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Randomized Controlled Trial
. 2025 Apr;21(4):e70118.
doi: 10.1002/alz.70118.

Effects of exercise versus usual care on older adults with amnestic mild cognitive impairment: EXERT versus ADNI

Aladdin H Shadyab  1   2   3 , Vahan Aslanyan  4 , Diane M Jacobs  2   5 , David P Salmon  2   5 , Rosemary Morrison  2 , Jeffrey A Katula  6 , Shelia Jin  1   2 , Ronald G Thomas  1   2   5 , Andrea Z LaCroix  1   2 , Judy Pa  2   5 , Carl W Cotman  7 , Howard H Feldman  2   5 , Laura D Baker  8 ; ADCS EXERT Study Group
Affiliations
Randomized Controlled Trial

Effects of exercise versus usual care on older adults with amnestic mild cognitive impairment: EXERT versus ADNI

Aladdin H Shadyab et al. Alzheimers Dement. 2025 Apr.

Abstract

Introduction: EXERT was a multisite randomized controlled trial (RCT) examining the effects of moderate-high intensity aerobic training (AX) versus lower-intensity stretching/balance/range of motion (SBR) on cognitive trajectories in older adults with amnestic mild cognitive impairment (aMCI).

Methods: Preplanned post-hoc analyses were conducted to compare each arm to a propensity-matched usual care (no intervention) group from Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) selected for similarity across key characteristics. Differences in 12-month trajectories in the primary endpoint (ADAS-Cog-Exec) and magnetic resonance imaging (MRI) volumes in prespecified brain regions were compared.

Results: AX and SBR showed significantly less 12-month cognitive decline than ADNI-1 (AX:n = 109, β = 0.169, 95% confidence interval [CI] 0.011-0.328; SBR:n = 105, β = 0.181, 95% CI 0.007-0.354). There were trends of less prefrontal cortex volume loss for both EXERT groups and less AD signature region volume loss for SBR relative to ADNI-1 over 12 months.

Discussion: Moderate-high intensity aerobic or low-intensity flexibility exercise for 12 months in participants with aMCI may provide protection against decline relative to usual care.

Clinical trial registration: The EXERT clinical trial is registered at clinicaltrials.gov (NCT02814526).

Highlights: EXERT was a randomized controlled trial in sedentary older adults with aMCI. EXERT arms were propensity-matched to a usual care (no intervention) group (Alzheimer's Disease Neuroimaging Initiative 1 [ADNI-1]). High and low-intensity exercise arms had less 12-mo cognitive decline than ADNI-1. There were trends of less prefrontal cortex volume loss for each arm versus ADNI-1.

Keywords: aging; clinical trial; cognition; cognitive function; exercise; mild cognitive impairment; older adults; physical activity; sedentary.

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Conflict of interest statement

Feldman receives grant funding from the National Institute on Aging (U19AG010483), from Biohaven Pharmaceuticals, Vivoryon (Probiodrug), Allyx Therapeutics, and LuMind Foundation; service agreements for consulting activities with LuMind, Axon Neuroscience, Novo Nordisk, Biosplice Therapeutics, Arrowhead Pharmaceuticals, Roche/Genentech Pharmaceuticals (DMC/DSMB), Tau Consortium (SAB), Janssen Research & Development (DSMB); support for travel from Novo Nordisk, Royal Society of Canada, Translating Research in Elder Care (TREC), Association for Frontotemporal Dementia (AFTD), and Rainwater Charitable Foundation; and a philanthropic donation for the Epstein Family Alzheimer Research Collaboration. No personal funds have been received for these activities. Feldman personally receives royalties for patent: Feldman HH (filed November 26, 2008). Detecting and Treating Dementia Serial Number 12/3‐2691 US Patent No. PCT/US2007/07008. Washington, DC: U.S. Patent and Trademark Office. Baker reports grant funding from NIH (U19 AG010483, AG062689, AG066910, U19 AG063744, P30AG049638‐01A1, HL 133684‐01A1, AG064440, U24 AG057437) and Alzheimer's Association (POINTER‐19‐611541), honoraria from Washington State University and National Academy of Neuropsychology, payments from Alzheimer's Association and Oregon State University for invited speakerships, and participation in the Data Safety Monitoring Board for the Alzheimer Center at Washington State University. Katula reports funding from NIH (U19 AG010483) and Alzheimer's Association, and participation in the Data Safety Monitoring Board for South Asians Active Together (SAATH) study. Morrison reports funding from NIA (U19 AG010483). LaCroix reports NIA funding from ADCS. Shadyab reports funding from NIH/NIA (U19 AG010483). Jacobs reports funding from NIH/NIA, Biohaven Pharmaceuticals, Vivoryon Therapeutics, and the Epstein Family Alzheimer Research Collaboration. There are no conflicts to report for this work by other authors. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Comparison of mean 12‐month change in ADAS‐Cog‐Exec between EXERT AX and SBR arms versus matched ADNI‐1 participants. The primary outcome for EXERT was a global cognition composite measure, the ADAS‐Cog‐Exec, which was constructed and validated based on prior evidence and hypotheses about sensitivity of the specific components to exercise effects in older adults (executive function) and to longitudinal change in adults with aMCI. Participants in each EXERT arm were frequency matched using propensity score methods to ADNI‐1 participants according to age, sex, race, ethnicity, education, APOE ε4 genotype, and baseline MMSE. ADAS, Alzheimer's Disease Assessment Scale; ADNI‐1, Alzheimer's Disease Neuroimaging Initiative 1; APOE, apolipoprotein E; aMCI, amnestic mild cognitive impairment; MMSE, Mini‐Mental State Examination; SBR, stretching, balance, and range of motion.
FIGURE 2
FIGURE 2
Comparison of mean 12‐month change in brain imaging outcomes between EXERT AX and matched ADNI‐1 participants. Participants in each EXERT arm were frequency matched using propensity score methods to ADNI‐1 participants according to age, sex, race, ethnicity, education, APOE ε4 genotype, and baseline MMSE. ADNI‐1, Alzheimer's Disease Neuroimaging Initiative 1; APOE, apolipoprotein E; MMSE, Mini‐Mental State Examination.
FIGURE 3
FIGURE 3
Comparison of mean 12‐month change in brain imaging outcomes between EXERT SBR and matched ADNI‐1 participants. Participants in each EXERT arm were frequency matched using propensity score methods to ADNI‐1 participants according to age, sex, race, ethnicity, education, APOE ε4 genotype, and baseline MMSE. ADNI‐1, Alzheimer's Disease Neuroimaging Initiative 1; APOE, apolipoprotein E; MMSE, Mini‐Mental State Examination; SBR, stretching, balance, and range of motion.
See this image and copyright information in PMC

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