Utility of plasma GFAP as a secondary endpoint for clinical trials in Alzheimer’s disease - 05/06/25

Doi : 10.1016/j.tjpad.2025.100205

Sarah Abbas ^a,^{^{1
These authors contributed equally.}}, Pamela C. L Ferreira ^a,^{^{1
These authors contributed equally.}}, Bruna Bellaver ^a, Guilherme Povala ^a, Francieli Rohden ^a,^b, Cristiano Schaffer Aguzzoli ^a,^c, Hussein Zalzale ^a, João Pedro Ferrari-Souza ^b, Douglas T. Leffa ^a, Firoza Z. Lussier ^a, Carolina Soares ^a, Guilherme Bauer-Negrini ^a, Markley Silva Oliveira-Junior ^a, Matheus Scarpatto Rodrigues ^a, Pampa Saha ^a, Emma Ruppert ^a, Marina Scop Medeiros ^a, Cécile Tissot ^a,^d,^e,^f, Joseph Therriault ^d,^e, Nesrine Rahmouni ^d, Stijn Servaes ^d, Andrea L. Benedet ^g,^h, Nicholas J. Ashton ^g,^h,^i,^j, Dana L. Tudorascu ^a, Serge Gauthier ^e, Helmet Karim ^a,^k, Chang Hyung Hong ^l, Hyun Woong Roh ^l, Eduardo R Zimmer ^b,^c,^m,ⁿ, Thomas K. Karikari ^a,^g, Henrik Zetterberg ^g,^h,^i,^o,^p,^q, Kaj Blennow ^g,^h, Anum Saeed ^r, Sang Joon Son ^l, Pedro Rosa-Neto ^d,^e, Tharick Pascoal ^a,^s,^⁎
for Alzheimer’s Disease Neuroimaging Initiative
^a Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
^b Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
^c Brain Institute of Rio Grande do Sul, PUCRS, 6690 Ipiranga Avenue, 90610-000, Porto Alegre, RS, Brazil
^d Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer’s Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Canada
^e Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
^f Department of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
^g Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
^h Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden
ⁱ Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
^j Department of Old Age Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
^k Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA
^l Department of Psychiatry, Ajou University School of Medicine, Suwon, Republic of Korea, South Korea
^m Department of Pharmacology, Universidade Federal do Rio Grande do Sul (UFRGS), 2500 Ramiro Barcelos Street, 90035-003, Porto Alegre, RS, Brazil
ⁿ Graduate Program in Biological Sciences: Pharmacology and Therapeutics, Universidade Federal do Rio Grande do Sul (UFRGS), 2500 Ramiro Barcelos Street, 90035-003, Porto Alegre, RS, Brazil
^o Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
^p UK Dementia Research Institute at UCL, London, UK
^q Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
^r Department of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA
^s Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

^⁎Corresponding author at: Associate Professor of Psychiatry and Neurology, University of Pittsburgh, 200 Meyran Ave, Pittsburgh, PA 15213, Brazil.Associate Professor of Psychiatry and NeurologyUniversity of Pittsburgh200 Meyran AvePittsburghPA15213Brazil

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Abstract

Background

Clinical trials have recently incorporated plasma glial fibrillary acidic protein (GFAP) as an exploratory endpoint. To include plasma GFAP as a secondary endpoint, it is essential to characterize its longitudinal progression in target populations.

Objective

To evaluate the potential use of plasma GFAP changes as a secondary endpoint in Alzheimer’s disease trials.

Methods

We longitudinally evaluated plasma GFAP in individuals with amyloid-beta (Aβ)-PET scans at baseline in three well-characterized cohorts. Cox proportional hazards regression tested the association between changes in plasma GFAP and cognitive function. Analysis of the 95 % confidence interval of annualized change in plasma GFAP provided statistical inference for a significant longitudinal change. Effect size was calculated as the group mean divided by the standard deviation (SD). We estimated the sample size needed to test a 25% drug effect with 80% power on reducing changes in GFAP.

Results

We assessed 487 individuals [176 cognitively unimpaired (CU; 29% Aβ positive) and 311 cognitively impaired (CI; 51% Aβ positive)] with some degree of cerebrovascular disease (Fazekas 1–3), over a mean (SD) follow-up of 1.84 (0.46) years. Changes in plasma GFAP were significantly associated with worsening in Clinical Dementia Rating sum of boxes (CDR-SB) score across the population (p < 0.0001). In CU, only Aβ positive individuals showed significant changes in GFAP (p < 0.001). On the other hand, both CI Aβ positive and negative individuals showed longitudinal progression in GFAP levels (p < 0.0001). The effect size of changes in plasma GFAP was higher in CU Aβ positive (0.44), followed by CI Aβ positive (0.42) and CI Aβ negative (0.38). Clinical trials focusing on CU Aβ positive would require 1320 individuals per study arm, while focusing on CI Aβ positive would require 1440 individuals per study arm.

Conclusion

Plasma GFAP increased in parallel with cognitive decline, making it a candidate for monitoring disease progression in trials aimed at mitigating cognitive deterioration. Although Aβ positivity significantly accelerated GFAP progression, the fact that GFAP was increased in CI Aβ negative with cerebrovascular disease supports its potential use as a secondary endpoint in this population as well.

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Keywords : Plasma GFAP, Biomarker, Clinical trial