Longitudinal trajectories of amyloid-β-driven alterations in voxel-mirrored homotopic connectivity and cognitive decline in mild cognitive impairment

BackgroundAmyloid-β (Aβ) deposition in mild cognitive impairment (MCI) disrupts interhemispheric homotopic connectivity, yet its longitudinal course is unclear.ObjectiveWe aim to characterize the longitudinal decay of voxel-mirrored homotopic connectivity (VMHC) in MCI patients, elucidate underlying Aβ-associated mechanisms, and link these processes to cognitive decline.MethodsEighty-three ADNI participants (60 MCI, 23 cognitively normal [CN]) underwent baseline and two-year follow-up. MCI cases were stratified by ¹⁸F-AV45 PET into Aβ-positive (MCI-Aβ+, n = 44) and Aβ-negative (MCI-Aβ-, n = 16) subgroups. VMHC and corpus-callosum volume were compared across groups (ANOVA). Spearman correlations linked regional VMHC to cognition, cerebrospinal fluid (CSF) biomarkers, and callosal volume. Linear mixed-effects models tested group-by-time interactions; two-year VMHC change was related to parallel cognitive decline.ResultsAt baseline, MCI-Aβ- patients showed lower VMHC in the fusiform and postcentral gyri, whereas MCI-Aβ+ patients exhibited additional reductions in the precuneus, superior frontal gyrus, cerebellum, and superior occipital gyrus. Lower VMHC correlated with poorer cognition, corpus-callosum atrophy, and abnormal CSF profiles; callosal volume itself did not differ between groups. Longitudinally, MCI-Aβ+ participants exhibited a slower VMHC decline across the posterior cingulate, cerebellum and thalamus. Two-year cumulative change in VMHC inversely correlated with change in cognitive performance.ConclusionsAβ burden shapes distinct trajectories of interhemispheric connectivity loss in MCI. VMHC decline tracks multi-domain cognitive deterioration and may serve as a biomarker of progression toward Alzheimer's disease.