A SMART Trial of Adaptive Exercises to Optimize Aerobic-Fitness Responses

Not Applicable

Recruiting

• Conditions: Mild Cognitive Impairment; Memory Impairment; Memory Loss; Alzheimer Disease; Cognitive Impairment; Cognitive Decline
• Interventions: Behavioral: High-Intensity Interval Training (HIIT); Behavioral: Chair-based Stretch; Behavioral: Moderate Intensity Continuous Training (MICT); Behavioral: Combined Aerobic Resistance Exercise (CARE)

• Registration Number: NCT05877196
• Lead Sponsor: Arizona State University

Brief Summary

The goal of this clinical trial is to test 6 months of aerobic exercise in older adults who are 65 years or older and have mild cognitive impairment (MCI) or probable/possible mild Alzheimer's Disease. The main questions it aims to answer are:

* test the effects of aerobic exercise on aerobic fitness, white matter hyperintensity (WMH) volume, and patient-centered outcomes;

* identify the best exercise to improve aerobic fitness and reduce non-responses over 6 months; and

* examines the mechanisms of aerobic exercise's action on memory in older adults with early AD.

Participants will receive 6 months of supervised exercise, undergo cognitive data collection and exercise testing 5 times over a year span, have an MRI brain scan 3 times over a one-year span, and have monthly follow-up discussions on health and wellness.

Detailed Description

The purpose of this Phase II, mechanistic Sequential, Multiple Assignment, Randomized Trial (SMART) is to test the effects of 6-month aerobic exercise on aerobic fitness and MRI and plasma biomarkers in community-dwelling older adults with early Alzheimer's disease (AD). The aims are to (I) test the effects of aerobic exercise on aerobic fitness, white matter hyperintensity (WMH) volume, and patient-centered outcomes; (II) identify the best exercise to improve aerobic fitness and reduce non-responses over 6 months; and (III) examines the mechanisms of aerobic exercise's action on memory in older adults with early AD. This trial builds on our previous work showing inter-individual differences in VO2peak responses to moderate-intensity continuous training (MICT); an ability of plasma neurofilament light chain (NfL) to predict cognition; and 6-month MICT maintained memory, reduced WMH, affected plasma p-tau181, and improved physical function, QoL, and caregiver distress. Aerobic exercise is a promising treatment for Alzheimer's disease (AD) and AD-related dementia (ADRD) but has shown mixed effects on cognition, physical function, behavioral and psychological symptoms of dementia (BPSD), quality of life (QoL), and caregiver burden. These findings are likely due to inter-individual differences in aerobic fitness responses, which have long been established in adults using VO2peak and were first reported in AD/ADRD by our team. Most AD/ADRD exercise trials did not measure VO2peak and those that reported large inter-individual differences in VO2peak responses to MICT. Mechanistically, animal studies support aerobic exercise modifying AD's ATN biomarkers (Amyloid-beta \[Aβ\], Tau, and Neurodegeneration), but human studies are few and have conflicting findings. Hence, precision exercise is critical to improving VO2peak responses with alternative interventions (high-intensity interval training (HIIT) or combined aerobic \& resistance exercise (CARE)). Because VO2peak can improve and peak from 3 months of MICT, 3 months is an ideal time to identify MICT non-responders and initiate HIIT or CARE.

Study Timeline

• Study First Submitted: 2023-04-03
• Study First Submitted QC: 2023-05-25
• Study First Posted: 2023-05-26
• Study Start: 2023-06-22
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-18
• Last Update Posted: 2025-04-22
• Primary Completion: 2027-04-01
• Study Completion: 2028-06-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 216

Inclusion Criteria

Participants:

• Clinical diagnosis of MCI or probable and possible mild AD dementia according to 2011 Alzheimer's association-NIA criteria.
• Community-dwelling, e.g., homes and assisted living
• Age 65 years and older
• Medical clearance from PCP or cardiovascular provider
• Have a qualified study partner
• Agree to the blood draws
• Verified MRI safety

Study Partner:

• Age 18 or older
• Contact with participant ≥ 2 times per week for ≥ 6 months
• Know the participant's memory status and ability to perform activities of daily living
• Consent to participant

Exclusion Criteria

Participants

• Resting HR ≤ 50 or ≥ 100 beats/min after 5-minutes of quiet resting
• American College of Sports Medicine contraindications to exercise
• New, unevaluated symptoms or diseases a healthcare provider has not evaluated
• Abnormal cardiac condition uncovered during VO2peak testing
• Enrollment in another intervention that aims at improving cognition
• Moderate to strenuous exercise ≥150 minutes a week in the previous 6 months
• ≥ 2 anti-depression medications, or poorly managed or unstable depression
• Poorly managed or unstable anxiety

Study partners:

• none

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
High-Intensity Interval Training (HIIT)	High-Intensity Interval Training (HIIT)	MICT for 3 months, and then cycling on recumbent stationary cycle at alternate high and moderate intensity for 40 minutes, 3 times per week for 3 months.
Chair-based Stretch	Chair-based Stretch	Stretching at low intensity for 30-50 minutes, 3 times per week for 6 months
Moderate Intensity Continuous Training (MICT)	Moderate Intensity Continuous Training (MICT)	Cycling on recumbent stationary cycle at moderate intensity for 30-50 minutes, 3 times per week for 3-6 months
Combined Aerobic Resistance Exercise (CARE)	Combined Aerobic Resistance Exercise (CARE)	MICT for 3 months, and then cycling on recumbent stationary cycle at moderate intensity for 30 minutes, followed by 20-minute strength-building exercise, 3 times per week for 3 months.

Primary Outcome Measures

Name	Time	Method
Peak oxygen consumption	measured at 0 and 6 months	VO2peak will be assessed from the symptom-limited peak cycle-ergometer test
White Matter Hyperintensity volume	measured at 0 and 6 months	WMH will be assessed from MRI.

Secondary Outcome Measures

Name	Time	Method
Blood phosphorylated tau 181	measured at 1, 3, 6, 9, & 12 months	20 mL blood sample collection
Memory	measured at 0, 6, and 12 months	Wechsler Memory Scale - Revised; Logical Memory; score 0-50; higher scores indicate less impairment
Physical function	measured at 0, 3, 6, 9, & 12 months	Short Physical Performance Battery: score 0-12; lower scores indicate poorer physical function
Behavioral and psychiatric symptoms of dementia (BPSD)	measured at 1, 3, 6, 9, & 12 months	Neuropsychiatric Inventory Questionnaire; symptoms present, if yes, then severity and caregiver distress are reported.
Blood total tau, neurofilament light chain	measured at 1, 3, 6, 9, & 12 months	20 mL blood sample collection
Caregiver burden	measured at 1, 3, 6, 9, & 12 months	4-item Zarit Burden Interview: score 0-16; higher scores reflect greater burden
Quality of Life (QoL)	measured at 1, 3, 6, 9, & 12 months	Quality of Life - AD: score 0-52; higher scores reflect greater life satisfaction
Blood amyloid-beta 42 and 40	measured at 1, 3, 6, 9, & 12 months	20 mL blood sample collection

Trial Locations

Locations (1)

Arizona State University; 🇺🇸 Phoenix, Arizona, United States