This study aimed to compare the effects of different exercise interventions on brain-derived neurotrophic factor (BDNF) levels in patients with neurodegenerative diseases and to explore regulatory factors.
Methods
Searched PubMed, Scopus, Web of Science Core Collection, CNKI and Cochrane Library databases up to March 15, 2025. Bayesian network meta-analysis was conducted using R software, and meta-regression analyzed the moderating effects of training period and frequency.
Results
42 randomized controlled trials covering 1482 patients were included. The Surface Under the Cumulative Ranking (SUCRA) indicated that stretching training (SUCRA = 78.92) and high-intensity interval training (SUCRA = 69.73) were ranked higher than other exercise modalities and exhibited more favorable effect on BDNF enhancement, although neither demonstrated statistically significant superiority over the blank control. In contrast, combined training (SUCRA = 35.58), aerobic training (SUCRA = 35.17), and resistance training (SUCRA = 12.98) showed relatively lower potential for BDNF enhancement (blank control SUCRA = 67.62). Meta-regression analysis showed that the effect of combined training was significantly and positively correlated with intervention period (P < 0.01).
Conclusions
Stretching training and high-intensity interval training appear promising for enhancing BDNF level in neurodegenerative diseases, while isolated aerobic or resistance training show relatively lower potential on improving BDNF. Combined training requires sustained implementation for significant benefits. These findings highlight the importance of tailored exercise prescription for improving BDNF levels.
AmorSPuentesFBakerDvan der ValkP. Inflammation in neurodegenerative diseases. Immunology. 2010;129(2):154-169.
2.
KovacsGG. Concepts and classification of neurodegenerative diseases. In: Handbook of Clinical Neurology, Vol. 145. Elsevier; 2018:301-307.
3.
FeiginVLAbajobirAAAbateKH. Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the global burden of disease study 2015. Lancet Neurol. 2017;16(11):877-897.
4.
TabriziSJSchobelSGantmanEC, et al.A biological classification of huntington’s disease: the integrated staging system. Lancet Neurol. 2022;21(7):632-644.
5.
WrigglesworthJRyanJVijayakumarNWhittleS. Brain-derived neurotrophic factor DNA methylation mediates the association between neighborhood disadvantage and adolescent brain structure. Psychiatry Res Neuroimaging. 2019;285:51-57.
6.
Tahami MonfaredAAByrnesMJWhiteLAZhangQ. The humanistic and economic burden of alzheimer’s disease. Neurol Ther. 2022;11(2):525-551.
SuzukiASternSABozdagiO, et al.Astrocyte-neuron lactate transport is required for long-term memory formation. Cell. 2011;144(5):810-823.
9.
GubertCHannanAJ. Exercise mimetics: harnessing the therapeutic effects of physical activity. Nat Rev Drug Discov. 2021;20(11):862-879.
10.
DoughertyRJBootsEALindheimerJB, et al.Fitness, independent of physical activity is associated with cerebral blood flow in adults at risk for alzheimer’s disease. Brain Imaging Behav. 2020;14(4):1154-1163.
11.
HuJYCaiMShangQHLiZRLouSJ. Improvement of cognitive function by high-intensity interval training and its mechanism. Sheng Li Xue Bao. 2021;73(1):126-136.
12.
ZhouBWangZZhuL, et al.Effects of different physical activities on brain-derived neurotrophic factor: a systematic review and bayesian network meta-analysis. Front Aging Neurosci. 2022;14:981002.
13.
ShobeiriPKarimiAMomtazmaneshS, et al.Exercise-induced increase in blood-based brain-derived neurotrophic factor (BDNF) in people with multiple sclerosis: a systematic review and meta-analysis of exercise intervention trials. PLoS One. 2022;17(3):e0264557.
14.
DinoffAHerrmannNSwardfagerW, et al.The effect of exercise training on resting concentrations of peripheral brain-derived neurotrophic factor (BDNF): a meta-analysis. PLoS One. 2016;11(9):e0163037.
15.
KnaepenKGoekintMHeymanEMMeeusenR. Neuroplasticity - exercise-induced response of peripheral brain-derived neurotrophic factor: a systematic review of experimental studies in human subjects. Sports Med. 2010;40(9):765-801.
16.
