학술논문
Astrocyte reactivity influences amyloid-beta effects on tau pathology in preclinical Alzheimer's disease
Document Type
Author
Bellaver, B.; Povala, G.; Ferreira, P. C. L.; Ferrari-Souza, J. P.; Leffa, D. T.; Lussier, F. Z.; Lessa Benedet, Andréa; Ashton, Nicholas J.; Triana-Baltzer, G.; Kolb, H. C.; Tissot, C.; Therriault, J.; Servaes, S.; Stevenson, J.; Rahmouni, N.; Lopez, O. L.; Tudorascu, D. L.; Villemagne, V. L.; Ikonomovic, M. D.; Gauthier, S.; Zimmer, E. R.; Zetterberg, Henrik, 1973; Blennow, Kaj, 1958; Aizenstein, H. J.; Klunk, W. E.; Snitz, B. E.; Maki, P.; Thurston, R. C.; Cohen, A. D.; Ganguli, M.; Karikari, Thomas; Rosa-Neto, P.; Pascoal, T. A.
Source
Nature Medicine. 29(7)
Subject
Language
English
ISSN
1078-8956
Abstract
Cross-sectional and longitudinal analyses of tau pathology in preclinical Alzheimer's disease reveal that tau tangles accumulate as a function of amyloid-beta burden only in individuals positive for an astrocyte reactivity biomarker. An unresolved question for the understanding of Alzheimer's disease (AD) pathophysiology is why a significant percentage of amyloid-beta (A beta)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash A beta 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 A beta with tau phosphorylation in CU individuals. We found that A beta 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 A beta only in CU Ast(+) individuals. Our findings suggest astrocyte reactivity as an important upstream event linking A beta with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials.