Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Network-dependent remote effects and local tau burden jointly shape neuronal dysfunction in Alzheimer's disease.
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Frontzkowski Lukas, Roemer-Cassiano Sebastian, Gnörich Johannes, Janowitz Daniel, Eyob Hannah, Probst Katharina, Dhoqina Dario, Dewenter Anna, Steward Anna, Zhu Zeyu, Klonowski Madleen, Hirsch Fabian, Biel Davina, Paulus Melina, Vöglein Jonathan, Schönecker Sonja, Rauchmann Boris-Stephan, Kurz Carolin, Koriath Carolin, Häckert Jan, Stöcklein Sophia, Palleis Carla, Perneczky Robert, Levin Johannes, Buerger Katharina, Werner Rudolf A, Höglinger Günter, Brendel Matthias, Franzmeier Nicolai
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
DISCUSSION: Tau epicenters shape the brain-wide pattern of neuronal dysfunction, while local tau burden determines the degree of damage driving cognitive decline.
METHODS: 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.
RESULTS: 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.
DISCUSSION: Tau epicenters shape the brain-wide pattern of neuronal dysfunction, while local tau burden determines the degree of damage driving cognitive decline.