Gantenerumab reduces brain amyloid-β proteoforms: Biochemical evaluation in dominantly inherited Alzheimer disease

Therapeutic strategies targeting amyloid-{beta} (A{beta}) in Alzheimer disease (AD) include antibodies directed against fibrillar amyloid plaques or soluble amyloid-{beta} (A{beta}) species, yet how these approaches reshape brain pathology remains poorly understood. Postmortem neuropathological assessment is crucial for evaluating the degree of A{beta} removal, providing information and context that fluid biomarkers and positron emission tomography (PET) alone cannot, and guiding development of more effective disease modifying therapies for AD. In this study, using high resolution mass spectrometry we quantitatively measured A{beta} and tau proteoforms in postmortem brain tissue homogenates to evaluate the impact of long-term treatment with anti-A{beta} monoclonal antibodies gantenerumab or solanezumab in a clinical trial of dominantly inherited Alzheimer disease (DIAD). Symptomatic DIAD participants who had been treated for ~ 4 years with anti-A{beta} monoclonal antibodies (gantenerumab, n=4 or solanezumab, n=4) were compared with untreated, symptomatic DIAD mutation carriers (n=40) and with age-relevant non-DIAD controls with modest or no plaque pathology (n=18). Consistent with antemortem A{beta}-PET findings in the clinical trial, gantenerumab-treated participant samples showed significantly lower levels of specific A{beta} proteoforms (A{beta} 42, A{beta}40) in the insoluble plaque associated pool (range: 60-80 % reduction); they also showed lower levels of post-translationally modified A{beta} proteoform A{beta}3pGlu in both the insoluble and soluble pool, compared to untreated DIAD participants, but without reaching the levels found in non-DIAD controls. Samples from gantenerumab-treated participants also showed regionally lower amounts of insoluble phosphorylated tau species (pT181, pT205, pT208) and MTBR tau species (354-369, 306-317, 299-317) without apparent differences in insoluble total tau levels. In contrast, brain tissue samples from solanezumab-treated participants did not show significant differences overall in soluble or insoluble levels of A{beta} and tau proteoforms in comparison to those from non-treated DIAD individuals. These findings support that amyloid targeting treatment (ATT) with gantenerumab, an antibody that targets fibrillar A{beta}, can remove insoluble A{beta} from the DIAD brain and also mitigate downstream biochemical and pathophysiological changes associated with AD.