Extended Abstract
Background and Purpose
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by gradual decline in cognitive function, mood disturbances, impaired physical performance, and reduced quality of life. Multi-component exercise (MCE) combining aerobic, resistance, balance, and flexibility training has emerged as a safe non-pharmacological strategy. Irisin, an exercise-induced myokine, is proposed as a molecular link between muscle activity and brain health. However, evidence regarding the effects of a structured MCE program on both clinical outcomes and serum irisin levels specifically in patients with mild cognitive impairment (MCI) due to Alzheimer's disease remains limited. Furthermore, the magnitude of changes in physical performance measures such as mobility, strength, balance, and flexibility following MCE in this population has not been fully characterized. Therefore, this study aimed to investigate the effects of a 12-week MCE program on cognitive function, depressive symptoms, physical performance, quality of life, and serum irisin levels in Alzheimer's patients with mild cognitive impairment.
Methods
This study was a randomized controlled trial (RCT) with a pretest-posttest design involving two groups (intervention and control). A total of 47 patients diagnosed with mild Alzheimer's disease (Mini-Mental State Examination [MMSE] score range: 21–26; mean age 74.62 ± 5.80 years) were recruited. Participants were randomly assigned to either an intervention group (n = 23) or a control group (n = 24). The intervention group completed a 12-week MCE program consisting of three 60-minute sessions per week. Each session included: (1) aerobic training (20 minutes on a treadmill or stationary bicycle at 50–70% of age-predicted maximal heart rate, continuously monitored); (2) resistance training (15 minutes using Theraband elastic bands, performing two sets of 10–12 repetitions of sit-to-stand, heel raises, shoulder press, seated row, and trunk rotation); (3) balance training (10 minutes including single-leg stance, heel-to-toe walking, weight shifting, and from week 5 onward, dual-task exercises combining balance with cognitive tasks such as backward counting); and (4) flexibility training (10 minutes of static stretching for major muscle groups, each stretch held for 15–30 seconds). Training load was progressed every four weeks (yellow → red → green Therabands) according to individual tolerance and the principles of progressive overload. The control group received usual medical care without any structured exercise program. All outcome measures were assessed at baseline and after 12 weeks. Cognitive function was measured using the MMSE. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). Physical performance included the TUG (seconds), 30s CST (number of repetitions), handgrip strength (kg) using a dynamometer, Berg Balance Scale (0–56 points), and lower trunk flexibility (sit-and-reach test, cm). Quality of life was measured using a validated scale. Serum irisin levels were quantified using a commercial ELISA kit. Data were analyzed using repeated measures analysis of variance (group × time) with partial eta squared (η²p) as the effect size measure. Statistical significance was set at p < 0.05.
Results
At baseline, no significant differences were observed between the intervention and control groups for any of the outcome variables (p > 0.05), confirming the homogeneity of the two groups. After 12 weeks of intervention, repeated measures ANOVA revealed significant group × time interactions for all measured outcomes, indicating that the changes over time differed significantly between the two groups in favor of the intervention group. Specifically, serum irisin levels increased significantly in the intervention group (p < 0.001, η²p = 0.69), whereas the control group showed no meaningful change. Cognitive function as measured by the MMSE improved significantly in the intervention group (p < 0.001, η²p = 0.444) with a large within-group effect size (Cohen's d = 1.28), while the control group did not show any significant change from baseline. The between-group comparison at post-test revealed a borderline but clinically relevant difference (p = 0.05, Cohen's d = 0.59), suggesting that the intervention had a moderate practical effect on global cognition. Depressive symptoms assessed by the BDI were substantially reduced in the intervention group (p < 0.001, η²p = 0.86), representing a clinically important improvement in mood, whereas the control group showed a worsening of depressive symptoms over the 12-week period. Regarding physical performance, the intervention group demonstrated significant improvements in all measured domains compared to the control group. TUG time decreased significantly (p < 0.001, η²p = 0.61), indicating better mobility and reduced fall risk. The 30s CST showed a significant increase in the number of repetitions (p < 0.001, η²p = 0.67), reflecting improved lower limb strength. Handgrip strength increased significantly (p < 0.001, η²p = 0.56), indicating enhanced upper limb muscle function. Berg Balance Scale scores improved significantly (p < 0.001, η²p = 0.51), demonstrating better postural control and balance. Flexibility also improved significantly (p < 0.001, η²p = 0.49). In contrast, the control group either showed no significant change or experienced declines across these physical performance measures. Quality of life improved significantly in the intervention group (p < 0.001, η²p = 0.72), while the control group showed a decline in quality of life over the same period. All effect sizes were large to very large (η²p ranging from 0.44 to 0.86), confirming the clinical significance of the improvements.
Conclusion
A 12-week multi-component exercise program combining aerobic, resistance, balance, and flexibility training significantly improves serum irisin levels, cognitive function, depressive symptoms, physical performance (mobility, lower and upper limb strength, balance, and flexibility), and quality of life in Alzheimer's patients with mild cognitive impairment. The large effect sizes and the consistent pattern of improvements in the intervention group compared to the control group (which either remained stable or declined) support MCE as an effective, safe, and low-cost non-pharmacological intervention. The significant increase in serum irisin and its association with cognitive and physical benefits suggest that irisin may serve as a key molecular mediator linking exercise to brain health, potentially through neuroprotective and anti-inflammatory mechanisms. These findings emphasize the importance of early, structured, multi-component exercise as a complementary and preventive strategy in the management of mild Alzheimer's disease. Integration of such exercise programs into routine care, rehabilitation protocols, geriatric clinics, and even home-based settings with appropriate supervision is strongly recommended.

Article Message
Twelve weeks of multi-component exercise is a safe, low-cost, and effective non-pharmacological intervention that significantly improves cognitive function, reduces depressive symptoms, enhances physical performance (mobility, strength, balance, flexibility), increases quality of life, and elevates serum irisin levels in Alzheimer's patients with mild cognitive impairment. Given the limitations and side effects of current pharmacological treatments, this program is recommended as a complementary therapy and early rehabilitation strategy for patients in the mild stage. The program is feasible in rehabilitation centers, geriatric clinics, and home-based settings with supervision. Serum irisin is proposed as a potential biomarker for monitoring individual responses to exercise, which could guide personalized exercise prescription in future studies. Further research with larger sample sizes, longer follow-up periods, neuroimaging, and official trial registration is needed to confirm the underlying mechanisms.
Ethical Considerations
Participation was voluntary, with written informed consent obtained from all participants. The study received ethical approval under code IR.UI.REC.1404.276 from the Ethics Committee of the University of Isfahan.
Authors' Contributions
SH, Hedayati: Topic selection, concept development, data collection, literature review, and manuscript writing
M. Kargarfard: Conceptualization, data analysis, manuscript editing and final revision, and project management
M.M. Hadavi: Clinical diagnosis of cognitive impairment and depression in participants, manuscript editing and revision
Conflict of Interest
The authors declare no conflict of interest.
Acknowledgments
The authors would like to thank the Vice-Chancellery for Research and Technology and the Faculty of Sport Sciences, University of Isfahan, for their financial and moral support. We also acknowledge the contributions of all staff and participants who made this research possible.