Understanding cerebral blood flow dynamics for Alzheimer’s disease prevention through acute exercise (flADex): Protocol for a randomized crossover trial
Authors: Martín-Fuentes Isabel , Fernandez-Gamez Beatriz , Vidal-Almela Sol , Caro-Rus Alfredo , Solis-Urra Patricio , Sánchez-Aranda Lucía , Fernández-Ortega Javier , Sanchez-Martinez Javier , Coca-Pulido Andrea , Olvera-Rojas Marcos , Barranco-Moreno Emilio J. , Marin-Alvarez Jose D. , Bakker Esmée A. , Toval Angel , Bellón Darío , Sclafani Alessandro , Karikari Thomas K. , Erickson Kirk I. , Gómez-Río Manuel , Ortega Francisco B. , Esteban-Cornejo Irene 
Published: January 2025

ABSTRACTINTRODUCTIONAlzheimer’s 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 APOEε4 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 (Aβ42, Aβ40, 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.HighlightsExercise may delay the development of AD, but its physiological mechanisms are unclear.flADex explores exercise-induced changes in CBF and blood biomarkers.20 older adults will undergo a bout of aerobic, resistance exercise, and resting.CBF may increase more after aerobic exercise, with changes varying by brain region.Standardized rest conditions before blood sampling may enhance diagnostic accuracy.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 #WO2020193500A1and patent applications #2450702-2, #63/693,956, #63/679,361, and63/672,952.