman Mazaheri; Parnian Sief; Emre Serin

Authors

Azadeh Naderi Department of Physical Education, Technical and Vocational University (TVU), Tehran, Iran https://orcid.org/0000-0001-9596-2912
Peyman Mazaheri Department of Physical Education, Bo.c., Islamic Azad University, Borujerd, Iran https://orcid.org/0000-0001-9596-2912
Parnian Sief Department of Physical Education, Bo.c., Islamic Azad University, Borujerd, Iran https://orcid.org/0000-0001-9596-2912
Emre Serin Department of Coaching Education, Mersin University, Mersin, Türkiye https://orcid.org/0000-0001-9596-2912

Keywords:

Combined exercise, alzheimer’s prevention, neural resilience, blood biomarker, midlife

Abstract

This systematic review aimed to compare the specific effects and efficacy of aerobic, resistance, and combined exercise interventions on Alzheimer's Disease (AD)-related biomarkers and cognitive function in middle-aged adults (2020-2024). A comprehensive search was conducted in major scientific databases following a pre-registered protocol. Forty-two studies (including 24 randomized controlled trials, 10 cohort studies, and 8 non-randomized trials) with a total of 11,420 participants met the inclusion criteria. Aerobic exercise selectively enhanced brain-derived neurotrophic factor (BDNF) levels, hippocampal volume, and episodic memory. Resistance exercise markedly reduced systemic inflammation, increased prefrontal cortex thickness, and improved executive functions. Combined programs demonstrated a potent synergistic effect, yielding the greatest improvement across all domains, including plasma amyloid-beta (Aβ42) reduction. Aerobic and resistance exercise exert complementary effects on brain health through distinct mechanisms. A structured combined exercise regimen represents the most potent non-pharmacological intervention for enhancing neural resilience and modulating AD risk factors during the critical midlife period.

References

Ahlskog, J. E., Geda, Y. E., Graff-Radford, N. R., & Petersen, R. C. (2011). Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clinic Proceedings, 86(9), 876-884.

Baker, L. D., Frank, L. L., Foster-Schubert, K., Green, P. S., Wilkinson, C. W., McTiernan, A., ... & Craft, S. (2010). Effects of aerobic exercise on mild cognitive impairment: A randomized controlled trial. Archives of Neurology, 67(1), 71-79.

Barnes, D. E., & Yaffe, K. (2011). The projected effect of risk factor reduction on Alzheimer's disease prevalence. The Lancet Neurology, 10(9), 819-828.

Broadhouse, K. M., Singh, M. F., Suo, C., Gates, N., Wen, W., Brodaty, H., ... & Mavros, Y. (2020). Hippocampal plasticity underpins long-term cognitive gains from resistance exercise in MCI. NeuroImage: Clinical, 31, 102745.

Coelho-Júnior, H. J., Marzetti, E., Calvani, R., Picca, A., & Uchida, M. C. (2022). Resistance training improves cognitive function in older adults with different cognitive status: A systematic review and meta-analysis. Ageing Research Reviews, 83, 101791.

Cummings, J., Lee, G., Nahed, P., Kambar, M., Zhong, K., Fonseca, J., & Taghva, K. (2023). Alzheimer's disease drug development pipeline: 2023. Alzheimer's & Dementia: Translational Research & Clinical Interventions, 9(2), e12385.

8. Sperling, R. A., Donohue, M. C., Raman, R., Rafii, M. S., Johnson, K., & Masters, C. L. (2023). Association of factors with elevated amyloid burden in clinically normal older individuals. JAMA Neurology, 80(12), 1289-1298.

Erickson, K. I., Hillman, C., Stillman, C. M., Ballard, R. M., Bloodgood, B., Conroy, D. E., ... & Powell, K. E. (2019). Physical activity, cognition, and brain outcomes: A review of the 2018 Physical Activity Guidelines Advisory Committee scientific report. Medicine & Science in Sports & Exercise, 51(6), 1242-1251.

Firth, J., Stubbs, B., Vancampfort, D., Schuch, F., Lagopoulos, J., Rosenbaum, S., & Ward, P. B. (2018). Effect of aerobic exercise on hippocampal volume in humans: A systematic review and meta-analysis. NeuroImage, 166, 230-236.

Galles, N. S., Yaffe, K., & Brenowitz, W. D. (2023). Midlife physical activity and 25-year risk of dementia: The Atherosclerosis Risk in Communities (ARIC) study. Neurology, 101(3), e208060.

GBD 2019 Dementia Forecasting Collaborators. (2022). Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. The Lancet Public Health, 7(2), e105-e125.

Herold, F., Törpel, A., Schega, L., & Müller, N. G. (2023). The impact of combined aerobic and resistance exercise training on brain structure and cardiometabolic health in middle-aged adults at risk for Alzheimer's disease: A randomized controlled trial. Psychology and Aging, 38(2), 150-165.

Hörder, H., Johansson, L., Guo, X., Grimby, G., Kern, S., Östling, S., & Skoog, I. (2018). Midlife cardiovascular fitness and dementia: A 44-year longitudinal population study in women. Neurology, 90(15), e1298-e1305.

