Astrocyte reactivity identifies p-tau217-positive individuals at elevated risk of cognitive decline across the Alzheimer’s disease continuum

Abstract Background Plasma phosphorylated tau at threonine 217 (p-tau217) is a robust marker of Alzheimer’s disease (AD) pathology and progression. However, individuals positive for p-tau217 show substantial clinical heterogeneity, suggesting the influence of modifying biological processes. Here, we investigated whether plasma glial fibrillary acidic protein (GFAP) modifies the association between p-tau217 and clinical progression. Methods We analyzed 3,505 individuals across the aging and AD spectrum from six independent cohorts. All participants had baseline Aβ PET, plasma GFAP, plasma p-tau217, and CDR-SB. Participants were classified into four biomarker groups based on GFAP and p-tau217 positivity. Cross-sectional associations with cognitive severity were examined using linear regression and ANCOVA. Longitudinal cognitive trajectories over five years were modeled using linear mixed-effects models. Variance partitioning decomposed biomarker-attributable variance in individual-level annual CDR-SB change rates. Time to clinical worsening (CDR-SB increase ≥ 0.5 points) was assessed using Kaplan–Meier survival analysis and Cox proportional hazards regression. Results We show that elevated plasma GFAP significantly modulates the association between p-tau217 and both cross-sectional cognitive severity and longitudinal clinical decline. Compared to individuals p-tau217-positive-only, individuals with co-elevated GFAP and p-tau217 exhibited worse baseline cognitive performance, faster annual CDR-SB progression (62% higher rate; p = 0.008), and an increased hazard of cognitive worsening (HR 1.28; 95% CI 1.01–1.61). The interaction between GFAP and p-tau217 accounted for a large proportion of biomarker-related variance in longitudinal cognitive decline (68.6%), far exceeding the independent contributions of p-tau217 (25.3%) and GFAP (1.1%). Conclusion These findings support that astrocyte reactivity is associated with greater cognitive impairment and faster clinical decline among individuals with elevated p-tau217, providing additional prognostic stratification within the p-tau217-positive population. Combining plasma GFAP and p-tau217 may therefore have value for identifying individuals at higher risk of progression, with potential implications for risk stratification and clinical trial enrichment.

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Journal
Molecular Neurodegeneration
Published
2026-09-21
DOI
https://doi.org/10.1186/s13024-026-00995-5
Primary Topic
Alzheimer's disease research and treatments
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article
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article

Astrocyte reactivity identifies p-tau217-positive individuals at elevated risk of cognitive decline across the Alzheimer’s disease continuum

Hyun Woong Roh, Joseph Therriault, Guilherme Povala, Ann D. Cohen et al.
Molecular Neurodegeneration
Alzheimer's disease research and treatments
article

Astrocyte reactivity identifies p-tau217-positive individuals at elevated risk of cognitive decline across the Alzheimer’s disease continuum

Hyun Woong Roh, Joseph Therriault, Guilherme Povala, Ann D. Cohen, Belén Pascual, Joseph C. Masdeu, Chang Hyung Hong, Sang Joon Son, Guilherme Bauer‐Negrini, Álvaro de Oliveira Franco, Nesrine Rahmouni, Thomas K. Karikari, Stijn Servaes, Tevy Chan, X. C. Hu, David N. Soleimani‐Meigooni, Suzanne Baker, Lívia Amaral, Selma Avdagic, Danielle Gray, Riddhi Patira, Oscar L. López, Hsin‐Yeh Tsai, Pampa Saha, Matheus S. Rodrigues, Andréa L. Benedet, Jenna Stevenson, Markley S. Oliveira, Lydia Trudel, Maxime Montembault, Rayan Mroué, the HEAD Study, Firoza Z. Lussier, Jesse Klostranec, Helmet T. Karim, Douglas T. Leffa, Victoria Tate, Emma Ruppert, Cristiano S. Aguzzoli, Emerine Cummings, Juli Singer, Marina S. Medeiros, Pedro Rosa-Neto, Tharick A. Pascoal, Pamela C. L. Ferreira, Eduardo R. Zimmer, João Pedro Ferrari-Souza, Dana L. Tudorascu, Arthur Macedo, Nicholas J. Ashton, Raphael L. Tuma, Bruna Bellaver, Vladimir Fonov, Henrik Zetterberg, Cecile Tissot, Juan Fortea, Carolina Soares, Suzanne L. Baker, Andréia Rocha, Val J. Lowe, Joseph C Masdeu, Arthur Toga, Hwamee Oh, Sid O’bryant, Tatiana Foroud, Yasser Iturria-Medina, Brian A. Gordon, WanLu Jia, Julia Koefler, Paolo Vitali
article en

Abstract

Abstract Background Plasma phosphorylated tau at threonine 217 (p-tau217) is a robust marker of Alzheimer’s disease (AD) pathology and progression. However, individuals positive for p-tau217 show substantial clinical heterogeneity, suggesting the influence of modifying biological processes. Here, we investigated whether plasma glial fibrillary acidic protein (GFAP) modifies the association between p-tau217 and clinical progression. Methods We analyzed 3,505 individuals across the aging and AD spectrum from six independent cohorts. All participants had baseline Aβ PET, plasma GFAP, plasma p-tau217, and CDR-SB. Participants were classified into four biomarker groups based on GFAP and p-tau217 positivity. Cross-sectional associations with cognitive severity were examined using linear regression and ANCOVA. Longitudinal cognitive trajectories over five years were modeled using linear mixed-effects models. Variance partitioning decomposed biomarker-attributable variance in individual-level annual CDR-SB change rates. Time to clinical worsening (CDR-SB increase ≥ 0.5 points) was assessed using Kaplan–Meier survival analysis and Cox proportional hazards regression. Results We show that elevated plasma GFAP significantly modulates the association between p-tau217 and both cross-sectional cognitive severity and longitudinal clinical decline. Compared to individuals p-tau217-positive-only, individuals with co-elevated GFAP and p-tau217 exhibited worse baseline cognitive performance, faster annual CDR-SB progression (62% higher rate; p = 0.008), and an increased hazard of cognitive worsening (HR 1.28; 95% CI 1.01–1.61). The interaction between GFAP and p-tau217 accounted for a large proportion of biomarker-related variance in longitudinal cognitive decline (68.6%), far exceeding the independent contributions of p-tau217 (25.3%) and GFAP (1.1%). Conclusion These findings support that astrocyte reactivity is associated with greater cognitive impairment and faster clinical decline among individuals with elevated p-tau217, providing additional prognostic stratification within the p-tau217-positive population. Combining plasma GFAP and p-tau217 may therefore have value for identifying individuals at higher risk of progression, with potential implications for risk stratification and clinical trial enrichment.

Molecular Neurodegeneration
University of North Texas (US), Houston Methodist (US), Universidade Federal do Rio Grande do Sul (BR), Lawrence Berkeley National Laboratory (US), University of North Texas Health Science Center (US), University of Pittsburgh (US), Washington University in St. Louis (US), Brown University (US), Sahlgrenska University Hospital (SE), Hospital de Sant Pau (ES), Banner Health (US), Hospital Moinhos de Vento (BR), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Southwestern Medical Center (US), University Memory and Aging Center (US), Mayo Clinic in Arizona (US), Banner Sun Health Research Institute (US), Centre Intégré Universitaire de Santé et de Services Sociaux du Centre-Sud-de-l'Île-de-Montréal (CA), Centres Intégré Universitaires de Santé et de Services Sociaux (CA), McGill University (CA), Ajou University (KR), The University of Texas Southwestern Medical Center (US), University of Gothenburg (SE)
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Alzheimer's disease research and treatments
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