# Precision exercise in older adults with early Alzheimer’s disease: The study protocol of the FIT-AD Sequential, Multiple Assignment, Randomized Trial (SMART)

## TL;DR

This study tests how tailoring aerobic exercise to individual fitness responses can improve outcomes in older adults with early Alzheimer's disease.

## Contribution

The study introduces a precision exercise approach based on aerobic fitness responses in early Alzheimer’s disease.

## Key findings

- The trial will assess effects of aerobic exercise on aerobic fitness and brain imaging markers in early Alzheimer’s patients.
- It aims to identify the best exercise strategy to improve fitness and reduce non-responders over six months.
- The study will examine mechanisms linking aerobic exercise to cognitive outcomes in Alzheimer’s.

## Abstract

Aerobic exercise is promising for preventing Alzheimer’s disease (AD) and AD-related dementia (ADRD), but exercise trials have shown mixed results. An important, understudied factor potentially contributing to mixed results is individual differences in aerobic fitness responses to moderate-intensity continuous training (MICT). This trial will test the effects and mechanisms of 6 months of aerobic exercise tailored on aerobic fitness response to MICT in community-dwelling older adults with early symptomatic AD. We aim to (I) test the effects of aerobic exercise on aerobic fitness, white matter hyperintensity volume (WMHv), and patient-centered outcomes in older adults with early symptomatic AD; (II) determine the best exercise to improve aerobic fitness and reduce non-responses over 6 months; and (III) examine the mechanisms of aerobic exercise’s action on cognition.

This stage II trial is a Sequential, Multiple Assignment, Randomized Trial (SMART). The hypothesis is that MICT augmented with high-intensity interval training (HIIT) or combined aerobic and resistance exercise (CARE) will improve aerobic fitness, WMHv, and AD/ADRD plasma biomarkers. This trial will enroll 108 dyads (participants and their study partners). Participants (n = 108) are randomized using a 2:1 allocation ratio to 3-month MICT or 6-month stretching control. After the initial 3-month intervention period for participants assigned to MICT, aerobic fitness is measured with peak oxygen consumption (VO2peak) from a cycle-ergometer exercise testing and the shuttle walk test to identify non-response (< 5% increase). Non-responders are subsequently re-randomized (1:1) to either HIIT or CARE for 3 months. Responders continue MICT. All participants are followed for an additional 6 months post-intervention. Primary outcomes are VO2peak measured at 0, 3, 6, 9, and 12 months and WMHv at 0, 6, and 12 months. Secondary outcomes include memory, physical function, behavioral and psychological symptoms of dementia (BPSD), quality of life (QoL), caregiver burden, and AD plasma biomarkers. This trial has 80% power, assuming 18% and 25% attrition at 6 and 12 months, respectively, to detect changes in aerobic fitness.

Individual differences in VO2peak responses were reported in older adults with AD/ADRD previously but how this affects response to exercise interventions is unknown, Precision exercise tailored to VO2peak is critical to advance exercise research in AD.

ClinicalTrials.gov NCT05877196. Registered on May 25, 2023.