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

Acta Neuropathol. 2025 Jun 3;149(1):57. doi: 10.1007/s00401-025-02890-7.

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.

Keywords: Alzheimer disease; Anti-amyloid-β monoclonal antibodies; CSF; Clinical trial; Digital pathology; PiB PET.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / metabolism
  • Antibodies, Monoclonal, Humanized* / therapeutic use
  • Brain* / drug effects
  • Brain* / metabolism
  • Brain* / pathology
  • Female
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged

Substances

  • Antibodies, Monoclonal, Humanized
  • Amyloid beta-Peptides
  • gantenerumab
  • solanezumab