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

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)

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.

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.

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