Plasma GFAP outperforms CSF GFAP in detecting amyloid pathology and is associated with increased risk of clinical progression in early Alzheimer’s disease - 28/03/26

Doi : 10.1016/j.tjpad.2026.100544

Arda C. Cetindag ^a,^c,^⁎ , Carola G. Schipke ^a, Hermann Esselmann ^d, Niels Kruse ^e, Jens Wiltfang ^d,^f,^ff, Anja Schneider ^g,^h, Klaus Fliessbach ^g,^h, Carolin Miklitz ^g,^h, Franziska Maier ⁱ, Katharina Buerger ^j,^k, Daniel Janowitz ^j, Michael Ewers ^j,^k, Sophia Stöcklein ^l, Robert Perneczky ^k,^m,^n,^o,^p, Boris-Stephan Rauchmann ^m,^q, Carolin Kurz ^m, Stefan Teipel ^r,^s, Ingo Kilimann ^r,^s, Doreen Goerss ^r,^s, Christoph Laske ^t,^v, Sebastian Sodenkamp ^u,^w, Elham Najafpour ^v, Michael Wagner ^h,^w, Sandra Roeske ^h, Ingo Frommann ^h,^w, Melina Stark ^h,^w, Frederic Brosseron ^h, Alfredo Ramirez ^h,^w,^x,^y,^z, Luca Kleineidam ^h,^w, Josef Priller ^b,^aa,^bb,^cc, Eike Jakob Spruth ^b,^aa, Maria Gemenetzi ^b,^aa, Slawek Altenstein ^b,^aa, Emrah Düzel ^dd,^ee, Wenzel Glanz ^dd, Enise I. Incesoy ^dd, Michaela Butryn ^dd, Chris Bauer ^gg, Frank Jessen ^h,ⁱ, Oliver Peters ^a,^b

^a Charité Universitätsmedizin Berlin, Department of Psychiatry and Neurosciences, Hindenburgdamm 30, 12203 Berlin, Germany

^b German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany

^c GLG Werner Forßmann Hospital, Department of Radiology and Neuroradiology, Rudolf-Breitscheid-Straße 100, 16225 Eberswalde, Germany

^d University Medical Center Göttingen (UMG), Department of Psychiatry and Psychotherapy, Von-Siebold-Straße 5, 37075 Goettingen, Germany

^e University Medical Center Göttingen (UMG), Department of Neuropathology, Robert-Koch-Straße 40, 37075 Goettingen, Germany

^f German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Straße 3a, 37075 Goettingen, Germany

^g Department of Old Age Psychiatry and Cognitive Disorders, University Hospital Bonn and University of Bonn, Bonn, Germany

^h German Center for Neurodegenerative Diseases (DZNE), Bonn, Venusberg-Campus 1, 53127 Bonn, Germany

ⁱ Department of Psychiatry, University of Cologne, Medical Faculty, Kerpener Strasse 62, 50924 Cologne, Germany

^j Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Feodor-Lynen-Strasse 17, 81377 Munich, Germany

^k German Center for Neurodegenerative Diseases (DZNE, Munich), Feodor-Lynen-Strasse 17, 81377 Munich, Germany

^l Department of Radiology, University Hospital, LMU Munich, Munich, Germany

^m Department of Psychiatry and Psychotherapy, LMU Hospital, LMU Munich, Germany

ⁿ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

^o Epidemiology of Aging (AGE) Research Unit, School of Public Health, Imperial College London, London, UK

^p Division of Neuroscience, University of Sheffield, Sheffield, UK

^q Department of Neuroradiology, LMU Hospital, LMU Munich, Germany

^r Department of Psychosomatic Medicine, Rostock University Medical Center, Gehlsheimer Str. 20, 18147 Rostock

^s German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany

^t Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany

^u Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany

^v German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany

^w Department for Cognitive Disorders and Old Age Psychiatry, University Hospital Bonn, Bonn, Germany

^x Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Köln, Germany

^y Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany

^z Department of Psychiatry & Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, TX, USA

^aa Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, 10117 Berlin, Germany

^bb University of Edinburgh and UK DRI, Edinburgh, UK

^cc Department of Psychiatry and Psychotherapy, School of Medicine and Health, Technical University of Munich, and German Center for Mental Health (DZPG), Munich, Germany

^dd German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany

^ee Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany

^ff Neurosciences and Signaling Group, Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193, Aveiro, Portugal

^gg MicroDiscovery GmbH, Berlin, Germany

^⁎ Corresponding author at: Charité Universitätsmedizin Berlin, Department of Psychiatry and Neurosciences, Hindenburgdamm 30, 12203 Berlin, Germany. Charité Universitätsmedizin Berlin, Department of Psychiatry and Neurosciences Hindenburgdamm 30 Berlin 12203 Germany

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Résumé

Background

Early and accurate detection of Alzheimer’s disease (AD) is essential for timely intervention and development of disease-modifying treatments. The DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) provides a deeply phenotyped cohort covering preclinical and early clinical stages, including subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Astrocyte reactivity and its biomarkers, particularly glial fibrillary acidic protein (GFAP), have gained increasing attention in AD research; however, the relationship between GFAP and amyloid in early disease, as well as its potential prognostic value beyond its association with amyloid status, remains insufficiently understood.

Objectives

To evaluate the performance of CSF and plasma GFAP across early disease stages, compare these measures according to amyloid status, and assess the prognostic value of GFAP for clinical progression across diagnostic stages during longitudinal follow-up.

Setting

This study used data from the multicenter DELCODE cohort in Germany, including participants with available plasma and/or CSF samples and standardized clinical, cognitive, imaging, and biomarker assessments.

Measurements

GFAP concentrations in plasma and CSF were quantified using validated immunoassay platforms. Standard CSF AD biomarkers and ApoE genotype were measured using established assays. Amyloid status was defined by the CSF Aβ42/40 ratio. Longitudinal follow-up occurred annually for up to ∼10 years, with clinical conversion determined according to NIA-AA criteria.

Results

Plasma and CSF GFAP increased across the AD continuum, with higher levels in MCI and AD (p < 0.001). Plasma GFAP showed a stronger association with amyloid status than CSF GFAP across all groups. In MCI, plasma GFAP combined with age and ApoE4 yielded an AUC of 0.87. Elevated plasma GFAP predicted increased risk of conversion to MCI (HR = 2.19, p < 0.001; adjusted HR = 1.70, p = 0.0056) and AD dementia (HR = 3.5; adjusted HR = 2.49 both p < 0.001).

Conclusion

Plasma GFAP is a sensitive, minimally invasive biomarker with diagnostic relevance for amyloid detection and prognostic relevance for clinical progression in early AD.

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Keywords : Alzheimer’s disease, Mild cognitive impairment, Subjective memory decline, Glial fibrillary acidic protein (GFAP), Cerebrospinal fluid (CSF), Blood biomarkers of Alzheimer’s disease

Abbreviations : AD, SCD, MCI, Ctrl, GFAP, CDR, ADAS-Cog, ApoE, CSF, ROC, Aβ, ND, AUC, CI, HR

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Vol 13 - N° 5

Article 100544- mai 2026 Retour au numéro

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Plasma GFAP outperforms CSF GFAP in detecting amyloid pathology and is associated with increased risk of clinical progression in early Alzheimer’s disease - 28/03/26

Résumé

Background

Objectives

Setting

Measurements

Results

Conclusion

Plan

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