Here, the authors hypothesized that neuronal hyperactivity and hypersynchronicity, resulting in functional connectivity increases, constitute a crucial mechanism by which A facilitates the spreading of tau pathology. By combining A positron emission tomography, resting-state functional magnetic resonance imaging, and longitudinal tau-PET in 69 cognitively normal amyloid-negative controls and 140 amyloid-positive patients covering the Alzheimer's disease spectrum, the authors confirmed that A induces hyperconnectivity of temporal lobe tau epicenters to posterior brain regions that are vulnerable to tau accumulation in Alzheimer's disease. This was replicated in an independent sample of 55 controls and 345 individuals with preclinical Alzheimer's disease and low cortical tau-PET uptake, suggesting that the emergence of A -related hyperconnectivity precedes neocortical tau spreading . Last, using longitudinal tau-PET and mediation analysis, the authors confirmed that these A -related connectivity increases in tau epicenters to typical tau-vulnerable brain regions in Alzheimer's disease mediated the effect of A on faster tau accumulation, unveiling increased connectivity as a potential causal link between the two Alzheimer's disease hallmark pathologies. Together, these findings suggest that A promotes tau spreading by eliciting neuronal hyperconnectivity and that targeting A -related neuronal hyperconnectivity may attenuate tau spreading in Alzheimer's disease.