ZoladzJAPilcA. The effect of physical activity on the brain derived neurotrophic factor: from animal to human studies. J Physiol Pharmacol. 2010;61(5):533-541.
17.
GrgicJMcllvennaLCFyfeJJ, et al.Does aerobic training promote the same skeletal muscle hypertrophy as resistance training? A systematic review and meta-analysis. Sports Med. 2019;49:233-254.
18.
BatacanRBDuncanMJDalboVJTuckerPSFenningAS. Effects of high-intensity interval training on cardiometabolic health: a systematic review and meta-analysis of intervention studies. Br J Sports Med. 2017;51(6):494-503.
19.
CoatesAMJoynerMJLittleJPJonesAMGibalaMJ. A perspective on high-intensity interval training for performance and health. Sports Med. 2023;53(Suppl 1):85-96.
20.
TakeuchiKNakamuraMKonradAMizunoT. Long‐term static stretching can decrease muscle stiffness: a systematic review and meta‐analysis. Scand J Med Sci Sports. 2023;33(8):1294-1306.
21.
KraemerWJRatamessNA. Fundamentals of resistance training: progression and exercise prescription. Med Sci Sports Exerc. 2004;36(4):674-688.
22.
CumpstonMLiTPageMJ, et al.Updated guidance for trusted systematic reviews: a new edition of the cochrane handbook for systematic reviews of interventions. Cochrane Database Syst Rev. 2019;10(10):ED000142.
23.
AllardJSNtekimOJohnsonSP, et al.APOEε4 impacts up-regulation of brain-derived neurotrophic factor after a six-month stretch and aerobic exercise intervention in mild cognitively impaired elderly African Americans: a pilot study. Exp Gerontol. 2017;87(Pt A):129-136.
24.
BakerLDFrankLLFoster-SchubertK, et al.Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch Neurol. 2010;67(1):71-79.
25.
BrikenSRosenkranzSCKeminerO, et al.Effects of exercise on irisin, BDNF and IL-6 serum levels in patients with progressive multiple sclerosis. J Neuroimmunol. 2016;299:53-58.
26.
CastellanoVWhiteLJ. Serum brain-derived neurotrophic factor response to aerobic exercise in multiple sclerosis. J Neurol Sci. 2008;269(1-2):85-91.
27.
DamirchiAHosseiniFBabaeiP. Mental training enhances cognitive function and BDNF more than either physical or combined training in elderly women with MCI: a small-scale study. Am J Alzheimers Dis Other Demen. 2018;33(1):20-29.
28.
DuXChenWZhanNBianXYuW. The effects of low-intensity resistance training with or without blood flow restriction on serum BDNF, VEGF and perception in patients with post-stroke depression. Neuroendocrinol Lett. 2021;42(4):229-235.
29.
EnetteLVogelTMerleS, et al.Effect of 9 weeks continuous vs. interval aerobic training on plasma BDNF levels, aerobic fitness, cognitive capacity and quality of life among seniors with mild to moderate alzheimer’s disease: a randomized controlled trial. Eur Rev Aging Phys Act. 2020;17:1-16.
30.
FrazzittaGMaestriRGhilardiMF, et al.Intensive rehabilitation increases BDNF serum levels in parkinsonian patients: a randomized study. Neurorehabilitation Neural Repair. 2014;28(2):163-168.
31.
MokhtarzadeMMotlRNegareshR, et al.Exercise-induced changes in neurotrophic factors and markers of blood-brain barrier permeability are moderated by weight status in multiple sclerosis. Neuropeptides. 2018;70:93-100.
32.
TsaiCLPaiMCUkropecJUkropcováB. Distinctive effects of aerobic and resistance exercise modes on neurocognitive and biochemical changes in individuals with mild cognitive impairment. Curr Alzheimer Res. 2019;16(4):316-332.
33.
CumpstonMLiTPageMJ, et al.Updated guidance for trusted systematic reviews: a new edition of the cochrane handbook for systematic reviews of interventions. Cochrane Database Syst Rev. 2019;10(10):ED000142.
34.
SmartNAWaldronMIsmailH, et al.Validation of a new tool for the assessment of study quality and reporting in exercise training studies: TESTEX. Int J Evid Base Healthc. 2015;13(1):9-18.
35.
