While amyloid-beta (Aβ) and tau are known to be the key neuropathological hallmarks of Alzheimer’s disease (AD), imaging and postmortem studies highlight significant variability in disease severity and progression even in subjects with similar burdens of Aβ and tau accumulation. This uncertainty in the trajectory of disease progression results in substantial challenges for patients and their families in understanding disease prognosis, as well as the research community in understanding heterogeneity in the rate of Aβ and tau accumulation, cognitive decline, and likelihood of progressing to dementia. In this study, we developed and validated the Tau Progression Index (TPI); a multimodally derived score that leverages strongly supported hypotheses and models of tau spread, to serve as a reliable, and clinically applicable biomarker of AD progression. TPI has 4 components: 1) Remote interaction (TPI-ri) interactions between Aβ and tau pathologies in regions that spatially separate; 2) Local interaction (TPI-li) between co-localized Aβ and tau pathology; 3) Functional connectivity (TPI- fc) is based on functional magnetic resonance imaging (fMRI)-measured inter-regional functional connections facilitate the spread of tau in the brain; and 4) Structural connectivity (TPI-sc) based on diffusion MRI (dMRI)-measured inter-regional structural connectivity. Importantly, all prior models of tau spread in AD were based on group-averaged structural and functional connectivity, derived from healthy and often young subjects. However, brain connectivity patterns are extremely subject-specific, often referred to as a human connectome fingerprint, and are significantly altered by aging and neurodegenerative diseases. Therefore, we have shown that TPI computed by subject-specific connectomes is crucial to accurately model subject-specific trajectories of tau spread.

The authors have declared no competing interest.

This study did not receive any funding

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The data and subsequent studies are approved with two IRBs. One at Columbia university and another one at Weill Cornell Medicine.

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The data for this project are confidential but may be obtained with Data Use Agreements with the Weill Cornell Medicine and Columbia University Irving Medical Center. It can take some weeks to negotiate data use agreements and gain access to the data. The author will assist with any reasonable replication attempts for the following publication.