Mapping brain change longitudinally: physical activity intervention reshapes structural alterations and functional connectivity in Alzheimer's disease

Abstract INTRODUCTION Physical activity is a promising non‐pharmacological approach to support brain health. Although prior studies suggest cognitive benefits, it remains unclear how exercise alters brain structure and connectivity on the Alzheimer's disease (AD) continuum and whether such neural changes translate to functional improvements. This study investigated whether a multicomponent physical‐activity program induced measurable brain changes across the AD continuum. METHODS In the Dementia‐MOVE (Multi‐Objective Validation of Exercise) randomized‐controlled trial, 46 participants with early AD were allocated to either a 6‐month multicomponent physical activity intervention ( n = 25) or a psychoeducation program ( n = 21). Magnetic resonance imaging (MRI) and clinical assessments were conducted at baseline (T 1 ), after intervention (T 3 ), and 18 months (T 4 ) after T 1 . Structural MRI was conducted at all timepoints; resting‐state functional MRI was conducted at T 1 and T 3 . Longitudinal analyses evaluated changes in brain volume and functional connectivity and their correlations with cognitive, physical, and fitness profiles. RESULTS Structural analyses revealed long‐term reductions in gray and white matter volumes and ventricular expansion in both groups, with no significant group‐by‐time interaction. There was no significant change on brain structure right after intervention at T 3 . In contrast, functional connectivity increased after an intervention in the physical activity group, particularly in frontal, limbic, and cerebellar regions. Between‐group comparisons showed higher connectivity in the intervention group at T 3 with no difference in connectivity between both groups at T 1 . Correlation analyses demonstrated stronger and more widespread association patterns between brain metrics, especially on the functional level, and cognitive, fitness, and activity measures in the intervention group at follow‐up. DISCUSSION These findings suggest that structured physical activity induces functional reorganization and strengthens brain–behavior coupling in early AD, while structural differences between groups stabilize first and decline after cessation of the intervention. Multimodal imaging may offer a sensitive approach to detecting early neuroplasticity responses, and sustained engagement may therefore be necessary to maintain effects.