Randomized Controlled Trial

. 2025 Jul;21(7):e70347.

doi: 10.1002/alz.70347.

Regional effects of gantenerumab on neuroimaging biomarkers in the DIAN-TU-001 trial

Austin McCullough¹, Charles D Chen¹, Brian A Gordon¹, Nelly Joseph-Mathurin¹, Clifford R Jack Jr², Robert Koeppe³, Russ Hornbeck¹, Deborah Koudelis¹, Nicole S McKay¹, Diana A Hobbs¹, Shaney Flores¹, Sarah J Keefe¹, Neelum T Aggarwal⁴, Ricardo F Allegri⁵, Sarah B Berman⁶, Thomas Bird⁷, Sandra E Black⁸, William S Brooks^{9

10}, Jasmeer P Chhatwal¹¹, Gregory S Day¹², Martin R Farlow¹³, Nick C Fox¹⁴, Serge Gauthier¹⁵, Lawrence S Honig¹⁶, Ging-Yuek Hsiung¹⁷, Mathias Jucker^{18

19}, Johannes Levin^{20

21

22}, Mario Masellis⁸, Colin Masters²³, Patricio Chrem Mendez⁵, John M Ringman²⁴, B Joy Snider¹, Stephen Salloway^{25

26}, Peter R Schofield^{9

10}, Hiroyuki Shimada²⁷, Kazushi Suzuki²⁸, Christopher H van Dyck²⁹, Gregory Klein³⁰, David B Clifford¹, Carlos Cruchaga¹, Jason Hassenstab¹, Yan Li¹, Eric McDade¹, Susan Mills¹, John C Morris¹, Richard J Perrin¹, Charlene Supnet-Bell¹, Guoqiao Wang¹, Chengjie Xiong¹, Randall J Bateman¹, Tammie L S Benzinger¹; DIAN‐TU Study Team

Affiliations

¹ Washington University School of Medicine in Saint Louis, St. Louis, Missouri, USA.
² Mayo Clinic, Rochester, Minnesota, USA.
³ University of Michigan, Ann Arbor, Michigan, USA.
⁴ Rush University Medical Center, Chicago, Illinois, USA.
⁵ Institute for Neurological Research FLENI, Buenos Aires, Argentina.
⁶ University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
⁷ University of Washington, Seattle, Washington, USA.
⁸ Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
⁹ Neuroscience Research Australia, Randwick, New South Wales, Australia.
¹⁰ The University of New South Wales, UNSW Sydney, Sydney, New South Wales, Australia.
¹¹ Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹² Mayo Clinic, Jacksonville, Florida, USA.
¹³ Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁴ UK Dementia Research Institute and Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.
¹⁵ McGill Center for Studies in Aging, McGill University, Montréal, Quebec, Canada.
¹⁶ Columbia University Irving Medical Center, New York, New York, USA.
¹⁷ University of British Columbia, Vancouver, British Columbia, Canada.
¹⁸ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
¹⁹ Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
²⁰ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
²¹ Ludwig Maximilian University of Munich, Munich, Germany.
²² Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
²³ University of Melbourne, Parkville, Victoria, Australia.
²⁴ Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
²⁵ Butler Hospital, Providence, Rhode Island, USA.
²⁶ Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
²⁷ Osaka City University, Sumiyoshi-ku, Osaka, Japan.
²⁸ National Defense Medical College, Tokorozawa, Saitama, Japan.
²⁹ Yale School of Medicine, New Haven, Connecticut, USA.
³⁰ Hoffmann-La Roche Ltd, Basel, Switzerland.

PMID: 40660741
PMCID: PMC12260115
DOI: 10.1002/alz.70347

Randomized Controlled Trial

Regional effects of gantenerumab on neuroimaging biomarkers in the DIAN-TU-001 trial

Austin McCullough et al. Alzheimers Dement. 2025 Jul.

. 2025 Jul;21(7):e70347.

doi: 10.1002/alz.70347.

