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<p>Clinical trials of anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer disease (AD) infer target engagement from Aβ positron emission tomography (PET) and/or fluid biomarkers such as cerebrospinal fluid (CSF) Aβ42/40. However, these biomarkers measure brain Aβ deposits indirectly and/or incompletely. In contrast, neuropathologic assessments allow direct investigation of treatment effects on brain Aβ deposits—and on potentially myriad ‘downstream’ pathologic features. From a clinical trial of anti-Aβ monoclonal antibodies in dominantly inherited AD (DIAD), in the largest study of its kind, we measured immunohistochemistry area fractions (AFs) for Aβ deposits (10D5), tauopathy (PHF1), microgliosis (IBA1), and astrocytosis (GFAP) in 10 brain regions from 10 trial cases—gantenerumab (<i>n</i> = 4), solanezumab (<i>n</i> = 4), placebo/no treatment (<i>n</i> = 2)—and 10 DIAD observational study cases. Strikingly, in proportion to total drug received, Aβ deposit AFs were significantly lower in the gantenerumab arm versus controls in almost all areas examined, including frontal, temporal, parietal, and occipital cortices, anterior cingulate, hippocampus, caudate, putamen, thalamus, and cerebellar gray matter; only posterior cingulate and cerebellar white matter comparisons were non-significant. In contrast, AFs of tauopathy, microgliosis, and astrocytosis showed no differences across groups. Our results demonstrate with direct histologic evidence that gantenerumab treatment in DIAD can reduce parenchymal Aβ deposits throughout the brain in a dose-dependent manner, suggesting that more complete removal may be possible with earlier and more aggressive treatment regimens. Although AFs of tauopathy, microgliosis, and astrocytosis showed no clear response to partial Aβ removal in this limited autopsy cohort, future examination of these cases with more sensitive techniques (e.g., mass spectrometry) may reveal more subtle ‘downstream’ effects.</p>

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Immunohistochemical evaluation of a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月3日

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  • Charles D. Chen,
  • Erin E. Franklin,
  • Yan Li,
  • Nelly Joseph-Mathurin,
  • Aime L. Burns,
  • Diana A. Hobbs,
  • Austin A. McCullough,
  • Stephanie A. Schultz,
  • Chengjie Xiong,
  • Guoqiao Wang,
  • Mario Masellis,
  • Ging-Yuek Robin Hsiung,
  • Serge Gauthier,
  • Sarah B. Berman,
  • Erik D. Roberson,
  • Lawrence S. Honig,
  • Roger Clarnette,
  • John M. Ringman,
  • James E. Galvin,
  • William Brooks,
  • Kazushi Suzuki,
  • Sandra Black,
  • Johannes Levin,
  • Neelum T. Aggarwal,
  • Mathias Jucker,
  • Matthew P. Frosch,
  • Julia K. Kofler,
  • Charles White III,
  • C. Dirk Keene,
  • Jie Chen,
  • Alisha Daniels,
  • Brian A. Gordon,
  • Laura Ibanez,
  • Celeste M. Karch,
  • Jorge Llibre-Guerra,
  • Eric McDade,
  • John C. Morris,
  • Charlene Supnet-Bell,
  • Ricardo F. Allegri,
  • Jae-Hong Lee,
  • Gregory S. Day,
  • Francisco Lopera,
  • Jee Hoon Roh,
  • Peter R. Schofield,
  • Susan Mills,
  • Tammie L. S. Benzinger,
  • Randall J. Bateman,
  • Richard J. Perrin,
  • Randall Bateman,
  • Alisha J. Daniels,
  • Laura Courtney,
  • Jorge J. Llibre-Guerra,
  • Chengie Xiong,
  • Xiong Xu,
  • Ruijin Lu,
  • Emily Gremminger,
  • Gina Jerome,
  • Elizabeth Herries,
  • Jennifer Stauber,
  • Bryce Baker,
  • Matthew Minton,
  • Carlos Cruchaga,
  • Alison M. Goate,
  • Alan E. Renton,
  • Danielle M. Picarello,
  • Tammie Benzinger,
  • Russell Hornbeck,
  • Jason Hassenstab,
  • Jennifer Smith,
  • Sarah Stout,
  • Andrew J. Aschenbrenner,
  • Jacob Marsh,
  • David M. Holtzman,
  • Nicolas Barthelemy,
  • Jinbin Xu,
  • James M. Noble,
  • Snezana Ikonomovic,
  • Neelesh K. Nadkarni,
  • Neill R. Graff-Radford,
  • Martin Farlow,
  • Jasmeer P. Chhatwal,
  • Takeshi Ikeuchi,
  • Kensaku Kasuga,
  • Yoshiki Niimi,
  • Edward D. Huey,
  • Stephen Salloway,
  • William S. Brooks,
  • Jacob A. Bechara,
  • Ralph Martins,
  • Nick C. Fox,
  • David M. Cash,
  • Natalie S. Ryan,
  • Christoph Laske,
  • Anna Hofmann,
  • Elke Kuder-Buletta,
  • Susanne Graber-Sultan,
  • Ulrike Obermueller,
  • Yvonne Roedenbeck,
  • Jonathan Vӧglein,
  • Raquel Sanchez-Valle,
  • Pedro Rosa-Neto,
  • Patricio Chrem Mendez,
  • Ezequiel Surace,
  • Silvia Vazquez,
  • Yudy Milena Leon,
  • Laura Ramirez,
  • David Aguillon,
  • Allan I. Levey,
  • Erik C. B. Johnson,
  • Nicholas T. Seyfried,
  • John Ringman,
  • Anne M. Fagan,
  • Hiroshi Mori

摘要

Clinical trials of anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer disease (AD) infer target engagement from Aβ positron emission tomography (PET) and/or fluid biomarkers such as cerebrospinal fluid (CSF) Aβ42/40. However, these biomarkers measure brain Aβ deposits indirectly and/or incompletely. In contrast, neuropathologic assessments allow direct investigation of treatment effects on brain Aβ deposits—and on potentially myriad ‘downstream’ pathologic features. From a clinical trial of anti-Aβ monoclonal antibodies in dominantly inherited AD (DIAD), in the largest study of its kind, we measured immunohistochemistry area fractions (AFs) for Aβ deposits (10D5), tauopathy (PHF1), microgliosis (IBA1), and astrocytosis (GFAP) in 10 brain regions from 10 trial cases—gantenerumab (n = 4), solanezumab (n = 4), placebo/no treatment (n = 2)—and 10 DIAD observational study cases. Strikingly, in proportion to total drug received, Aβ deposit AFs were significantly lower in the gantenerumab arm versus controls in almost all areas examined, including frontal, temporal, parietal, and occipital cortices, anterior cingulate, hippocampus, caudate, putamen, thalamus, and cerebellar gray matter; only posterior cingulate and cerebellar white matter comparisons were non-significant. In contrast, AFs of tauopathy, microgliosis, and astrocytosis showed no differences across groups. Our results demonstrate with direct histologic evidence that gantenerumab treatment in DIAD can reduce parenchymal Aβ deposits throughout the brain in a dose-dependent manner, suggesting that more complete removal may be possible with earlier and more aggressive treatment regimens. Although AFs of tauopathy, microgliosis, and astrocytosis showed no clear response to partial Aβ removal in this limited autopsy cohort, future examination of these cases with more sensitive techniques (e.g., mass spectrometry) may reveal more subtle ‘downstream’ effects.