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Astrocyte reactivity influences amyloid-beta effects on tau pathology in preclinical Alzheimer's disease

Bellaver, B. (author)
Povala, G. (author)
Ferreira, P. C. L. (author)
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Ferrari-Souza, J. P. (author)
Leffa, D. T. (author)
Lussier, F. Z. (author)
Lessa Benedet, Andréa (author)
Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Ashton, Nicholas J. (author)
Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Triana-Baltzer, G. (author)
Kolb, H. C. (author)
Tissot, C. (author)
Therriault, J. (author)
Servaes, S. (author)
Stevenson, J. (author)
Rahmouni, N. (author)
Lopez, O. L. (author)
Tudorascu, D. L. (author)
Villemagne, V. L. (author)
Ikonomovic, M. D. (author)
Gauthier, S. (author)
Zimmer, E. R. (author)
Zetterberg, Henrik, 1973 (author)
Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Blennow, Kaj, 1958 (author)
Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Aizenstein, H. J. (author)
Klunk, W. E. (author)
Snitz, B. E. (author)
Maki, P. (author)
Thurston, R. C. (author)
Cohen, A. D. (author)
Ganguli, M. (author)
Karikari, Thomas (author)
Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Rosa-Neto, P. (author)
Pascoal, T. A. (author)
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 (creator_code:org_t)
2023
2023
English.
In: Nature Medicine. - 1078-8956. ; 29:7
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

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art (subject category)

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