Efficacy of sequential aerobic exercise and cognitive training in older adults with amnestic mild cognitive impairment

Background: Multi-component interventions may be critical for reducing Alzheimer's disease (AD) risk since AD pathogenesis is multi-factorial. Combined Aerobic exercise and Cognitive Training (ACT) may have synergistic effects, but studies are limited with mixed findings. Methods: A 3-site, single-blinded Stage II 2 × 2 factorial trial aimed to test the effects of 6-month ACT on cognition in older adults with amnestic mild cognitive impairment in academic research facilities and gyms. Among 325 participants consented, 146 were enrolled and randomized equally to 6-month ACT, cycling only, speed of processing (SOP) cognitive training only, or control. Primary outcomes, executive function and episodic memory, were measured with alternating EXAMINER and Brief Visuospatial Memory Test-Revised (BVMT-R) forms at baseline, 3, 6, 12, and 18 months, and global cognition with the Montreal Cognitive Assessment (MoCA) and EXAMINER/BVMT-R composite. Results: Executive function improved significantly from baseline to 6 months (ds = 0.58–1.18, adjusted Ps < 0.001–0.026) in all groups except SOP. Global cognition composite increased in cycling only (d = 0.73; adjusted P = 0.012). MoCA decreased over 18 months (adjusted P = 0.030) in the control group only. Between-group comparison was significant between ACT and SOP groups at 6 months (adjusted P = 0.029), but sensitivity analyses showed ACT being superior to both cycling- and SOP-only groups (Ps = 0.030 and 0.002, respectively) among in-person interventions (48.6% of all sessions were delivered in person as designed due to COVID-19). Conclusions: ACT's synergistic effects remain to be determined. All interventions are feasible for clinical practice. Trial Registration: www.clinicaltrials.gov (NCT03313895; date of registration: 10/18/2017).