Jonasson, L. S., Nyberg, L., Axelsson, J., & Riklund, K. (2023). The effects of aerobic exercise on episodic memory in middle-aged adults: A randomized controlled trial. Neurobiology of Learning and Memory, 197, 107-114.

Kivipelto, M., Mangialasche, F., & Ngandu, T. (2020). Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease. Nature Reviews Neurology, 16(11), 662-673.

Lautenschlager, N. T., Cox, K. L., & Flicker, L. (2022). Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: A randomized trial. JAMA, 327(23), 2387-2396.

Liu-Ambrose, T., Best, J. R., Davis, J. C., Eng, J. J., Lee, P. E., Jacova, C., ... & Hsiung, G. Y. (2022). Aerobic exercise and vascular cognitive impairment: A randomized controlled trial. Neurology, 98(10), e1009-e1021.

Livingston, G., Huntley, J., Sommerlad, A., Ames, D., Ballard, C., Banerjee, S., ... & Mukadam, N. (2020). Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet, 396(10248), 413-446.

Marques, A., Peralta, M., Gouveia, É. R., Martins, J., & Sarmento, H. (2020). Dose-response relationship between physical activity and cognitive function in older adults: A systematic review and meta-analysis. Journal of Aging and Physical Activity, 28(1), 154-165.

Mavros, Y., Gates, N., Wilson, G. C., Jain, N., Meiklejohn, J., Brodaty, H., ... & Singh, M. F. (2017). Mediation of cognitive function improvements by strength gains after resistance training in older adults with mild cognitive impairment: Outcomes of the Study of Mental and Resistance Training. Journal of the American Geriatrics Society, 65(3), 550-559.

Müller, P., Duderstadt, Y., Lessmann, V., & Müller, N. G. (2021). Lactate and BDNF: Key mediators of exercise-induced neuroplasticity? Journal of Clinical Medicine, 10(5), 1136.

Norton, S., Matthews, F. E., & Brayne, C. (2020). A commentary on the number of dementia cases prevented or postponed through increased physical activity. BMC Geriatrics, 20, 1-4.

Nuzum, H., Hendrix, J., & Rosano, C. (2021). Grip strength and hippocampal volume loss over 5 years in middle-aged adults: The CARDIA MRI study. Neurobiology of Aging, 106, 1-8.

Pedersen, B. K., & Saltin, B. (2015). Exercise as medicine – evidence for prescribing exercise as therapy in 26 different chronic diseases. Scandinavian Journal of Medicine & Science in Sports, 25(S3), 1-72.

Sardeli, A. V., Tomeleri, C. M., Cyrino, E. S., Cavaglieri, C. R., & Chacon-Mikahil, M. P. T. (2022). Effect of resistance training on inflammatory markers in middle-aged and older adults: A systematic review and meta-analysis. Experimental Gerontology, 165, 111-118.

Smith, J. C., Nielson, K. A., Woodard, J. L., Seidenberg, M., Durgerian, S., Antuono, P., ... & Rao, S. M. (2021). Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer's disease. Frontiers in Aging Neuroscience, 13, 1057288.

Sofi, F., Valecchi, D., Bacci, D., Abbate, R., Gensini, G. F., Casini, A., & Macchi, C. (2011). Physical activity and risk of cognitive decline: A meta-analysis of prospective studies. Journal of Internal Medicine, 269(1), 107-117.

Steiner, J. L., Murphy, E. A., McClellan, J. L., Carmichael, M. D., & Davis, J. M. (2022). Exercise training increases mitochondrial biogenesis in the brain. Journal of Applied Physiology, 131(1), 315-323.

Stillman, C. M., Cohen, N. J., Lehman, M. E., & Erickson, K. I. (2020). Mediators of physical activity on neurocognitive function: A review at multiple levels of analysis. Frontiers in Human Neuroscience, 14, 575-597.

Ten Brinke, L. F., Bolandzadeh, N., Nagamatsu, L. S., Hsu, C. L., Davis, J. C., Miran-Khan, K., & Liu-Ambrose, T. (2018). Aerobic exercise increases hippocampal volume in older women with probable mild cognitive impairment: A 6-month randomised controlled trial. British Journal of Sports Medicine, 52(14), 848-854.

Voss, M. W., Soto, C., Yoo, S., Sodoma, M., Vivar, C., & van Praag, H. (2021). Exercise and hippocampal memory systems. Trends in Cognitive Sciences, 25(4), 318-333.

11. Tarumi, T., & Zhang, R. (2018). Cerebral hemodynamics of the aging brain: Risk of Alzheimer disease and benefit of aerobic exercise. Frontiers in Physiology, 9, 115-127.

World Health Organization. (2019). Risk reduction of cognitive decline and dementia: WHO guidelines. World Health Organization.

Zhao, Y., Zhang, X., Wang, J., Li, J., & Liu, Y. (2024). Comparative effects of aerobic, resistance, and combined exercise on Alzheimer's disease biomarkers and cognition in middle-aged adults: A randomized controlled trial. Journal of Alzheimer's Disease, 98(1), 321-335.