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

Chen, Charles D.; Franklin, Erin E.; Li, Yan; Joseph-Mathurin, Nelly; Burns, Aime L.; Hobbs, Diana A.; McCullough, Austin A.; Schultz, Stephanie A.; Xiong, Chengjie; Wang, Guoqiao; Masellis, Mario; Hsiung, Ging-Yuek Robin; Gauthier, Serge; Berman, Sarah B.; Roberson, Erik D.; Honig, Lawrence S.; Clarnette, Roger; Ringman, John M.; Galvin, James E.; Brooks, William; Suzuki, Kazushi; Black, Sandra; Levin, Johannes und Aggarwal, Neelum T. (2025): Immunohistochemical evaluation of a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease. In: Acta Neuropathologica, Bd. 149, 57

Abstract

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy) ; Medizin > Klinikum der LMU München > Neurologische Klinik und Poliklinik mit Friedrich-Baur-Institut
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1432-0533
• Bemerkung: for the DIAN-TU Study Team & For the DIAN-Obs Study Team; a complete list of members is available within the article
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198