Journal Article

DZNE-2025-00232

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer's disease.

Roemer-Cassiano, S. N. ; Wagner, F. ; Evangelista, L. ; Rauchmann, B.-S.Extern* ; Dehsarvi, A. ; Steward, A. ; Dewenter, A. ; Biel, D. ; Zhu, Z. ; Pescoller, J. ; Gross, M. ; Perneczky, R.DZNE* ; Malpetti, M. ; Ewers, M. ; Schöll, M. ; Dichgans, M.DZNE* ; Höglinger, G. U.DZNE* ; Brendel, M.Extern* ; Jäkel, S. ; Franzmeier, N.

2025
AAAS Washington, DC

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Please use a persistent id in citations: doi:10.1126/scitranslmed.adp2564

Abstract: 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.

Keyword(s): Humans (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Alzheimer Disease: diagnostic imaging (MeSH) ; tau Proteins: metabolism (MeSH) ; Brain: metabolism (MeSH) ; Brain: diagnostic imaging (MeSH) ; Brain: pathology (MeSH) ; Aged (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Positron-Emission Tomography (MeSH) ; Male (MeSH) ; Female (MeSH) ; Magnetic Resonance Imaging (MeSH) ; Middle Aged (MeSH) ; Case-Control Studies (MeSH) ; Aged, 80 and over (MeSH) ; tau Proteins ; Amyloid beta-Peptides

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Contributing Institute(s):

1. Vascular Cognitive Impairment & Post-Stroke Dementia (AG Dichgans)
2. Clinical Research (Munich) (Clinical Research (Munich))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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