Understanding Cerebral Blood Flow Dynamics for Alzheimer's Disease Prevention Through Acute Exercise (flADex): Protocol for a Randomized Crossover Trial

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Abstract
Introduction: Alzheimer'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 remain 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. Methods: flADex is a counterbalanced crossover trial in 20 older adults, aged 68–83 years old, with negative brain amyloid status (< 12 centiloid) who are APOEε4 noncarriers. Participants will complete a 30‐min session of each condition in a randomized order: (i) moderate‐intensity aerobic exercise (60%–70% age‐predicted maximal heart rate), (ii) moderate‐intensity resistance exercise (rating of perceived exertion: 4–6 points out of 10), and (iii) resting condition. Changes in CBF are 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 min). 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 min). Moreover, cognitive outcomes and mood status will be measured pre‐ and post‐condition. Conclusion: flADex will highlight the acute effects of different 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 postexercise. This will provide critical insights into exercise's impact on vascular and molecular pathways associated with AD pathology and potential recommendations for standardized blood sampling to enhance diagnostic accuracy.

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