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 - ABSTRACT Aerobic exercise is a promising treatment for Alzheimer’s disease (AD) and AD-related dementia (ADRD), but exercise trials have 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 Individual differences in aerobic-fitness responses, long established in adults using peak oxygen consumption (VO2peak) and first reported in older adults with ADRD by our team. AD/ADRD exercise trials report large variance in VO2peak changes from moderate-intensity continuous training (MICT). Mechanistically, animal studies support aerobic exercise modifying AD’s AT(N) biomarkers (Amyloid-beta [Aβ], Tau, and Neurodegeneration), but similar human studies are rare. Hence, precision exercise is critical to identify MICT non-response early to initiate alternative interventions (High Intensity Interval Training [HIIT] or Combined Aerobic and Resistance Exercise [CARE]). Because VO2peak can improve and peak from 3-month MICT, it is logical to use VO2peak at 3 months to identify non-response and initiate HIIT or CARE. This Phase II, pilot trial will be a Sequential, Multiple Assignment, Randomized Trial. Its purpose is to test the effects of 6-month aerobic exercise on aerobic fitness and its mechanisms of action in community-dwelling older adults with mild AD dementia. Our central hypothesis is that MICT augmented with HIIT or CARE will improve aerobic fitness, white matter hyperintensity (WMH), and plasma biomarkers, which underlie exercise’s cognitive effects. This trial builds on our previous work showing: successful recruitment, retention, adherence, and safety; 6-month MICT maintained memory and reduced WMH; individual differences in VO2peak and cognitive responses to MICT; MICT improved physical function, QoL, and caregiver distress; plasma neurofilament light chain (NfL) predicted cognition; and MICT affected plasma p-tau181. It will randomize 108 participants 2:1 to 3-month MICT or 6-month stretching control after baseline. VO2peak will be assessed after 3-month MICT to identify non- responders (<5% increase) and re-randomize them 1:1 to HIIT or CARE for 3 months. Responders will continue MICT for 3 months. Participants will be followed for another 6 months. Primary outcomes are aerobic fitness measured at 0, 3, 6, 9, and 12 months and WMH volume at 0, 6, and 12 months. Secondary outcomes (memory, physical function, BPSD, QoL, caregiver burden) and plasma Aβ42/40, p-tau181, t-tau, and NfL will be assessed at 0, 3, 6, 9, and 12 months. This trial has 80% power for all primary hypotheses, assuming 18% and 25% attrition at 6 and 12 months, respectively. The specific aims are to: I) test the effects of aerobic exercise on aerobic fitness, WMH volume, and patient-centered outcomes in older adults with mild AD dementia; II) the best exercise to improve aerobic fitness and reduce non-responses over 6 months in older adults with mild AD dementia; and III) examine the mechanisms of aerobic exercise’s action on memory in mild AD dementia. This trial is the first precision-exercise trial in AD, and will utilize MRI/blood biomarkers, which are scalable.