Authors

Affiliations

¹ Washington University School of Medicine in Saint Louis, St. Louis, Missouri, USA.
² Mayo Clinic, Rochester, Minnesota, USA.
³ University of Michigan, Ann Arbor, Michigan, USA.
⁴ Rush University Medical Center, Chicago, Illinois, USA.
⁵ Institute for Neurological Research FLENI, Buenos Aires, Argentina.
⁶ University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
⁷ University of Washington, Seattle, Washington, USA.
⁸ Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
⁹ Neuroscience Research Australia, Randwick, New South Wales, Australia.
¹⁰ The University of New South Wales, UNSW Sydney, Sydney, New South Wales, Australia.
¹¹ Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹² Mayo Clinic, Jacksonville, Florida, USA.
¹³ Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁴ UK Dementia Research Institute and Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.
¹⁵ McGill Center for Studies in Aging, McGill University, Montréal, Quebec, Canada.
¹⁶ Columbia University Irving Medical Center, New York, New York, USA.
¹⁷ University of British Columbia, Vancouver, British Columbia, Canada.
¹⁸ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
¹⁹ Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
²⁰ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
²¹ Ludwig Maximilian University of Munich, Munich, Germany.
²² Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
²³ University of Melbourne, Parkville, Victoria, Australia.
²⁴ Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
²⁵ Butler Hospital, Providence, Rhode Island, USA.
²⁶ Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
²⁷ Osaka City University, Sumiyoshi-ku, Osaka, Japan.
²⁸ National Defense Medical College, Tokorozawa, Saitama, Japan.
²⁹ Yale School of Medicine, New Haven, Connecticut, USA.
³⁰ Hoffmann-La Roche Ltd, Basel, Switzerland.

PMID: 40660741
PMCID: PMC12260115
DOI: 10.1002/alz.70347

Abstract

Introduction: Monoclonal anti-amyloid therapies are now accessible, but how these treatments influence changes within the brain is still not clear. We investigated overall and regional change in amyloid removal, glucose metabolism, and atrophy in trial participants with dominantly inherited Alzheimer's disease (DIAD).

Methods: In the DIAN-TU-001 trial, 92 carriers received gantenerumab or placebo and underwent serial neuroimaging assessments including [¹¹C]-Pittsburgh compound-B (PiB) positron emission tomography (PET), [¹⁸F]-fluoro-2-deoxyglucose (FDG) PET, and magnetic resonance imaging (MRI).

Results: Gantenerumab significantly reduced PiB-PET uptake overall and in most regions and showed no changes in FDG-PET or MRI measures. Drug effects were associated with baseline PiB-PET uptake, and the largest effects occurred in medial regions.

Discussion: Treated DIAD participants, and especially those with higher amyloid burden, showed a decrease in PiB-PET uptake, which was more pronounced in the basal ganglia and medial frontal structures. These results may inform patient response and future drug trial design.

Highlights: Gantenerumab unevenly decreased Aβ burden as measured by PiB-PET across brain regions. The strongest decrease in PiB-PET uptake was in basal ganglia and medial frontal structures. Variable drug effect on Aβ was partly due to the amount of burden present before treatment. There was no regional effect on FDG-PET metabolism or MRI volumetrics after 4 years.

Keywords: DIAN‐TU; FDG‐PET; MRI measures; PET; amyloid targeted monoclonal antibody; autosomal dominant Alzheimer's disease (ADAD); dominantly inherited Alzheimer's disease (DIAD); gantenerumab; imaging outcomes; regional PiB‐PET uptake; regional variability.

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Conflict of interest statement

