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Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer's disease. 2023
Bruna Bellaver, and
Guilherme Povala, and
Pamela C L Ferreira, and
João Pedro Ferrari-Souza, and
Douglas T Leffa, and
Firoza Z Lussier, and
Andréa L Benedet, and
Nicholas J Ashton, and
Gallen Triana-Baltzer, and
Hartmuth C Kolb, and
Cécile Tissot, and
Joseph Therriault, and
Stijn Servaes, and
Jenna Stevenson, and
Nesrine Rahmouni, and
Oscar L Lopez, and
Dana L Tudorascu, and
Victor L Villemagne, and
Milos D Ikonomovic, and
Serge Gauthier, and
Eduardo R Zimmer, and
Henrik Zetterberg, and
Kaj Blennow, and
Howard J Aizenstein, and
William E Klunk, and
Beth E Snitz, and
Pauline Maki, and
Rebecca C Thurston, and
Ann D Cohen, and
Mary Ganguli, and
Thomas K Karikari, and
Pedro Rosa-Neto, and
Tharick A Pascoal
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
An unresolved question for the understanding of Alzheimer's disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast+). Cross-sectional and longitudinal tau-positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast+ individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aβ with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials.
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