LiTPuhanMAVedulaSSSinghSDickersinKAd Hoc Network Meta-analysis Methods Meeting Working Group. Network meta-analysis-highly attractive but more methodological research is needed. BMC Med. 2011;9:1-5.
36.
PetersJLSuttonAJJonesDRAbramsKRRushtonL. Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry. J Clin Epidemiol. 2008;61(10):991-996.
37.
AbbaspoorEZolfaghariMAhmadiBKhodaeiK. The effect of combined functional training on BDNF, IGF-1, and their association with health-related fitness in the multiple sclerosis women. Growth Hormone IGF Res. 2020;52:101320.
38.
BanitalebiEGhahfarrokhiMMNegareshR, et al.Exercise improves neurotrophins in multiple sclerosis independent of disability status. Mult Scler Relat Disord. 2020;43:102143.
39.
di CagnoABuonsensoACentorbiM, et al.Whole body-electromyostimulation effects on serum biomarkers, physical performances and fatigue in Parkinson’s patients: a randomized controlled trial. Front Aging Neurosci. 2023;15:1086487.
40.
DevenneyKEGuinanEMKellyÁM, et al.Acute high-intensity aerobic exercise affects brain-derived neurotrophic factor in mild cognitive impairment: a randomised controlled study. BMJ Open Sport Exerc Med. 2019;5(1):e000499.
41.
EftekhariEEtemadifarM. Interleukin-10 and brain-derived neurotrophic factor responses to the mat pilates training in women with multiple sclerosis. Sci Med. 2018;28(4):7.
42.
El-TamawyMSAbd-AllahFAhmedSMDarwishMHKhalifaHA. Aerobic exercises enhance cognitive functions and brain derived neurotrophic factor in ischemic stroke patients. NeuroRehabilitation. 2014;34(1):209-213.
43.
FreidleMJohanssonHEkmanU, et al.Behavioural and neuroplastic effects of a double-blind randomised controlled balance exercise trial in people with Parkinson’s disease. npj Parkinson's Dis. 2022;8(1):12.
44.
FungweTVNgwaJSNtekimOE, et al.Exercise training induced changes in nuclear magnetic resonance-measured lipid particles in mild cognitively impaired elderly African American volunteers: a pilot study. Clin Interv Aging. 2019;14:2115-2123.
45.
HsuCCFuTCHuangSCChenCPCWangJS. Increased serum brain-derived neurotrophic factor with high-intensity interval training in stroke patients: a randomized controlled trial. Ann Phys Rehabil Med. 2021;64(4):101385.
46.
JørgensenMLKKjølhedeTDalgasU, et al.Plasma brain-derived neurotrophic factor (BDNF) and sphingosine-1-phosphat (S1P) are NOT the main mediators of neuroprotection induced by resistance training in persons with multiple sclerosis-a randomized controlled trial. Mult Scler Relat Disord. 2019;31:106-111.
47.
KhademosharieMTadibiVBehpoorN, et al.The effect of 12-weeks resistance and endurance training on the serum levels NGF, BDNF, and VDBP in women with multiple sclerosis. Int J Appl Exerc Physiol. 2018;7(1):76-86.
48.
KohanpourMAPeeriMAzarbayjaniMA. The effects of aerobic exercise with lavender essence use on cognitive state and serum brain-derived neurotrophic factor levels in elderly with mild cognitive impairment. J Herbmed Pharmacol. 2017;6(2):80-84.
49.
KimTGBaeSHKimKY. Effects of dual-task training with different intensity of aerobic exercise on cognitive function and neurotrophic factors in chronic stroke patients. Res J Pharm Technol. 2019;12(2):693-698.
50.
KüsterOCLaptinskayaDFisslerP, et al.Novel blood-based biomarkers of cognition, stress, and physical or cognitive training in older adults at risk of dementia: preliminary evidence for a role of BDNF, irisin, and the kynurenine pathway. J Alzheim Dis. 2017;59(3):1097-1111.
51.
LiuITLeeWJLinSYChangSTKaoCLChengYY. Therapeutic effects of exercise training on elderly patients with dementia: a randomized controlled trial. Arch Phys Med Rehabil. 2020;101(5):762-769.
52.
