Work

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

Year: 2026

Type: article

Abstract: • The stability of FC GW was confirmed, along with its association with tau burden. • Simulated tau spread pattern emphasized the critical role of white matter in facilitating tau propagation. • Future tau accumulation in AD could be predicted by baseline tau levels and both FC GG and FC GW . • These findings support the hypothesis that pathological tau spreads between brain regions via GM–WM functional connectivity in AD. 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.

Source: NeuroImage

DOI: 10.1016/j.neuroimage.2026.121904