Triple network effective connectivity imbalance across the Alzheimer’s disease spectrum and its modulation by intermittent theta burst stimulation

Alzheimer’s disease (AD) is characterized by progressive cognitive decline, yet the directed network mechanisms underlying this process and their responsiveness to neuromodulation remain incompletely understood. Guided by the triple network model, we investigated effective connectivity (EC) among the default mode network (DMN), central executive network (CEN), and salience network (SN) across the AD spectrum and examined its modulation by intermittent theta burst stimulation (iTBS). Resting-state functional magnetic resonance imaging data were analyzed from two cohorts: a cross-sectional Alzheimer’s Disease Neuroimaging Initiative discovery cohort including 280 participants, and an independent pilot longitudinal interventional cohort including 37 mild cognitive impairment patients randomized to active or sham iTBS. Group independent component analysis (ICA) and spectral dynamic causal modeling were used to estimate EC within the triple network, followed by exploratory imaging-transcriptomic of ICA-derived network maps analysis using the Allen Human Brain Atlas. Across the AD spectrum, seven connections showed significant group differences, indicating DMN-centered network dysregulation, with posterior DMN (pDMN) dysfunction emerging as a central feature. Subsequently, pre- to post-intervention changes in the seven altered connections were compared in the longitudinal cohort, and iTBS was associated with greater decreases in ‘SN-to-aDMN’ and ‘pDMN self-inhibition’, with these changes associated with cognitive improvement. Exploratory imaging-transcriptomic analysis further showed that pDMN spatial topography was associated with cortical gene expression profiles enriched for postsynaptic organization and synaptic regulatory processes. These findings suggest DMN-centered EC alterations across the AD spectrum and provide preliminary support for further evaluation of iTBS as a potential therapeutic strategy.