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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Precision Medicine in Alzheimer's Disease: A SMART Trial of Adaptive Exercises and Their Mechanisms of Action Using AT(N) Biomarkers to Optimize Aerobic-Fitness Responses (The FIT-AD SMART Trial)

Conditions
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Mild Cognitive Impairment, Alzheimer Disease, Cognitive Impairment, Cognitive Decline, Memory Loss, Memory Impairment

Intervention / Treatment
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* Behavioral: Moderate Intensity Continuous Training (MICT)
* Behavioral: Chair-based Stretch
* Behavioral: High-Intensity Interval Training (HIIT)
* Behavioral: Combined Aerobic Resistance Exercise (CARE)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Sequential, Multiple Assignment, Randomized Trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Moderate Intensity Continuous Training (MICT)<br>Cycling on recumbent stationary cycle at moderate intensity for 30-50 minutes, 3 times per week for 3-6 months | Behavioral: Moderate Intensity Continuous Training (MICT)<br>* Aerobic cycling at a moderate intensity (50-75% of heart rate reserve) for 30-50 minutes, 3 times per week for 3-6 months.<br>* Other names: Cardio;|
| Sham Comparator: Chair-based Stretch<br>Stretching at low intensity for 30-50 minutes, 3 times per week for 6 months | Behavioral: Chair-based Stretch<br>* Stretching while seated for 30-50 minutes, 3 times per week for 6 months.<br>* Other names: flexibility;|
| Active Comparator: High-Intensity Interval Training (HIIT)<br>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. | Behavioral: High-Intensity Interval Training (HIIT)<br>* Aerobic cycling at a vigorous intensity (80-90% of heart rate reserve 4-minute bouts with 4-minute recovery intervals) for 40 minutes, 3 times per week for 3 months.<br>* Other names: Hard exercise;|
| Active Comparator: Combined Aerobic Resistance Exercise (CARE)<br>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. | Behavioral: Combined Aerobic Resistance Exercise (CARE)<br>* 6 full-body strength-building exercises followed by 30 minutes of MICT cycling (described above). Total duration is 60 minutes, 3 times per week for 3 months.<br>* Other names: Exercise training;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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