The SYNERGIC Trial: A Randomized Controlled Trial Assessing Multimodal Interventions to Improve Cognition in Mild Cognitive Impairment in Older Adults

Background Older adults with Mild Cognitive Impairment (MCI) have increased risk of dementia. Physical exercise, cognitive training, and vitamin D supplementation are emerging interventions for improving cognition. However, the potential synergism of combining them to improve cognition in MCI has not been yet tested. Methods The SYNERGIC trial (SYNnchronizing Exercises, Remedies in Gait and Cognition)— a multi‐site, double‐blinded, controlled, quasi‐factorial trial—assessed the efficacy and synergistic effect of combining bi‐modal exercises (aerobic + progressive resistance training = E), cognitive training (CT) and, vitamin D supplementation (D = 10000IU 3xweekly) to improve cognition in MCI. Personalized interventions were delivered for 20 weeks in 5 arms: Arm 1 received 3 active interventions (E+CT+D), Arm 2 received E+CT+placebo D, Arm 3 received E+ sham CT+ D, Arm 4 received E+ sham CT and placebo D, and Arm 5 received all control interventions (Control E‐balance and toning‐, sham CT and placebo D). Change in ADAS‐Cog‐13 was the primary outcome assessed with linear mixed effects models adjusting for age, sex, education, and number of comorbidities. Results 170 MCI participants were randomized. As compared to the control group (Arm 5), multimodal intervention (Arm 1) had significant improvements in ADAS‐Cog‐13 scores (difference = ‐2.3 ADAS‐Cog‐13 points; 95% CI: ‐1.06 ‐3.54). Following analyses guidelines for factorial trials, interactions of intervention across arms were analyzed and no significant interactions were found for vitamin D supplementation. Therefore, we collapsed Arms 1 and 2 (combined E + CT), and we collapsed Arms 3 and 4 (E), and compared them to Arm 5 (control). Relative to the control group (Arm 5), the combined exercise and cognitive intervention (Arms 1+2) had significantly improved cognitive function (difference = ‐2.2 ADAS‐Cog‐13 points; 95% CI: ‐0.70, ‐3.72). In contrast, the exercise only intervention (Arms 3+4) did not have significantly improved cognition as compared to the control group (difference = ‐1.24 ADAS‐Cog‐13 points; 95% CI: ‐0.21, 2.69). Conclusion A synergistic effect of combined bi‐modal exercise with sequential computerized cognitive training was found to improve cognition in older adults with MCI with a large effect size = 0.62. Addition of vitamin D supplementation did not improve the effect.