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. 2025 Feb;21(2):e14414.
doi: 10.1002/alz.14414. Epub 2025 Jan 30.

Biomarker treatment effects in two phase 3 trials of gantenerumab

Tobias Bittner  1   2 , Matteo Tonietto  2 , Gregory Klein  2 , Anton Belusov  2 , Vittorio Illiano  2 , Nicola Voyle  3 , Paul Delmar  2 , Marzia A Scelsi  3 , Susanna Gobbi  2 , Erica Silvestri  2   4 , Muhamed Barakovic  2 , Antonio Napolitano  2   4 , Christopher Galli  2 , Maryam Abaei  2   4 , Kaj Blennow  5   6   7 , Frederik Barkhof  8   9
Affiliations

Biomarker treatment effects in two phase 3 trials of gantenerumab

Tobias Bittner et al. Alzheimers Dement. 2025 Feb.

Abstract

Introduction: We report biomarker treatment effects in the GRADUATE I and II phase 3 studies of gantenerumab in early Alzheimer's disease (AD).

Methods: Amyloid and tau positron emission tomography (PET), volumetric magnetic resonance imaging (vMRI), cerebrospinal fluid (CSF), and plasma biomarkers used to assess gantenerumab treatment related changes on neuropathology, neurodegeneration, and neuroinflammation over 116 weeks.

Results: Gantenerumab reduced amyloid PET load, CSF biomarkers of amyloid beta (Aβ)40, total tau (t-tau), phosphorylated tau 181 (p-tau181), neurogranin, S100 calcium-binding protein B (S100B), neurofilament light (NfL), alpha-synuclein (α-syn), neuronal pentraxin-2 (NPTX2), and plasma biomarkers of t-tau, p-tau181, p-tau217, and glial fibrillary acidic protein (GFAP) while increasing plasma Aβ40, Aβ42. vMRI showed increased reduction in whole brain volume and increased ventricular expansion, while hippocampal volume was unaffected. Tau PET showed no treatment effect.

Discussion: Robust treatment effects were observed for multiple biomarkers in GRADUATE I and II. Comparison across anti-amyloid antibodies indicates utility of p-tau and GFAP as biomarkers of amyloid plaque removal while NfL and tau PET seem unsuitable as consistent indicators of clinical efficacy. vMRI might be confounded by non-neurodegenerative brain volume changes. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV IDENTIFIER): NCT03444870 and NCT03443973.

Highlights: Gantenerumab significantly reduced brain amyloid load. Tau positron emission tomography showed no treatment effect in a small subset of participants. Volumetric magnetic resonance imaging showed increased whole brain volume reduction under treatment while hippocampal volume was unaffected. Robust treatment effects on cerebrospinal fluid and plasma biomarkers were found, despite lack of clinical efficacy.

Keywords: Alzheimer's disease; amyloid beta; anti‐amyloid; biomarkers; blood‐based biomarkers; cerebrospinal fluid; gantenerumab; neurofilament light; phase 3; phosphorylated tau 217; phosphorylated tau181; positron emission tomography; tau; volumetric magnetic resonance imaging.

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Conflict of interest statement

