Abstracts of the 100th Annual Meeting June 6–9, 2024 Olympic Valley, California
Unknown authors
Abstract
Background: Clinical trials of anti-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 Aβ deposits indirectly and/or incompletely.In contrast, postmortem neuropathologic assessments allow direct investigation of treatment effects on brain Aβ deposits and on many other pathologic features.Methods: From a clinical trial of anti-Aβ monoclonal antibodies in dominantly inherited AD, we measured immunohistochemistry area fractions (AFs) for Aβ (10D5), tauopathy (PHF1), microgliosis (IBA1) and astrocytosis (GFAP) in 10 brain regions from 10 trial cases-representing gantenerumab (n ¼ 4), solanezumab (n ¼ 4), and placebo/notreatment (n ¼ 2) arms-and 10 observational study cases.Gantenerumab, solanezumab, and control (placebo/no-treatment/observational) groups were compared based on these AFs, antemortem Aβ PET (11C-PiB) standardized uptake value ratios (SUVRs), and CSF (Aβ42/40, p-tau181, t-tau) biomarkers.Five controls lacked CSF and PET data.Results: CSF Aβ42/40 showed significant increase in the gantenerumab arm versus controls; CSF t-tau showed a corroborating decrease; CSF p-tau181 showed no significant difference.Aβ PET SUVRs showed significant decreases in the gantenerumab arm versus controls in temporal cortex, caudate, putamen, and thalamus.Strikingly, after continued gantenerumab administration between Aβ PET and autopsy, Aβ AFs were significantly lower in the gantenerumab arm versus control in 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.Conclusions: Our results suggest that gantenerumab treatment, as administered, reduced Aβ deposits-albeit incompletely-in a dose-dependent manner, without significantly altering tauopathy, microgliosis, or astrocytosis.They also suggest that this partial reversal of AD pathology may be optimized with higher doses, more effective anti-Aβ therapeutics, earlier intervention, and/or combined treatments in future clinical trials.