TY  - JOUR
AU  - Roemer-Cassiano, Sebastian N
AU  - Wagner, Fabian
AU  - Evangelista, Lisa
AU  - Rauchmann, Boris-Stephan
AU  - Dehsarvi, Amir
AU  - Steward, Anna
AU  - Dewenter, Anna
AU  - Biel, Davina
AU  - Zhu, Zeyu
AU  - Pescoller, Julia
AU  - Gross, Mattes
AU  - Perneczky, Robert
AU  - Malpetti, Maura
AU  - Ewers, Michael
AU  - Schöll, Michael
AU  - Dichgans, Martin
AU  - Höglinger, Günter U
AU  - Brendel, Matthias
AU  - Jäkel, Sarah
AU  - Franzmeier, Nicolai
TI  - Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer's disease.
JO  - Science translational medicine
VL  - 17
IS  - 782
SN  - 1946-6234
CY  - Washington, DC
PB  - AAAS
M1  - DZNE-2025-00232
SP  - eadp2564
PY  - 2025
AB  - In 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.
KW  - Humans
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: pathology
KW  - Alzheimer Disease: diagnostic imaging
KW  - tau Proteins: metabolism
KW  - Brain: metabolism
KW  - Brain: diagnostic imaging
KW  - Brain: pathology
KW  - Aged
KW  - Amyloid beta-Peptides: metabolism
KW  - Positron-Emission Tomography
KW  - Male
KW  - Female
KW  - Magnetic Resonance Imaging
KW  - Middle Aged
KW  - Case-Control Studies
KW  - Aged, 80 and over
KW  - tau Proteins (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39841807
DO  - DOI:10.1126/scitranslmed.adp2564
UR  - https://pub.dzne.de/record/276160
ER  -