Defining patient‐centered amyloid PET thresholds for the onset of tauopathy in Alzheimer's disease

Zhu, Zeyu; Steward, Anna; Dehsarvi, Amir; Roemer‐Cassiano, Sebastian N.; Dewenter, Anna; Biel, Davina; Hirsch, Fabian; Frontzkowski, Lukas; Pescoller, Julia; Klonowski, Madleen; Gnörich, Johannes; Pontecorvo, Michael J.; Shcherbinin, Sergey; Schöll, Michael; Buckley, Rachel; Ossenkoppele, Rik; Xie, Fang; Guo, Tengfei; Höglinger, Günter; Brendel, Matthias; Franzmeier, Nicolai (2026): Defining patient‐centered amyloid PET thresholds for the onset of tauopathy in Alzheimer's disease. Alzheimer's & Dementia, 22 (1): e71064. ISSN 1552-5260

Abstract

INTRODUCTION:
Amyloid-induced tauopathy drives clinical decline in Alzheimer's disease (AD). Because age and sex shape tau trajectories, defining patient-centered amyloid thresholds for tauopathy onset could facilitate pre-tauopathy AD identification and aid treatment decisions and prognosis.

METHODS:
By including two samples (Alzheimer's Disease Neuroimaging Initiative [ADNI, n = 301]; and 18F-AV-1451-A05 [A05, n = 143]), we explored whether age and sex affect tauopathy transition and determined patient-centered amyloid positron emission tomography (PET) thresholds that mark tauopathy onset.

RESULTS:
We found a consistent amyloid PET × age interaction on global tau PET increase in men (ADNI/A05: p = 0.0078/0.018), with younger men showing faster amyloid-associated tau accumulation. We then established patient-centered, amyloid PET–inferred tauopathy transition cut-offs. Women reached this transition at lower amyloid PET levels, and these cutoffs predicted both earlier onset and accelerated cognitive decline (p < 0.001).

DISCUSSION:
This study highlights the effect of age and sex on the amyloid-to-tauopathy transition, establishes patient-centered amyloid PET thresholds for tauopathy onset, and links these thresholds to accelerated cognitive decline.

Highlights:
Younger age is related to faster amyloid-related tau accumulation in men.
We defined a series of amyloid positron emission tomography (PET) thresholds to enable patient-centered inference of amyloid-related tauopathy.
Crossing the amyloid PET–defined tauopathy phase is associated with more progressive tau deposition and cognitive decline.

• Doc-Type: Article (LMU Hospital)
• Organisational unit (Faculties): 07 Medicine > Medical Center of the University of Munich > Institute for Stroke and Dementia Research (ISD)
• DFG subject classification of scientific disciplines: Life sciences
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 491502892