LandersMRNavaltaJWMurtishawASKinneyJWPirio RichardsonS. A high-intensity exercise boot camp for persons with parkinson disease: a phase II, pragmatic, randomized clinical trial of feasibility, safety, signal of efficacy, and disease mechanisms. J Neurol Phys Ther. 2019;43(1):12-25.
53.
NascimentoCMCPereiraJRPires de AndradeL, et al.Physical exercise improves peripheral BDNF levels and cognitive functions in mild cognitive impairment elderly with different bdnf Val66Met genotypes. J Alzheimers Dis. 2015;43(1):81-91.
54.
O’CallaghanAHarveyMHoughtonD, et al.Comparing the influence of exercise intensity on brain-derived neurotrophic factor serum levels in people with parkinson’s disease: a pilot study. Aging Clin Exp Res. 2020;32(9):1731-1738.
55.
OzkulCGuclu-GunduzAIrkecC, et al.Effect of combined exercise training on serum brain-derived neurotrophic factor, suppressors of cytokine signaling 1 and 3 in patients with multiple sclerosis. J Neuroimmunol. 2018;316:121-129.
56.
PloughmanMEskesGAKellyLP, et al.Synergistic benefits of combined aerobic and cognitive training on fluid intelligence and the role of IGF-1 in chronic stroke. Neurorehabilitation Neural Repair. 2019;33(3):199-212.
57.
SavšekLStergarTStrojnikV, et al.Impact of aerobic exercise on clinical and magnetic resonance imaging biomarkers in persons with multiple sclerosis: an exploratory randomized controlled trial. J Rehabil Med. 2021;53(4):jrm00178.
58.
SchulzKHGoldSMWitteJ, et al.Impact of aerobic training on immune-endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis. J Neurol Sci. 2004;225(1-2):11-18.
59.
SeguraCErasoMBonillaJ, et al.Effect of a high-intensity tandem bicycle exercise program on clinical severity, functional magnetic resonance imaging, and plasma biomarkers in parkinson’s disease. Front Neurol. 2020;11:656.
60.
SokeFKocerBFidanIKeskinogluPGuclu-GunduzA. Effects of task-oriented training combined with aerobic training on serum BDNF, GDNF, IGF-1, VEGF, TNF-α, and IL-1β levels in people with parkinson’s disease: a randomized controlled study. Exp Gerontol. 2021;150:111384.
61.
SungkaratSBoripuntakulSKumfuSLordSRChattipakornN. Tai chi improves cognition and plasma BDNF in older adults with mild cognitive impairment: a randomized controlled trial. Neurorehabilitation Neural Repair. 2018;32(2):142-149.
62.
SzymuraJKubicaJWiecekMPeraJ. The immunomodulary effects of systematic exercise in older adults and people with parkinson’s disease. J Clin Med. 2020;9(1):184.
63.
ValkenborghsSRvan VlietPNilssonM, et al.Aerobic exercise and consecutive task-specific training (AExaCTT) for upper limb recovery after stroke: a randomized controlled pilot study. Physiother Res Int. 2019;24(3):e1775.
64.
WensIKeytsmanCDeckxNCoolsNDalgasUEijndeBO. Brain derived neurotrophic factor in multiple sclerosis: effect of 24 weeks endurance and resistance training. Eur J Neurol. 2016;23(6):1028-1035.
65.
ZhangQZhuMHuangL, et al.A study on the effect of traditional Chinese exercise combined with rhythm training on the intervention of older adults with mild cognitive impairment. Am J Alzheimers Dis Other Demen. 2023;38:15333175231190626.
66.
ZimmerPBlochWSchenkA, et al.High-intensity interval exercise improves cognitive performance and reduces matrix metalloproteinases-2 serum levels in persons with multiple sclerosis: a randomized controlled trial. Mult Scler. 2018;24(12):1635-1644.
67.
YinLQTangCFLuoWQ, et al.Effect of multi-mode exercise on cognitive function and neuroplasticityin the elderly with MCI. China Sport Sci. 42:78-87+97.
68.
YinLQTangCFLuoWQ, et al.Effects of multimodal exercise on cognitive function, neurotrophic factors and whole brain volume in older adults with mild cognitive impairment. China Sports Science and Technology. 2023;59(3):50-57.
69.
JenkinsDGQuintana-AscencioPF. A solution to minimum sample size for regressions. PLoS One. 2020;15(2):e0229345.
70.
