INTRODUCTION

In Alzheimer's disease (AD), fibrillar tau gradually progresses from initial seed to larger brain area. However, those brain properties underlying the region-dependent susceptibility to tau accumulation remain unclear.

METHODS

We constructed multimodal spatial gradients to characterize molecular properties and connectomic architecture. A predictive model for regional tau deposition was developed by integrating embeddings in the principal gradients of global connectome gradients with gene expression, neurotransmitters, myelin, and amyloid-beta. The model was trained on amyloid-beta-positive participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) and externally validated in independent datasets.

RESULTS

The combination of gradients explained up to 77.7% of cross-sectional and 77.3% of longitudinal inter-regional variance of tau deposition. Gene set enrichment analysis of a major gene expression gradient points to synaptic transmission to confer increased susceptibility to tau.

DISCUSSION

Our findings reveal a spatially heterogeneous molecular landscape shaping regional susceptibility to tau deposition, presenting a powerful system-level explanatory model of tau pathology in AD.

HIGHLIGHTS

Spatial gradients of fundamental molecular brain properties associated with tau pathology. The explanatory power showed high consistency across studies. Genetic analyses suggested that synapse expression plays a vital role in tau accumulation.