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. 2025 May;21(5):e70209.
doi: 10.1002/alz.70209.

Plasma GFAP for populational enrichment of clinical trials in preclinical Alzheimer's disease

Bruna Bellaver  1 , Guilherme Povala  1 , Pamela C L Ferreira  1 , Guilherme Bauer-Negrini  1 , Firoza Z Lussier  1 , Douglas T Leffa  1 , João Pedro Ferrari-Souza  2 , Matheus S Rodrigues  1 , Livia Amaral  1 , Markley S Oliveira  1 , Carolina Soares  1 , Andreia Rocha  1 , Pampa Saha  1 , Nesrine Rahmouni  3   4 , Arthur Macedo  3   4 , Cécile Tissot  3   4   5 , Joseph Therriault  3   4 , Stijn Servaes  3   4 , Jesse Klostranec  3   4 , Maxime Montembeault  3   4 , Andréa L Benedet  6 , Nicholas J Ashton  6 , Rebecca Langhough Koscik  7   8 , Tobey J Betthauser  7   8 , Brad T Christian  7   8 , Rachael Wilson  7   8 , Gallen Triana-Baltzer  9 , Paolo Vitali  3   4 , Serge Gauthier  3   4 , Henrik Zetterberg  6   8   10   11   12 , Kaj Blennow  6   13   14 , Thomas K Karikari  1   6 , Dana Tudorascu  1   15 , Eduardo R Zimmer  2   16   17   18 , Sterling Johnson  7   8 , Pedro Rosa-Neto  3   4   19 , Tharick A Pascoal  1   20
Affiliations

Plasma GFAP for populational enrichment of clinical trials in preclinical Alzheimer's disease

Bruna Bellaver et al. Alzheimers Dement. 2025 May.

Abstract

Introduction: Cognitively unimpaired (CU) amyloid beta (Aβ)+ individuals with elevated plasma glial fibrillary acidic protein (GFAP) have an increased risk of Alzheimer's disease (AD)-related progression. We tested the utility of plasma GFAP for population enrichment CU populations in clinical trials.

Methods: We estimated longitudinal progression, effect size, and costs of hypothetical clinical trials designed to test an estimated 25% drug effect on reducing tau positron emission tomography (PET) accumulation in the medial temporal lobe (MTL) and temporal neocortical region (NEO-T).

Results: CU GFAP+/Aβ+ individuals present an increased annual rate of change and effect size in tau PETMTL and tau PETNEO-T compared to the other groups. An enrichment strategy selecting CU GFAP+/Aβ+ individuals would require a smaller sample size (≈ 57% reduction) and fewer Aβ PET scans (≈ 74% reduction) than trials enriched with Aβ PET alone, reducing total clinical trial costs by up to 64%.

Discussion: Our results suggest that clinical trials focusing on preclinical AD recruiting Aβ+ individuals with elevated GFAP levels would improve cost effectiveness.

Highlights: Cognitively unimpaired (CU) glial fibrillary acidic protein (GFAP)+/amyloid beta (Aβ)+ shows increased changes in tau positron emission tomography (PET) . CU GFAP+/Aβ+ enriched clinical trials require a reduced sample size compared to Aβ+ only. CU GFAP+/Aβ+ enrichment reduces Aβ PET scans required and costs. CU GFAP+/Aβ+ enrichment allows the selection of individuals at early stages of the Alzheimer's disease continuum.

Keywords: clinical trial enrichment; glial fibrillary acidic protein; positron emission tomography imaging; preclinical Alzheimer's disease; tau deposition.

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Conflict of interest statement

