Impact of amyloid-Beta on the functional hierarchies and clinical outcomes in late-life depression

Abstract

Late-life depression (LLD) is characterized by high treatment resistance, particularly in patients with significant cerebral amyloid-beta (Aβ) deposition. However, the underlying mechanisms through which Aβ compromises clinical recovery remain poorly understood. We investigated whether Aβ burden drives treatment resistance by inducing hierarchical rigidity in the brain's macroscale functional organization. We analyzed longitudinal resting-state fMRI and amyloid-PET data from 93 LLD patients (44 Aβ+, 49 Aβ-) over a one-year treatment interval. Functional connectivity (FC) gradients were constructed using diffusion map embedding to characterize the sensory-to-transmodal cortical hierarchy. At baseline, Aβ + patients exhibited widespread FC gradient aberrations, primarily within the frontoparietal control and default mode networks, despite equivalent depression severity to Aβ- patients. Following treatment, the Aβ + group showed significantly poorer clinical remission (p < 0.001). Longitudinal analysis revealed a lack of significant group × time interaction, indicating that gradient disorganization in Aβ + LLD remained unresolved. Cerebral Aβ acts as a physiological constraint on the hierarchical plasticity required for antidepressant response. This “hierarchical rigidity” suggests that Aβ anchors the brain in a dysfunctional, compressed state, precluding the adaptive reorganization necessary for recovery. Baseline functional gradients may serve as a potent prognostic marker for identifying amyloid-associated treatment resistance in LLD.