Efficacy and Mechanisms of Combined Aerobic Exercise and Cognitive Training in MCI_The ACT Trial COVID Admin Sup

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Brief Summary of Protocol (5,000 characters max) The purpose of this single-blinded, 2×2 factorial Phase II randomized controlled trial (RCT) is to test the efficacy and additive/synergistic effects of a 6-month combined cycling and speed of processing (SOP) training intervention on cognition and relevant mechanisms (aerobic fitness, AD signature cortical thickness, and functional connectivity in the default mode network [DMN]) in older adults with amnestic MCI (aMCI). Our preliminary studies have shown that enhanced aerobic fitness is associated with better cognition and resting- state functional connectivity in the DMN in AD, and ~20 hours of SOP training improves executive function and maintains functional connectivity in the DMN in aMCI. This RCT will randomize 128 participants equally to 4 arms: ACT, cycling only, SOP training only, or attention control for 6 months, and then follow them for another 12 months. Cognition and aerobic fitness will be assessed at baseline, 3, 6, 12, and 18 months; AD signature cortical thickness and functional connectivity in the DMN at baseline, 6, 12, and 18 months; AD conversion at 3, 6, 12, and 18 months. The specific aims are to: Aim I. Determine the efficacy and additive/synergistic effects of ACT on cognition over 6 months. H1: ACT will have the greatest effects on executive function and episodic memory compared with other groups. Aim II. Examine the underlying mechanisms of ACT over 6 months. H2a: ACT will have the greatest effects on AD signature cortical thickness, functional connectivity in the DMN, and aerobic fitness compared with other groups. H2b: Changes in the mechanistic measures are related to cognitive changes. H2c: Changes in AD signature cortical thickness and DMN mediate aerobic fitness' effects on cognition. Aim III (exploratory). Calculate the long-term effect sizes of ACT on cognition and clinical and pathological AD conversion to inform future Phase III RCTs. Analysis will use intention-to-treat and linear mixed-effect modeling. This trial will be the first to test the synergistic effects on cognition and mechanisms (relevant to AD-associated neurodegeneration) of a uniquely conceptualized and rigorously designed ACT in older adults with aMCI. It will advance AD prevention research by providing precise effect-size estimates of the ACT intervention. Our long-term goal is to delay AD onset and slow AD progression.