Journal Article

DZNE-2026-01039

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Network-dependent remote effects and local tau burden jointly shape neuronal dysfunction in Alzheimer's disease.

Frontzkowski, L. ; Roemer-Cassiano, S. ; Gnoerich, J.Extern* ; Janowitz, D.Extern* ; Eyob, H. ; Probst, K. ; Dhoqina, D. ; Dewenter, A. ; Steward, A. ; Zhu, Z. ; Klonowski, M. ; Hirsch, F. ; Biel, D. ; Paulus, M. ; Vöglein, J.DZNE* ; Schönecker, S. ; Rauchmann, B.-S.Extern* ; Kurz, C. ; Koriath, C. ; Häckert, J. ; Stöcklein, S.Extern* ; Palleis, C.Extern* ; Perneczky, R.DZNE* ; Levin, J.DZNE* ; Buerger, K.Extern* ; Werner, R. A. ; Höglinger, G.DZNE* ; Brendel, M.DZNE* ; Franzmeier, N.

2026
Wiley Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/alz.71914

Abstract: Tau pathology in Alzheimer's disease (AD) propagates along the brain's connectome, yet the mechanisms by which tau drives neuronal dysfunction remain unclear. We hypothesized that dysfunction primarily emerges in regions close to tau-harboring epicenters.One hundred thirty-one amyloid-positive individuals underwent dynamic [18F]PI-2620 tau positron emission tomography. Kinetic modeling yielded distribution volume ratios (DVRs) and perfusion (R1). Tau epicenters were defined as top 10% DVR regions. Connectivity-based distance to epicenters was derived from normative resting-state functional connectivity.At the individual level, hypoperfusion was more closely related to distance from tau epicenters than to local tau deposition, particularly in early AD, consistent with diaschisis-like disconnection. With advancing biological disease severity, local tau deposition increasingly converged with hypoperfusion. Critically, hypoperfusion mediated the relationship between tau accumulation and cognitive decline.Tau epicenters shape the brain-wide pattern of neuronal dysfunction, while local tau burden determines the degree of damage driving cognitive decline.

Keyword(s): Humans (MeSH) ; Alzheimer Disease: diagnostic imaging (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Alzheimer Disease: physiopathology (MeSH) ; tau Proteins: metabolism (MeSH) ; Positron-Emission Tomography (MeSH) ; Brain: diagnostic imaging (MeSH) ; Brain: metabolism (MeSH) ; Brain: pathology (MeSH) ; Female (MeSH) ; Male (MeSH) ; Aged (MeSH) ; Neurons: pathology (MeSH) ; Aged, 80 and over (MeSH) ; Alzheimer's disease ; neuronal dysfunction ; perfusion ; tau ; tau positron emission tomography ; tau Proteins

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))
2. Vascular Cognitive Impairment & Post-Stroke Dementia (AG Dichgans)
3. Clinical Neurodegeneration (AG Levin)
4. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DEAL Wiley ; Essential Science Indicators ; IF >= 10 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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