Network‐dependent remote effects and local tau burden jointly shape neuronal dysfunction in Alzheimer's disease

Abstract BACKGROUND Tau pathology in Alzheimer's disease (AD) propagates along the brain's connectome, yet the mechanisms by which tau drives neuronal dysfunction remain unclear. We hypothesized that dysfunction primarily emerges in regions close to tau‐harboring epicenters. METHODS One hundred thirty‐one amyloid‐positive individuals underwent dynamic [ 18 F]PI‐2620 tau positron emission tomography. Kinetic modeling yielded distribution volume ratios (DVRs) and perfusion (R1). Tau epicenters were defined as top 10% DVR regions. Connectivity‐based distance to epicenters was derived from normative resting‐state functional connectivity. RESULTS At the individual level, hypoperfusion was more closely related to distance from tau epicenters than to local tau deposition, particularly in early AD, consistent with diaschisis‐like disconnection. With advancing biological disease severity, local tau deposition increasingly converged with hypoperfusion. Critically, hypoperfusion mediated the relationship between tau accumulation and cognitive decline. DISCUSSION Tau epicenters shape the brain‐wide pattern of neuronal dysfunction, while local tau burden determines the degree of damage driving cognitive decline.