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

Official title

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)

Overview

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.

Interventions

• Behavioral Moderate Intensity Continuous Training (MICT)
  Aerobic cycling at a moderate intensity (50-75% of heart rate reserve) for 30-50 minutes, 3 times per week for 3-6 months.
• Behavioral Chair-based Stretch
  Stretching while seated for 30-50 minutes, 3 times per week for 6 months.
• Behavioral High-Intensity Interval Training (HIIT)
  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.
• Behavioral Combined Aerobic Resistance Exercise (CARE)
  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.

Primary outcome measures

• Peak oxygen consumption [Time frame: measured at 0 and 6 months]
• White Matter Hyperintensity volume [Time frame: measured at 0 and 6 months]

Secondary outcome measures (8)

• Memory [Time frame: measured at 0, 6, and 12 months]
• Physical function [Time frame: measured at 0, 3, 6, 9, & 12 months]
• Behavioral and psychiatric symptoms of dementia (BPSD) [Time frame: measured at 1, 3, 6, 9, & 12 months]
• Caregiver burden [Time frame: measured at 1, 3, 6, 9, & 12 months]
• Quality of Life (QoL) [Time frame: measured at 1, 3, 6, 9, & 12 months]
• Blood amyloid-beta 42 and 40 [Time frame: measured at 1, 3, 6, 9, & 12 months]
• Blood phosphorylated tau 181 [Time frame: measured at 1, 3, 6, 9, & 12 months]
• Blood total tau, neurofilament light chain [Time frame: measured at 1, 3, 6, 9, & 12 months]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Sequential

Masking

Double blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Arizona State University — Phoenix

Publications

• Almirall D, Nahum-Shani I, Sherwood NE, Murphy SA. Introduction to SMART designs for the development of adaptive interventions: with application to weight loss research. Transl Behav Med. 2014 Sep;4(3):260-74. doi: 10.1007/s13142-014-0265-0. PMID 25264466
• Salisbury D, Mathiason MA, Yu F. Exercise Dose and Aerobic Fitness Response in Alzheimer's Dementia: Findings from the FIT-AD Trial. Int J Sports Med. 2022 Sep;43(10):850-858. doi: 10.1055/a-1639-2307. Epub 2021 Sep 7. PMID 34492709
• Pandey A, Swift DL, McGuire DK, Ayers CR, Neeland IJ, Blair SN, Johannsen N, Earnest CP, Berry JD, Church TS. Metabolic Effects of Exercise Training Among Fitness-Nonresponsive Patients With Type 2 Diabetes: The HART-D Study. Diabetes Care. 2015 Aug;38(8):1494-501. doi: 10.2337/dc14-2378. Epub 2015 Jun 17. PMID 26084342
• Huang G, Wang R, Chen P, Huang SC, Donnelly JE, Mehlferber JP. Dose-response relationship of cardiorespiratory fitness adaptation to controlled endurance training in sedentary older adults. Eur J Prev Cardiol. 2016 Mar;23(5):518-29. doi: 10.1177/2047487315582322. Epub 2015 Apr 21. PMID 25901000
• Salisbury D, Yu F. Establishing Reference Cardiorespiratory Fitness Parameters in Alzheimer's Disease. Sports Med Int Open. 2020 Jan 30;4(1):E1-E7. doi: 10.1055/a-1089-4957. eCollection 2020 Jan. PMID 32010759
• Gomes-Neto M, Duraes AR, Conceicao LSR, Roever L, Silva CM, Alves IGN, Ellingsen O, Carvalho VO. Effect of combined aerobic and resistance training on peak oxygen consumption, muscle strength and health-related quality of life in patients with heart failure with reduced left ventricular ejection fraction: a systematic review and meta-analysis. Int J Cardiol. 2019 Oct 15;293:165-175. doi: 10.1016/j PMID 31345646
• Lee J, Lee R, Stone AJ. Combined Aerobic and Resistance Training for Peak Oxygen Uptake, Muscle Strength, and Hypertrophy After Coronary Artery Disease: a Systematic Review and Meta-Analysis. J Cardiovasc Transl Res. 2020 Aug;13(4):601-611. doi: 10.1007/s12265-019-09922-0. Epub 2019 Oct 27. PMID 31656988
• Lee J, Stone AJ. Combined Aerobic and Resistance Training for Cardiorespiratory Fitness, Muscle Strength, and Walking Capacity after Stroke: A Systematic Review and Meta-Analysis. J Stroke Cerebrovasc Dis. 2020 Jan;29(1):104498. doi: 10.1016/j.jstrokecerebrovasdis.2019.104498. Epub 2019 Nov 13. PMID 31732460

Identifiers

NCT: NCT05877196 · STUDY00017678

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