Discussion
dementia, MCI
The primary objective of the SYNERGIC Trial was to evaluate the effect of a multidomain intervention (combination of progressive exercise with cognitive training and vitamin D supplementation) on cognition compared with both an active control and exercise alone in older adults with MCI. Exercise with cognitive training significantly improved ADAS-Cog-13 scores, driven by improvements in episodic memory, attention, and orientation. Exercise alone did not improve cognition, nor did adding vitamin D. ADAS-Cog-Plus did not improve with any of the interventions. Compared with our multidomain interventions, the control arm revealed a slight decline in cognition, suggesting that balance and toning exercises may not sustain cognitive function in MCI individuals. Cognitive improvements observed in the ADAS-Cog-13 immediately after the intervention were slightly attenuated at 12-month assessment but they did not revert to baseline scores, suggesting a lasting effect even without participants engaging in exercise regimes during the follow-up period. Finally, our multidomain intervention achieved high compliance and adherence, and was safe and feasible to perform in older adults with MCI.A 2.64-point improvement in the ADAS-Cog-13 for the multidomain intervention is larger than changes seen in previous pharmaceutical trials among individuals with MCI or mild dementia,The lack of significant effect on the ADAS-Cog-Plus was against our hypotheses. Changes for arms 1 and 2 (exercise plus cognitive training) were in the expected direction, which prompted us to conduct exploratory analyses to evaluate whether adding items to the ADAS-Cog-13 may have reduced its responsiveness to our interventions. These post hoc analyses revealed that the ADAS-Cog-Plus variant without the verbal category fluency item (just adding 4 out of 5 plus items to the ADAS-Cog-13) was sensitive in detecting significant improvements for our multidomain intervention. Adding items to a composite measure would increase its sensitivity only to the extent that it may improve the mean-to-SD ratio of change over the course of the study. In other words, the optimal composite maximizes the signal and minimizes the noise. Adding the category fluency may have reduced the responsiveness of the Plus variant to our intervention because exercise and dual-task cognitive training interventions typically show greatest effects on measures of attention and pure executive function rather than on verbal fluency.Our results align with a 2022 meta-analysisThe lack of improvement with vitamin D may be related to normal-high serum values (greater than 70 nmol/L) in our participants at enrollment, whereas benefits of vitamin D supplementation may only occur in the presence of severe 25-hydroxyvitamin D deficiency (below 30 nmol/L).Exercise training cessation may induce detraining effects,