N.J.M. received travel support from the Alzheimer's Association to present at AAIC and an honorarium from the PeerView Institute for Medical Education for participating as a facilitator in training workshops at AAIC. C.R.J. served on a Data Safety Monitoring Board for Roche with no compensation. N.S.M. acknowledges support from BrightFocus (A2022013F) and the Alzheimer's Association (AARF‐21‐722077) and received honoraria from PeerView Institute for Medical Education for participating as a facilitator in training workshops at AAIC. N.T.A. acknowledges institutional support from Eisai, Lilly, Pfizer, and Roche. R.F.A. acknowledges institutional support from the Alzheimer's Association (LatamFINGER, iLEADS) and Washington University in St. Louis. S.E.B. acknowledges institutional support from Genentech, Optina, Roche, Lilly, Eisai/Biogen Idec, NovoNordisk, Lilly Avid, ICON, Aribio Co., Ontario Brain Institute, CIHR, Leducq Foundation, Heart and Stroke Foundation of Canada, Brain Canada, Weston Brain Institute, Canadian Partnership for Stroke Recovery, Canadian Foundation for Innovation, Focused Ultrasound Foundation, Alzheimer's Association US, Queen's University, Compute Canada Resources for Research Groups, CANARIE, Networks of Centres of Excellence Canada, and received consulting fees from Roche, Biogen, NovoNordisk, Eisai, Eli Lilly, and DSR, as well as support for presentations from Biogen, Roche, and Eisai. W.S.B. received support for a presentation at Dementia Trials Australia Annual scientific meeting. J.C. received consulting fees from Humana, MedaCorp, and ExpertConnect. G.S.D. acknowledges institutional support from the NIH (R01AG089380, K23AG064029, U01NS120901, U01AG057195, U19AG032438), and received consulting fees from Parabon Nanolabs and Arialys Pharmaceuticals, support for presentations from PeerView Media, Continuing Education Inc., Eli Lilly, Ionis Pharmaceuticals, and DynaMed, personal compensation from ANI Pharmaceuticals, and material support of clinical trial (NCT04372615) from Amgen Therapeutics. M.F. received support for conduct of clinical trials from Eli Lilly, Roche/Genentech, Avanir, Biogen, Cognition Therapeutics, Green Valley, Otsuka, Neurotrope Biosciences, AZTherapies, Athira, Ionis, and Lexeo. N.C.F. received consulting fees from Eisai, Roche, Eli Lilly, and Biogen, and support for presentations from Roche. S.G. received consulting fees from AmyriAD, Eisai Canada, Enigma USA, Lilly Canada, Nordisk Canada, TauRx, and support for presentations from Otsuka Canada, and Lilly Canada. L.S.H. acknowledges institutional support from Abbvie, Acumen, Alector, AstraZeneca, Avanir, Axovant, Biogen, Bristol‐Myer Squibb, Eisai, Eli Lilly, Envivo/Forum, Genentech, Janssen/Johnson & Johnson, Lundbeck, Merck, Pfizer, Roche, TauRx, Vaccinex, and received consulting fees from Biogen, Cortexyme, Eisai, Medscape, Miller Communications, and Prevail and support for presentations from Biogen, Eisai, and Medscape. G.Y.H. acknowledges institutional support from Biogen, Cassava, Eli Lilly, Eisai, NIH, and CIHR and received consulting fees from Biogen, Eli Lilly, Eisai, NovoNordisk, Roche. M.J. acknowledges institutional support from German Center for Neurodegenerative Diseases. J.L. acknowledges institutional support from German Ministry for Research and Education, Ehrmann Foundation, Lüneburg Foundation, InnovationsFonds, Michael J. Fox Foundation, CurePSP, Jerome Lejeune Foundation, Alzheimer Forschungs Initiative, Deutsche Stiftung Down Syndrom, Else Kröner Fresenius Stiftung, DZNE MODAG GmbH, DFG (XC 2145 SyNergy – ID 390857198), and received consulting fees from Eisai, and Biogen, support for presentations from Bayer Vital, Biogen, Eisai, TEVA, Roche, Esteve, Zambon, support for attending meetings from AbbVie, and involvement in patents EP 23 156 122.6 and EP 22 159 408.8. M.M. acknowledges institutional support from Canadian Institutes of Health Research, Weston Brain Institute, Ontario Brain Institute, Brain Canada, Roche, and Alector, received consulting fees from Arkuda Therapeutics, Ionis, Alector, Wave Life Sciences, and Biogen Canada, and received support for presentations from Alcetor, Arkuda Therapeutics. J.M.R. acknowledges institutional support from the NIH (R01AG06901), Avid Pharmaceuticals, AltaMed, and CurePSP. J.S. acknowledges institutional support from the NIH, Roche, Lilly, Johnson & Johnson, and Eisai and received consulting fees from Eisai and Roche. S.S. acknowledges institutional support from Biogen, Eisai, Genentech, Roche, CognitionRx, Lilly, and Janssen, and received consulting fees from Abbvie, Acumen, Alector, Biogen, Biohaven, Cognition, Eisai, Fujirebio, Genentech, Kisbee, Labcorp, Lilly, Merck, Neurophet, NovoNordisk, Prothena, Quest, and Roche and support for meeting attendance from AbbVie, Acumen, Lilly, and Neurophet. P.R.S. acknowledges institutional support from the NIH, Anonymous Foundation, Roth Charitable Foundation, NHMRC, and MRFF and received consulting fees from Outside Opinion Pty Ltd., Moira Clay Consulting Pty Ltd., and Neuroscience Research Australia. C.H.vD. acknowledges institutional support from Lilly, Roche, Biogen, Genentech, Eisai, UCB, Cerevel, and Janssen and received consulting fees from Eisai, Roche, Ono, and Cerevel. G.K. acknowledges employment and stock incentives at F Hoffman La Roche at time of study. D.B.C. received consulting fees from Seagen and Roche and payment for services from NYU Langone Medical Center, Loughren, Loughren, & Loughren PC, Powell Gilbert LLP. C.C. acknowledges institutional support from the NIH, the Alzheimer's Association, and the Michael J. Fox Foundation and received consulting fees from Circular Genomics, Alector, and leadership and stock incentives at Vivid Genetics and Circular Genomics. J.H. received consulting fees from Prothena and AlzPath. E.M. acknowledges institutional support from the NIH (U19AG032438, U01AG059798, R13AG055232, K‐award) and the Alzheimer's Association and received payment for services from Eisai, AAN, and financial incentives from C2N diagnostics. J.C.M. acknowledges institutional support from the NIH (P30 AG066444, P01AG003991, P01AG026276) and received consulting fees from Barcelona Brain Research Center, Native Alzheimer Disease‐Related Resource Center in Minority Aging Research, and payment for presentations from AAIM, International Brain Health Symposium. R.J.P. acknowledges institutional support from the NIH. C.X. acknowledges institutional support from the NIH and received consulting fees from Diadem. R.J.B. acknowledges institutional support from the NIH, GHR Foundation, Alzheimer's Association, and DIAN‐TU Pharma Consortium and receives financial incentives from C2N Diagnostics, support for presentations from the Korean Dementia Association, American Neurological Association, Weill Cornell Medical College, Fondazione Prada, Harvard University, University of Pennsylvania, involvement in US patents 12/267,974; 13/005,233; 62/492,718; 16/610,428; 17/015,985; 15/515,909, leadership role in C2N Diagnostics, and receipt of equipment and materials from Eisai, Janssen, and Hoffman La Roche. T.L.S.B. acknowledges institutional support from Siemens and received consulting fees from Biogen, Eli Lilly, Eisai, Bristol Myers Squibb, Johnson & Johnson, Merck, MedScape, PeerView, involvement in US patents 16/097,457; 12/016,701, and receipt of equipment and materials from Avid Radiopharmaceuticals/Eli Lilly, LMI, Lantheus, and Hyperfine. The other authors report no conflicts of interest. Author disclosures are available in the Supporting Information.

