Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer's disease

In Alzheimer's disease (AD), amyloid-beta (A beta) triggers the aggregation and spreading of tau pathology, which drives neurodegeneration and cognitive decline. However, the pathophysiological link between A beta and tau remains unclear, which hinders therapeutic efforts to attenuate A beta-related tau accumulation. A beta has been found to trigger neuronal hyperactivity and hyperconnectivity, and preclinical research has shown that tau spreads across connected neurons in an activity-dependent manner. Here, we hypothesized that neuronal hyperactivity and hypersynchronicity, resulting in functional connectivity increases, constitute a crucial mechanism by which A beta facilitates the spreading of tau pathology. By combining A beta positron emission tomography (PET), resting-state functional magnetic resonance imaging, and longitudinal tau-PET in 69 cognitively normal amyloid-negative controls and 140 amyloid-positive patients covering the AD spectrum, we confirmed that A beta induces hyperconnectivity of temporal lobe tau epicenters to posterior brain regions that are vulnerable to tau accumulation in AD. This was replicated in an independent sample of 55 controls and 345 individuals with preclinical AD and low cortical tau-PET uptake, suggesting that the emergence of A beta-related hyperconnectivity precedes neocortical tau spreading . Last, using longitudinal tau-PET and mediation analysis, we confirmed that these A beta-related connectivity increases in tau epicenters to typical tau-vulnerable brain regions in AD mediated the effect of A beta on faster tau accumulation, unveiling increased connectivity as a potential causal link between the two AD hallmark pathologies. Together, these findings suggest that A beta promotes tau spreading by eliciting neuronal hyperconnectivity and that targeting A beta-related neuronal hyperconnectivity may attenuate tau spreading in AD.