IMPORTANCE: Exercise, cognitive training, and vitamin D may enhance cognition in older adults with mild cognitive impairment (MCI). OBJECTIVE: To determine whether aerobic-resistance exercises would improve cognition relative to an active control and if a multidomain intervention including exercises, computerized cognitive training, and vitamin D supplementation would show greater improvements than exercise alone. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial (the SYNERGIC Study) was a multisite, double-masked, fractional factorial trial that evaluated the effects of aerobic-resistance exercise, computerized cognitive training, and vitamin D on cognition. Eligible participants were between ages 65 and 84 years with MCI enrolled from September 19, 2016, to April 7, 2020. Data were analyzed from February 2021 to December 2022. INTERVENTIONS: Participants were randomized to 5 study arms and treated for 20 weeks: arm 1 (multidomain intervention with exercise, cognitive training, and vitamin D), arm 2 (exercise, cognitive training, and placebo vitamin D), arm 3 (exercise, sham cognitive training, and vitamin D), arm 4 (exercise, sham cognitive training, and placebo vitamin D), and arm 5 (control group with balance-toning exercise, sham cognitive training, and placebo vitamin D). The vitamin D regimen was a 10000 IU dose 3 times weekly. MAIN OUTCOMES AND MEASURES: Primary outcomes were changes in ADAS-Cog-13 and Plus variant at 6 months. RESULTS: Among 175 randomized participants (mean (SD) age 73.1 (6.6) years; 86 (49.1%) women), 144 (82%) completed the intervention and 133 (76%) completed the follow-up (month 12). At 6 months, all active arms (ie, arms 1 through 4) with aerobic-resistance exercise regardless of the addition of cognitive training or vitamin D, improved ADAS-Cog-13 when compared with control (mean difference -1.79 points; 95% CI -3.27 to -0.31 points; p = 0.02; d = 0.64). Compared with exercise alone (arms 3 and 4), exercise and cognitive training (arms 1 and 2) improved the ADAS-Cog-13 (mean difference -1.45 points; 95% CI -2.70 to -0.21 points; p = 0.02; d = 0.39). No significant improvement was found with vitamin D. Finally, the multidomain intervention (arm 1) improved the ADAS-Cog-13 score significantly compared with control (mean difference -2.64 points; 95% CI -4.42 to -0.80 points; p = 0.005; d = 0.71). Changes in ADAS-Cog-Plus were not significant. CONCLUSIONS AND RELEVANCE: In this clinical trial, older adults with MCI receiving aerobic-resistance exercises with sequential computerized cognitive training significantly improved cognition, although some results were inconsistent. Vitamin D supplementation had no effect. Our findings suggest that this multidomain intervention may improve cognition and potentially delay dementia onset in MCI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02808676.

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