1 Gait and Brain Lab, Parkwood Institute, Lawson Health Research Institute, London, Ontario, Canada.
2 Department of Medicine, Division of Geriatric, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
3 Department of Epidemiology and Biostatistics, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
4 Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
5 Carespace Health & Wellness, Waterloo, Ontario, Canada.
6 Movement Disorders Research & Rehabilitation Centre, Department of Kinesiology and Physical Education, Wilfrid Laurier University, Waterloo, Ontario, Canada.
7 Department of Physical Therapy, University of British Columbia, Vancouver, British Columbia, Canada.
8 Department of Kinesiology and Health Sciences, University of Waterloo, Waterloo, Ontario, Canada.
9 Department of Medicine, Division of Neurology, University of Alberta, Edmonton, Alberta, Canada.
10 School of Kinesiology, Faculty of Health Sciences, University of Western Ontario, London, Ontario, Canada.
11 PERFORM Centre and Department of Psychology, Concordia University, Montréal, Quebec, Canada.
12 Faculty of Health Sciences, Interdisciplinary School of Health Sciences, University of Ottawa, Ontario, Canada.
13 Département des sciences de l'activité physique Université du Québec à Montréal, Montréal, Quebec, Canada.
14 Research Centre, Institut Universitaire de Gériatrie de Montréal, Montréal, Quebec, Canada.
15 Integrated Health and Social Services University Network for South-Central Montreal, Montreal, Quebec, Canada.
16 Research Centre, Montreal Heart Institute, and Department of Medicine, University of Montréal, Montréal, Quebec, Canada.

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 10 000 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 = .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 = .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 = .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.