Tobias Bittner is a full‐time employee of F. Hoffmann‐La Roche Ltd and Genentech, Inc., a member of the Roche Group, and owns stock in F. Hoffmann‐La Roche Ltd. Matteo Tonietto, Gregory Klein, Anton Belousov, Vittorio Illiano, Paul Delmar, and Susanna Gobbi are full‐time employees of F. Hoffmann‐La Roche Ltd and own stock in F. Hoffmann‐La Roche Ltd. At the time of the study, Christopher Galli was full‐time employee of F. Hoffmann‐La Roche Ltd and owned stock in F. Hoffmann‐La Roche Ltd. Marzia A. Scelsi is a full‐time employee of Roche Products Ltd. Nicola Voyle is a full‐time employee of Roche Products Ltd. and owns stock in F. Hoffmann‐La Roche Ltd. Muhamed Barakovic is an employee of Hays plc and a consultant for F. Hoffmann‐La Roche Ltd. Maryam Abaei, Erica Silvestri, and Antonio Napolitano are employees of A4P Consulting Ltd. and consultants for F. Hoffmann‐La Roche Ltd. Kaj Blennow has served as a consultant and on advisory boards for AC Immune, Acumen, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd., 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. Frederik Barkhof has served on steering committees or as data safety monitoring board member for Biogen, Merck, Eisai, and Prothena; as an advisory board member for Combinostics, Scottish Brain Sciences; and as a consultant for Roche, Celltrion, Rewind Therapeutics, Merck, and Bracco. He has research agreements with ADDI, Merck, Biogen, GE Healthcare, and Roche and is a co‐founder and shareholder of Queen Square Analytics Ltd. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Amyloid PET. Top row shows the adjusted mean change from baseline to week 116 in the amyloid load as measured by Centiloid using amyloid PET imaging (G I solid line and G II dotted line). Bottom row shows the individual trajectory of amyloid load for each participant enrolled in the amyloid PET substudy of G I (left) and G II (right). Aβ, amyloid beta; CI, confidence interval; CL, Centiloid; G I, GRADUATE I; G II, GRADUATE II; PET, positron emission tomography.
FIGURE 2
FIGURE 2
Tau PET. Adjusted mean change from baseline to week 116 in the tau load in seven brain regions of interest as measured by [18F]GTP1 tau PET SUVR. P values not corrected for multiplicity. CI, confidence interval; GTP1, Genentech tau probe 1; PET, positron emission tomography; SUVR, standardized uptake value ratio.
FIGURE 3
FIGURE 3
vMRI. Adjusted mean change from baseline to week 116 in vMRI in whole brain, hippocampus, whole cortex, and brain lateral ventricles, as well as the adjusted mean change from baseline to week 116 in cortical thickness of the whole cortex and temporal‐meta ROI. P values not corrected for multiplicity. CI, confidence interval; G I, GRADUATE I; G II, GRADUATE II; ROI, region of interest; vMRI, volumetric magnetic resonance imaging.
FIGURE 4
FIGURE 4
CSF biomarkers. Adjusted mean plot of ANCOVA for CSF biomarker percent change from baseline to Week 116. P values not corrected for multiplicity. ANCOVA, analysis of covariance; Aβ, amyloid beta; α‐syn, alpha‐synuclein; CI, confidence interval; CSF, cerebrospinal fluid; GFAP, glial fibrillary acidic protein; NfL, neurofilament light; NPTX2, neuronal pentraxin‐2; pTau, phosphorylated tau; sTREM2, soluble triggering receptor expressed on myeloid cells‐2; S100B, S100 calcium‐binding protein B; tTau, total tau; YKL‐40, chitinase 3‐like 1.
FIGURE 5
FIGURE 5
Blood‐based biomarkers. Adjusted mean plot of plasma biomarker percent change from baseline to Week 116. An MMRM model was used on log‐transformed data. P values not corrected for multiplicity. Aβ, amyloid beta; CI, confidence interval; G, GRADUATE; GDF15, growth differentiation factor 15; GFAP, glial fibrillary acidic protein; IGFBP7, insulin‐like growth factor‐binding protein 7; MMRM, mixed models for repeated measures; NfL, neurofilament light; pTau, phosphorylated tau; sTREM2, soluble triggering receptor expressed on myeloid cells‐2; tTau, total tau; YKL‐40, chitinase 3‐like 1.
FIGURE 5
FIGURE 5
Blood‐based biomarkers. Adjusted mean plot of plasma biomarker percent change from baseline to Week 116. An MMRM model was used on log‐transformed data. P values not corrected for multiplicity. Aβ, amyloid beta; CI, confidence interval; G, GRADUATE; GDF15, growth differentiation factor 15; GFAP, glial fibrillary acidic protein; IGFBP7, insulin‐like growth factor‐binding protein 7; MMRM, mixed models for repeated measures; NfL, neurofilament light; pTau, phosphorylated tau; sTREM2, soluble triggering receptor expressed on myeloid cells‐2; tTau, total tau; YKL‐40, chitinase 3‐like 1.
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