YangHSKimHJLeeHG. Effects of a single session of brain yoga on brain-derived neurotrophic factor and cognitive short-term memory in men aged 20-29 years. J Korean Soc Integr Med. 2021;9(4):91-103.
71.
RaichlenDAAlexanderGE. Adaptive capacity: an evolutionary neuroscience model linking exercise, cognition, and brain health. Trends Neurosci. 2017;40(7):408-421.
72.
De BruijnAGKostonsDDVan Der FelsIM, et al.Effects of aerobic and cognitively-engaging physical activity on academic skills: a cluster randomized controlled trial. J Sports Sci. 2020;38(15):1806-1817.
73.
KaagmanDGvan WegenEECignettiNRothermelEVanbellingenTHirschMA. Effects and mechanisms of exercise on brain-derived neurotrophic factor (BDNF) levels and clinical outcomes in people with parkinson’s disease: a systematic review and meta-analysis. Brain Sci. 2024;14(3):194.
74.
Cabral-SantosCCastrillónCIMMirandaRAT, et al.Inflammatory cytokines and BDNF response to high-intensity intermittent exercise: effect the exercise volume. Front Physiol. 2016;7:509.
75.
GomesESAVan den HeuvelOARietbergMB, et al.(HIIT-The track) high-intensity interval training for people with parkinson’s disease: individual response patterns of (non-) motor symptoms and blood-based biomarkers—a crossover single-case experimental design. Brain Sci. 2023;13(6):849.
76.
GravesteijnASRietbergMBde GrootV, et al.HIITing anxiety and depression in parkinson’s disease and multiple sclerosis—a study protocol of a transdiagnostic randomized controlled trial (HersenFIT). Brain Sci. 2025;15(9):945.
77.
Elboim-GabyzonMBuxbaumRKleinR. The effects of high-intensity interval training (HIIT) on fall risk factors in healthy older adults: a systematic review. Int J Environ Res Publ Health. 2021;18(22):11809.
78.
DourisPDourisCBalderN, et al.Martial art training and cognitive performance in middle-aged adults. J Hum Kinet. 2015;47:277-283.
79.
LunnyCHigginsJPWhiteIR, et al.Risk of bias in network meta-analysis (RoB NMA) tool. Bmj. 2025;388:r673.
80.
LunnyCVeronikiAHigginsJP, et al.Methodological review of NMA bias concepts provides groundwork for the development of a list of concepts for potential inclusion in a new risk of bias tool for network meta-analysis (RoB NMA tool). Syst Rev. 2024;13(1):25.
81.
ChoHCKimJKLeeNJKimSYYoonNK. Effects of combined exercise on cardiovascular risk factors and serum BDNF level in mid-aged women. J Exerc Nutrition Biochem. 2014;18(1):61-67.
82.
MarinusNHansenDFeysPMeesenRTimmermansASpildoorenJ. The impact of different types of exercise training on peripheral blood brain-derived neurotrophic factor concentrations in older adults: a meta-analysis. Sports Med. 2019;49(10):1529-1546.
83.
EricksonKIMillerDLRoeckleinKA. The aging hippocampus: interactions between exercise, depression, and BDNF. Neuroscientist. 2012;18(1):82-97.
84.
GriffinÉWMullallySFoleyCWarmingtonSAO'MaraSMKellyAM. Aerobic exercise improves hippocampal function and increases BDNF in the serum of young adult males. Physiol Behav. 2011;104(5):934-941.
85.
WalshJJTschakovskyME. Exercise and circulating BDNF: mechanisms of release and implications for the design of exercise interventions. Applied Physiology, Nutrition, and Metabolism = Physiologie Appliquee, Nutrition Et Metabolisme. 2018;43(11):1095-1104.
86.
KempermannGFabelKEhningerD, et al.Why and how physical activity promotes experience-induced brain plasticity. Front Neurosci. 2010;4:189.
87.
BrickNMacIntyreTCampbellM. Attentional focus in endurance activity: new paradigms and future directions. Int Rev Sport Exerc Psychol. 2014;7(1):106-134.
88.
BarcelosNShahNCohenK, et al.Aerobic and cognitive exercise (ACE) pilot study for older adults: executive function improves with cognitive challenge while exergaming. J Int Neuropsychol Soc. 2015;21(10):768-779.
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