Understanding cerebral blood flow dynamics for Alzheimer's disease prevention through acute exercise (flADex): Protocol for a randomized crossover trial

INTRODUCTIONAlzheimers disease (AD) is a leading cause of disability worldwide. Alterations in cerebral blood flow (CBF) and AD blood biomarkers are fundamental at early stages of AD. Exercise shows promise in delaying physiological changes, but its mechanisms for enhancing brain health remains unclear. FlADex aims to examine the acute effects of different exercise types on CBF and blood biomarkers in older adults. This protocol describes the methodology and rationale of flADex. METHODSFlADex is a counterbalanced crossover trial that will include 20 older adults aged 68 to 83 years old with negative brain amyloid status (<12 centiloid) and APOE{varepsilon}4 noncarriers. Participants will complete a 30-minute session of each condition in a randomized order: (i) moderate-intensity aerobic exercise (60-70% maximal heart rate), (ii) moderate-intensity resistance exercise (rating of perceived exertion: 4-6 points out of 10), and (iii) resting condition. Changes in the CBF is the primary outcome and will be assessed by magnetic resonance imaging using pseudo-continuous arterial spin labeling at pre- and at 3 timepoints post-condition (starting at 20, 27, 34 minutes). Secondary outcomes are biomarkers of AD pathology and neurodegeneration (A{beta}42, A{beta}40, p-tau217, p-tau181, BD-tau, GFAP, NfL) and growth factors (BDNF, IGF-1), measured through blood samples collected at pre- and post-condition (at 3, 50, 70 minutes). Moreover, cognitive outcomes and mood status will be measured pre- and post-condition. DISCUSSIONFlADex will highlight the acute effects of exercise types on CBF and biomarkers before beta-amyloid accumulation. Acute effects on CBF dynamics and blood biomarkers are expected to be greater with aerobic than resistance exercise when compared to resting. CBF is expected to vary by brain region, and biomarkers to fluctuate dynamically post-exercise. This will provide critical insights into exercise impact on vascular and molecular pathways associated with AD pathology, and potential recommendations for standardized blood sampling to enhance diagnostic accuracy. HighlightsO_LIExercise may delay the development of AD, but its physiological mechanisms are unclear. C_LIO_LIflADex explores exercise-induced changes in CBF and blood biomarkers. C_LIO_LI20 older adults will undergo a bout of aerobic, resistance exercise, and resting. C_LIO_LICBF may increase more after aerobic exercise, with changes varying by brain region. C_LIO_LIStandardized rest conditions before blood sampling may enhance diagnostic accuracy. C_LI Declarations of interestTKK has consulted for Quanterix Corp., has received honoraria from the NIH for study section membership, and honoraria for speaker/grant review engagements from UPENN, UW-Madison, Advent Health, Brain Health conference, Barcelona-Pittsburgh conference and CQDM Canada, all outside of the submitted work. TKK has received blood biomarker data on defined research cohorts from Janssen and Alamar Biosciences for independent analysis and publication, with no financial incentive and/or research funding included. TKK is an inventor on patent #WO2020193500A1 and patent applications #2450702-2, #63/693,956, #63/679,361, and 63/672,952.