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

Alzheimer’s disease is marked by progressive cognitive decline, but the directed network mechanisms behind that decline—and how they respond to neuromodulation—remain incompletely understood. A new study guided by the triple network model set out to map effective connectivity among three key brain networks: the default mode network, the central executive network, and the salience network, across the Alzheimer’s disease spectrum, and then to test whether intermittent theta burst stimulation could modify those connections.

The researchers analyzed resting-state functional magnetic resonance imaging data from two separate cohorts. The first was a cross-sectional discovery cohort from the Alzheimer’s Disease Neuroimaging Initiative comprising 280 participants. The second was an independent pilot longitudinal interventional cohort of 37 patients with mild cognitive impairment, who were randomized to receive either active or sham intermittent theta burst stimulation.

To estimate effective connectivity within the triple network, the team used group independent component analysis together with spectral dynamic causal modeling. They then performed an exploratory imaging-transcriptomic analysis of the network maps derived from the independent component analysis, drawing on gene expression data from the Allen Human Brain Atlas.

The cross-sectional analysis revealed that seven connections showed significant group differences across the Alzheimer’s disease spectrum. This pattern pointed to a dysregulation centered on the default mode network, with dysfunction of the posterior default mode network emerging as a central feature of the disease process.

With those seven altered connections identified, the investigators turned to the longitudinal cohort to see whether neuromodulation could shift them. They compared changes in the seven connections from before to after the intervention between patients receiving active stimulation and those receiving sham stimulation.

The results showed that intermittent theta burst stimulation was associated with greater decreases in two specific connections: the pathway from the salience network to the anterior default mode network, and the self-inhibition of the posterior default mode network. Importantly, these connectivity changes were associated with cognitive improvement in the patients.

The exploratory imaging-transcriptomic analysis added a molecular dimension to the findings. The spatial topography of the posterior default mode network was associated with cortical gene expression profiles enriched for postsynaptic organization and synaptic regulatory processes, hinting at the biological pathways that may underlie this network’s vulnerability.

The authors conclude that the study identifies default mode network-centered effective connectivity alterations across the Alzheimer’s disease spectrum and provides preliminary support for further evaluation of intermittent theta burst stimulation as a potential therapeutic strategy. Because the interventional arm was a small pilot study of 37 patients with mild cognitive impairment, and the transcriptomic analysis was exploratory, these findings will require confirmation in larger, longer-term trials before any clinical recommendations can be drawn.

The study, published open access in Alzheimer’s Research & Therapy on 17 October 2026, is being shared early as a peer-reviewed, accepted version of record that remains citable and carries a permanent DOI, with a final version to follow automatically.

Subject of Research: Effective connectivity among the default mode, central executive, and salience networks across the Alzheimer's disease spectrum and its modulation by intermittent theta burst stimulation

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

Article References: Zheng, W., Zhang, Y., Shan, Q., Lv, T., Yao, W., Liu, Y., Yu, Q., Song, Y., Bai, Y., & Bai, F. (2026). Triple network effective connectivity imbalance across the Alzheimer’s disease spectrum and its modulation by intermittent theta burst stimulation. Alzheimer's Research & Therapy. https://doi.org/10.1186/s13195-026-02233-y

Image Credits: AI Generated

DOI: 10.1186/s13195-026-02233-y

Keywords: Alzheimer's disease, effective connectivity, default mode network, salience network, central executive network, intermittent theta burst stimulation, neuromodulation, mild cognitive impairment, resting-state fMRI, dynamic causal modeling, imaging transcriptomics, Allen Human Brain Atlas