TY  - JOUR
AU  - Chen, Charles D
AU  - Franklin, Erin E
AU  - Li, Yan
AU  - Joseph-Mathurin, Nelly
AU  - Burns, Aime L
AU  - Hobbs, Diana A
AU  - McCullough, Austin A
AU  - Schultz, Stephanie A
AU  - Xiong, Chengjie
AU  - Wang, Guoqiao
AU  - Masellis, Mario
AU  - Hsiung, Ging-Yuek Robin
AU  - Gauthier, Serge
AU  - Berman, Sarah B
AU  - Roberson, Erik D
AU  - Honig, Lawrence S
AU  - Clarnette, Roger
AU  - Ringman, John M
AU  - Galvin, James E
AU  - Brooks, William
AU  - Suzuki, Kazushi
AU  - Black, Sandra
AU  - Levin, Johannes
AU  - Aggarwal, Neelum T
AU  - Jucker, Mathias
AU  - Frosch, Matthew P
AU  - Kofler, Julia K
AU  - White, Charles
AU  - Keene, C Dirk
AU  - Chen, Jie
AU  - Daniels, Alisha
AU  - Gordon, Brian A
AU  - Ibanez, Laura
AU  - Karch, Celeste M
AU  - Llibre-Guerra, Jorge
AU  - McDade, Eric
AU  - Morris, John C
AU  - Supnet-Bell, Charlene
AU  - Allegri, Ricardo F
AU  - Lee, Jae-Hong
AU  - Day, Gregory S
AU  - Lopera, Francisco
AU  - Roh, Jee Hoon
AU  - Schofield, Peter R
AU  - Mills, Susan
AU  - Benzinger, Tammie L S
AU  - Bateman, Randall J
AU  - Perrin, Richard J
TI  - Immunohistochemical evaluation of a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease.
JO  - Acta neuropathologica
VL  - 149
IS  - 1
SN  - 0001-6322
CY  - Heidelberg
PB  - Springer
M1  - DZNE-2025-00663
SP  - 57
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Antibodies, Monoclonal, Humanized: therapeutic use
KW  - Alzheimer Disease: drug therapy
KW  - Alzheimer Disease: pathology
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: metabolism
KW  - Male
KW  - Female
KW  - Amyloid beta-Peptides: metabolism
KW  - Aged
KW  - Brain: pathology
KW  - Brain: drug effects
KW  - Brain: metabolism
KW  - Middle Aged
KW  - Immunohistochemistry
KW  - Aged, 80 and over
KW  - Alzheimer disease (Other)
KW  - Anti-amyloid-β monoclonal antibodies (Other)
KW  - CSF (Other)
KW  - Clinical trial (Other)
KW  - Digital pathology (Other)
KW  - PiB PET (Other)
KW  - Antibodies, Monoclonal, Humanized (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - gantenerumab (NLM Chemicals)
KW  - solanezumab (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40459787
DO  - DOI:10.1007/s00401-025-02890-7
UR  - https://pub.dzne.de/record/278999
ER  -