Efficacy and mechanisms of combined aerobic exercise and cognitive training in mild cognitive impairment: Study protocol of the ACT trial

Fang Yu, Feng Vankee Lin, Dereck L. Salisbury, Krupa N. Shah, Lisa Chow, David Vock, Nathaniel W. Nelson, Anton P. Porsteinsson, Clifford Jack

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Background: Developing non-pharmacological interventions with strong potential to prevent or delay the onset of Alzheimer's disease (AD) in high-risk populations is critical. Aerobic exercise and cognitive training are two promising interventions. Aerobic exercise increases aerobic fitness, which in turn improves brain structure and function, while cognitive training improves selective brain function intensively. Hence, combined aerobic exercise and cognitive training may have a synergistic effect on cognition by complementary strengthening of different neural functions. Few studies have tested the effects of such a combined intervention, and the findings have been discrepant, largely due to varying doses and formats of the interventions. Methods/design: The purpose of this single-blinded, 2 × 2 factorial phase II randomized controlled trial is to test the efficacy and synergistic effects of a 6-month combined cycling and speed of processing training intervention on cognition and relevant mechanisms (aerobic fitness, cortical thickness, and functional connectivity in the default mode network) in older adults with amnestic mild cognitive impairment. This trial will randomize 128 participants equally to four arms: cycling and speed of processing, cycling only, speed of processing only, or attention control for 6 months, and then follow them for another 12 months. Cognition and aerobic fitness will be assessed at baseline and at 3, 6, 12, and 18 months; cortical thickness and functional connectivity at baseline and at 6, 12, and 18 months; Alzheimer's disease (AD) conversion at 6, 12, and 18 months. The specific aims are to (1) determine the efficacy and synergistic effects of the combined intervention on cognition over 6 months, (2) examine the underlying mechanisms of the combined intervention, and (3) calculate the long-term effect sizes of the combined intervention on cognition and AD conversion. The analysis will use intention-to-treat and linear mixed-effects modeling. Discussion: This trial will be among the first to test the synergistic effects on cognition and mechanisms (relevant to Alzheimer's-associated neurodegeneration) of a uniquely conceptualized and rigorously designed aerobic exercise and cognitive training intervention in older adults with mild cognitive impairment. It will advance Alzheimer's prevention research by providing precise effect-size estimates of the combined intervention. Trial registration: ClinicalTrials.gov, NCT03313895. Registered on 18 October 2017.

Original languageEnglish (US)
Article number700
Issue number1
StatePublished - Dec 22 2018

Bibliographical note

Funding Information:
The research study reported in this publication was supported by the National Institute on Aging of the NIH, Award Number R01AG055469-01A1.

Funding Information:
The purpose of this phase II RCT is to test the efficacy and additive/synergistic effects of an ACT intervention (cycling and SOP training), by comparing it to cycling and SOP training alone and an attention control (stretching and mental leisure activities), on cognition and relevant mechanisms (aerobic fitness, AD signature cortical thickness, and DMN) in older adults with amnestic MCI (aMCI). Here we choose AD signature cortical thickness [49] and DMN [50] since they are common neural markers detected early in the progression of AD. The study is funded by the NIH’s National Institute on Aging (R01AG055469-01A1, 9/15/2017–5/31/2022). The specific aims and hypotheses of the study are described as follows:

Funding Information:
The Clinical & Translational Science Institute (CTSI) and the Center for Magnetic Resonance Research were supported by the NIH National Center for Advancing Translational Sciences, Award Number UL1TR000114, and the National Institute of Biomedical Imaging and Bioengineering, Award Number P41 EB1058941, respectively. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank the DSMB members: Kenneth Hepburn, Ph.D., Professor, Nell Hodgson Woodruff School of Nursing, Emory University; Mark Mapstone, Ph.D., Professor, Department of Neurology, University of California, Irvine; and George W. Rebok, Ph.D., MA, Professor, Department of Mental Health, Johns Hopkins University. We also appreciate the contributions of the study staff.

Publisher Copyright:
© 2018 The Author(s).


  • Aerobic exercise
  • Aerobic fitness
  • Alzheimer's disease
  • Cognitive training
  • Executive function
  • Memory
  • Neuroimaging


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