Individual gray-white matter functional connection predicts tau spread and cognitive decline in Alzheimer's disease

Alzheimer's disease is characterized by progressive accumulation of hyperphosphorylated tau protein, which propagates in a prion-like manner along connected neuronal pathways. However, it remains unclear whether functional connectivity between gray and white matter (FC_GW) can predict tau spread. This study aimed to determine the association between FC_GW and tau deposition and to evaluate its value in predicting longitudinal tau spread.

We integrated resting-state fMRI with cross-sectional and longitudinal tau-PET data from two independent cohorts. We assessed baseline associations between FC_GW and tau deposition and then constructed an individual-level spreading model to predict longitudinal tau accumulation.

In both cohorts, FC_GW showed a positive correlation with tau deposition. Model-simulated white-matter tau deposition was associated with clinical scales and predicted cognitive decline. The spreading model, which incorporated baseline tau-PET and the top 10% of gray and white matter, yielded the highest predictive performance for future tau accumulation.

FC_GW captures key network pathways underlying tau spread in AD and improves prediction of future tau accumulation. These findings highlight the importance of FC_GW in understanding tau propagation and support development of network-targeted therapeutic strategies.