Figures

**FIGURE 1**
Voxel‐wise mean PiB PET SUVR levels in 4‐year completer participants by drug status. Voxel‐wise mean PiB PET SUVR levels across the subset of participants who completed the 4‐year trial course at (A) baseline (Year 0) in drug group, (B) Year 4 in drug group, (C) baseline (Year 0) in placebo group, and (D) Year 4 in placebo group. To visualize voxel‐wise results, non‐partial‐volume‐corrected data were used. PET, positron emission tomography; PiB, Pittsburgh compound B; SUVR, standardized uptake value ratio.

**FIGURE 2**
Regional differences in estimated drug effect on PiB PET signal levels. (A) Regional linear mixed‐effects models were used to estimate effect of longitudinal gantenerumab use on PiB PET signal. Regional PiB PET signal was dependent variable, with fixed‐effects covariates age, sex, CDR, ApoE ε4 status, and drug × time interaction term, and subject‐specific random slopes and intercepts were modeled. (A) Beta weights for drug × time interaction term are displayed. (B) Regional mean baseline PiB PET signal for trial participants. (C) Pearson correlation between regional estimated drug‐effect beta weights and baseline PiB PET pathology levels observed. Colors classify each region by spatial location in the brain. ApoE, apolipoprotein E; CDR, Clinical Dementia Rating; PET, positron emission tomography; PiB, Pittsburgh compound B.

**FIGURE 3**
PiB PET SUVR values for key estimated drug regions. Baseline normalized PiB PET SUVR values at end of trial (Year 4) for a subcortical high estimated drug effect region (caudate), a cortical high estimated drug effect region (rostral anterior cingulate), a key region in DIAD amyloid pathology (precuneus), and a cortical region with much lower estimated drug effect results (inferior parietal) are shown to demonstrate region‐specific amyloid clearance rates. Longitudinal mixed‐effects model β weights and p values for each region are listed for context. PET, positron emission tomography; PiB, Pittsburgh compound B; SUVR, standardized uptake value ratio.

See this image and copyright information in PMC

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Regional effects of gantenerumab on neuroimaging biomarkers in the DIAN-TU-001 trial

Affiliations

Regional effects of gantenerumab on neuroimaging biomarkers in the DIAN-TU-001 trial

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

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Grants and funding

LinkOut - more resources

Full Text Sources

Medical