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000276160 1001_ $$00000-0003-3423-457X$$aRoemer-Cassiano, Sebastian N$$b0
000276160 245__ $$aAmyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer's disease.
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000276160 520__ $$aIn Alzheimer's disease (AD), amyloid-β (Aβ) triggers the aggregation and spreading of tau pathology, which drives neurodegeneration and cognitive decline. However, the pathophysiological link between Aβ and tau remains unclear, which hinders therapeutic efforts to attenuate Aβ-related tau accumulation. Aβ has been found to trigger neuronal hyperactivity and hyperconnectivity, and preclinical research has shown that tau spreads across connected neurons in an activity-dependent manner. Here, we hypothesized that neuronal hyperactivity and hypersynchronicity, resulting in functional connectivity increases, constitute a crucial mechanism by which Aβ facilitates the spreading of tau pathology. By combining Aβ positron emission tomography (PET), resting-state functional magnetic resonance imaging, and longitudinal tau-PET in 69 cognitively normal amyloid-negative controls and 140 amyloid-positive patients covering the AD spectrum, we confirmed that Aβ induces hyperconnectivity of temporal lobe tau epicenters to posterior brain regions that are vulnerable to tau accumulation in AD. This was replicated in an independent sample of 55 controls and 345 individuals with preclinical AD and low cortical tau-PET uptake, suggesting that the emergence of Aβ-related hyperconnectivity precedes neocortical tau spreading . Last, using longitudinal tau-PET and mediation analysis, we confirmed that these Aβ-related connectivity increases in tau epicenters to typical tau-vulnerable brain regions in AD mediated the effect of Aβ on faster tau accumulation, unveiling increased connectivity as a potential causal link between the two AD hallmark pathologies. Together, these findings suggest that Aβ promotes tau spreading by eliciting neuronal hyperconnectivity and that targeting Aβ-related neuronal hyperconnectivity may attenuate tau spreading in AD.
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000276160 650_7 $$2NLM Chemicals$$atau Proteins
000276160 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000276160 650_2 $$2MeSH$$aHumans
000276160 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000276160 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000276160 650_2 $$2MeSH$$aAlzheimer Disease: diagnostic imaging
000276160 650_2 $$2MeSH$$atau Proteins: metabolism
000276160 650_2 $$2MeSH$$aBrain: metabolism
000276160 650_2 $$2MeSH$$aBrain: diagnostic imaging
000276160 650_2 $$2MeSH$$aBrain: pathology
000276160 650_2 $$2MeSH$$aAged
000276160 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000276160 650_2 $$2MeSH$$aPositron-Emission Tomography
000276160 650_2 $$2MeSH$$aMale
000276160 650_2 $$2MeSH$$aFemale
000276160 650_2 $$2MeSH$$aMagnetic Resonance Imaging
000276160 650_2 $$2MeSH$$aMiddle Aged
000276160 650_2 $$2MeSH$$aCase-Control Studies
000276160 650_2 $$2MeSH$$aAged, 80 and over
000276160 7001_ $$00009-0009-7350-465X$$aWagner, Fabian$$b1
000276160 7001_ $$00009-0006-2396-4656$$aEvangelista, Lisa$$b2
000276160 7001_ $$0P:(DE-2719)9001808$$aRauchmann, Boris-Stephan$$b3
000276160 7001_ $$00000-0001-7116-9741$$aDehsarvi, Amir$$b4
000276160 7001_ $$00000-0002-8438-3760$$aSteward, Anna$$b5
000276160 7001_ $$aDewenter, Anna$$b6
000276160 7001_ $$00000-0002-2597-1992$$aBiel, Davina$$b7
000276160 7001_ $$00000-0003-0970-4832$$aZhu, Zeyu$$b8
000276160 7001_ $$aPescoller, Julia$$b9
000276160 7001_ $$00009-0001-7729-2182$$aGross, Mattes$$b10
000276160 7001_ $$0P:(DE-2719)2812234$$aPerneczky, Robert$$b11
000276160 7001_ $$00000-0001-8923-9656$$aMalpetti, Maura$$b12
000276160 7001_ $$0P:(DE-2719)9000543$$aEwers, Michael$$b13
000276160 7001_ $$00000-0001-7800-1781$$aSchöll, Michael$$b14
000276160 7001_ $$0P:(DE-2719)2000030$$aDichgans, Martin$$b15
000276160 7001_ $$0P:(DE-2719)2811373$$aHöglinger, Günter U$$b16
000276160 7001_ $$0P:(DE-2719)9001539$$aBrendel, Matthias$$b17$$udzne
000276160 7001_ $$00000-0002-9634-2472$$aJäkel, Sarah$$b18
000276160 7001_ $$00000-0001-9736-2283$$aFranzmeier, Nicolai$$b19
000276160 773__ $$0PERI:(DE-600)2518839-2$$a10.1126/scitranslmed.adp2564$$gVol. 17, no. 782, p. eadp2564$$n782$$peadp2564$$tScience translational medicine$$v17$$x1946-6234$$y2025
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