Alzheimer's Imaging Consortium.

Area of Science:

• Neuroscience
• Neuroimaging
• Connectomics

Background:

• Previous research on tau spread focused on short-range connections within anatomical space.
• This study introduces connectome gradients, a novel coordinate system reflecting brain hierarchy, to analyze tau spread along long-range connections.
• Understanding tau spread in this new framework offers insights into network alterations and susceptibility in Alzheimer's disease (AD).

Purpose of the Study:

• To investigate tau spread along long-range connections using connectome gradients.
• To explore alterations in connectivity patterns associated with tau pathology in Alzheimer's disease.
• To understand how tau spread relates to the brain's hierarchical organization and network susceptibility.

Main Methods:

• Included 213 participants (A- CN, A+ CN, A+ CI) with diffusion-weighted MRI, resting-state fMRI, and 18F-MK6240 tau-PET.
• Employed graph theory-based stepwise connectivity analyses to map long-range connections from the entorhinal cortex.
• Investigated connectivity patterns in relation to tau within a coordinate system defined by functional and structural connectome gradients.

Main Results:

• Preclinical AD (A+ CN) showed increased connectivity in functional gradient space compared to controls (A- CN).
• Clinical AD (A+ CI) exhibited reduced connectivity from the entorhinal cortex to specific gradient ends (transmodal/DMN/limbic and posterior/temporo-occipital).
• Tau-connectivity correlations shifted spatially within gradient space with disease progression, indicating network reorganization.

Conclusions:

• A novel integration of stepwise connectivity and connectome gradients enhances understanding of tau spread along major brain organization axes.
• Widespread network reorganization was observed in Alzheimer's disease.
• Tau-connectivity correlations shift between major functional connectome networks during disease progression.