This is a summary of Roemer-Cassiano et al. (2025). Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer’s disease as published in Science Translational Medicine DOI: 10.1126/scitranslmed.adp2564.
The challenge
In Alzheimer’s disease (AD), the protein amyloid-β (Aβ) is responsible for triggering the aggregation and spread of tau pathology, resulting in neurodegeneration and cognitive decline. Previous research has shown that Aβ triggers neuronal hyperactivity and hyperconnectivity. Moreover, preclinical research has shown that tau spreads across connected neurons activity-dependently. We, therefore, wanted to examine whether neuronal hyperactivity and hypersynchronicity are some of the crucial mechanisms by which Aβ drives the spread of tau.
Our approach
We combined Aβ 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 across the AD spectrum. We replicated the study in an independent sample of 55 controls and 345 individuals with preclinical AD and low cortical tau-PET uptake.
Our findings
Our study shows that Aβ causes hyperconnectivity of temporal lobe tau epicenters to posterior brain regions that are vulnerable to tau accumulation in AD. This was replicated in the independent sample, suggesting that the emergence of Aβ-related hyperconnectivity precedes the spread of neocortical tau. We confirmed that the effect of Aβ on the faster accumulation of tau was mediated by the increases in tau epicenters to typical tau-vulnerable brain regions. This suggests that an increased connectivity is a potential causal link between Aβ and tau pathology.
The implications
Our findings suggest that Aβ promotes tau spreading by evoking neuronal hyperconnectivity. Targeting Aβ-related neuronal hyperconnectivity may be a therapeutic strategy to reduce the spread of tau in AD.
Creating SyNergies
The study was led by SyNergy member Nicolai Franzmeier who was joined by our members Robert Perneczky, Martin Dichgans, Günter Höglinger, Matthias Brendel and Sarah Jäkel.