H.Z. has served on scientific advisory boards and/or as a consultant for Abbvie, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, reMYND, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). K.B. has served as a consultant and on advisory boards for Abbvie, AC Immune, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served on data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials, and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai, and Roche Diagnostics; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. S.G. received consulting fees as a member of the scientific advisory boards in Abbvie, Alzheon, AmyriAD, Eisai, Enigma/Meilleur, Lilly, Okutsa, Novo Nordisk, TauRx; honoraria for educational videos from Lundbeck; and reimbursement for AD/PD 2024 travel expenses by TauRx. S.G. is a board member at the Sharon and Robert Francis Foundation, Toronto, Canada, and the Canadian Conference on Dementia (CCD). E.R.Z. has served on the scientific advisory board of Nintx, Novo Nordisk, and Masima. He is also a co‐founder and a minority shareholder at Masima. P.R‐N. has served on scientific advisory boards and/or as a consultant for Roche, Novo Nordisk, Eisai, and Cerveau radiopharmaceuticals. N.J.A. has given lectures in symposia sponsored by Lilly and Quanterix. J.T. has served as a consultant for the Neurotorium educational platform and for Alzheon Inc. P.V. has served on scientific advisory boards for Novo Nordisk, Eisai, and Lilly. G.T.B. receives salary and has stocks from Janssen R&D. S.C.J. serves on advisory boards for AlzPATH and Enigma Biomedical. The other authors declare that they have no conflict of interest. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Longitudinal changes and effect size of tau PET according to Aβ and GFAP status. A, Annual rate of change in tau PETMTL, (B) effect size of changes in tau PETMTL, and (C) sample size required for detecting changes in tau PETMTL in CU stratified by Aβ and GFAP status. D, Annual rate of change in tau PETNEO‐T, (E) effect size of changes in tau PETNEO‐T, and (F) sample size required for a study detecting changes in tau PETNEO‐T in CU individuals stratified by Aβ and GFAP status. Group comparisons were assessed using analysis of variance accounting for age, sex, and cohort, with Tukey correction. The graphs show the mean and 95% confidence interval. Effect sizes were calculated adjusting for age, sex, and cohort. For effect size and sample size calculation, the Aβ+ group was divided regardless their GFAP levels. Aβ, amyloid beta; CU, cognitively unimpaired; GFAP, plasma glial fibrillary acidic protein; MTL, medial temporal lobe region; NEO‐T, temporal neocortical region; PET, positron emission tomography.
FIGURE 2
FIGURE 2
Plasma GFAP enrichment strategy for participant selection in clinical trials focusing on CU individuals. A, Schematic representation of population enrichment strategies with and without prescreening using plasma GFAP before clinical and Aβ PET assessments. B, C, Comparison of number of individuals in each step of clinical trial workflow using only Aβ+ biomarker and GFAP+ plus Aβ+ biomarkers to select participants in hypothetical clinical trials aiming at detecting changes in tau (B) PETMTL and (C) PETNEO‐T. Aβ, amyloid beta; CU, cognitively unimpaired; GFAP, plasma glial fibrillary acidic protein; MTL, medial temporal lobe region; NEO‐T, temporal neocortical region; PET, positron emission tomography.
FIGURE 3
FIGURE 3
Plasma GFAP cost‐efficiency impact in CU trials. Estimated costs are based on a hypothetical 25% drug effect on changes in (A) tau PETMTL and (B) tau PETNEO‐T. For the calculation, we estimated the following costs: recruitment = $100; plasma GFAP = $200; Aβ PET or tau PET = $3000; clinical assessments = $1000. Tau PET and clinical assessments were calculated to two time points (baseline and follow‐up to determine change). Aβ, amyloid beta; CU, cognitively unimpaired; GFAP, plasma glial fibrillary acidic protein; MTL, medial temporal lobe region; NEO‐T, temporal neocortical region; PET, positron emission tomography.
FIGURE 4
FIGURE 4
Population enrichment with GFAP+/Aβ+ allows the selection of CU individuals with similar tau progression levels compared to p‐tau+/Aβ+ but who are earlier in the AD continuum. A, Baseline Aβ PET Centiloid and (B) plasma p‐tau217 values in GFAP+/Aβ+ and p‐tau+/Aβ+ CU individuals. Effect size of changes in tau (C) PETMTL and (D) PETNEO‐T in CU individuals stratified according to their Aβ and/or GFAP and p‐tau217 status. Effect sizes of changes in tau (E) PETMTL and (F) PETNEO‐T adjusting for Aβ levels, Aβ and p‐tau levels (only for the GFAP+/Aβ+ group), and Aβ and GFAP levels (only for the p‐tau+/Aβ+ group). Effect sizes were further adjusted for age, sex, and cohort. Nine individuals without plasma p‐tau217 available were removed from this analysis. Group comparisons were assessed using analysis of variance. Aβ, amyloid beta; AD, Alzheimer's disease; CU, cognitively unimpaired; GFAP, plasma glial fibrillary acidic protein; MTL, medial temporal lobe region; NEO‐T, temporal neocortical region; PET, positron emission tomography; p‐tau, phosphorylated tau.
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References

    1. Sperling RA, Rentz DM, Johnson KA, et al. The A4 study: stopping AD before symptoms begin?. Sci Transl Med. 2014;6:228fs13. - PMC - PubMed
    1. Ossenkoppele R, Pichet Binette A, Groot C, et al. Amyloid and tau PET‐positive cognitively unimpaired individuals are at high risk for future cognitive decline. Nat Med. 2022;28:2381‐2387. - PMC - PubMed
    1. Cogswell PM, Lundt ES, Therneau TM, et al. Modeling the temporal evolution of plasma p‐tau in relation to amyloid beta and tau PET. Alzheimers Dement. 2024;20(2):1225‐1238. - PMC - PubMed
    1. Johansson C, Thordardottir S, Laffita‐Mesa J, et al. Plasma biomarker profiles in autosomal dominant Alzheimer's disease. Brain. 2023;146:1132‐1140. - PMC - PubMed
    1. Benedet AL, Milà‐Alomà M, Vrillon A, et al. Differences between plasma and cerebrospinal fluid glial fibrillary acidic protein levels across the Alzheimer Disease Continuum. JAMA Neurol. 2021;78:1471‐1483. - PMC - PubMed

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