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

@misc{mukherjee2026gantenerumab,
  title = {{Gantenerumab reduces brain amyloid-β proteoforms: Biochemical evaluation in dominantly inherited Alzheimer disease}},
  author = {S. Mukherjee and N. R. Barthelemy and T. Atri and Y. Li and D. Yen and Y. He and R. Coyle and V. Ovod and E. E. Franklin and C. Xiong and G. Wang and J. Xu and H. Farsad and C. J. Mummery and C. L. Masters and R. Sanchez-Valle and M. Masellis and G.-Y. R. Hsiung and S. Guthier and J. J. Lah and S. B. Berman and E. D. Roberson and G. Surti and L. S. Honig and R. Clarnette and P. Vitali and J. Ringman and T. D. Bird and W. S. Brook and N. C. Fox and K. Suzuki and S. E. Black and J. Levin and M. R. Farlow and J. Chhatwal and N. T. Aggarwal and M. Jucker and M. P. Frosch and J. K. Kofler and C. White and D. Keene and J. Chen and J. Glass and M. Gearing and N. S. Ryan and D. Aguillon},
  howpublished = {medRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.22.26363432},
  url = {https://www.medrxiv.org/content/10.64898/2026.09.22.26363432v1},
  note = {CC BY-NC-ND},
}

TY  - UNPB
TI  - Gantenerumab reduces brain amyloid-β proteoforms: Biochemical evaluation in dominantly inherited Alzheimer disease
AU  - S. Mukherjee
AU  - N. R. Barthelemy
AU  - T. Atri
AU  - Y. Li
AU  - D. Yen
AU  - Y. He
AU  - R. Coyle
AU  - V. Ovod
AU  - E. E. Franklin
AU  - C. Xiong
AU  - G. Wang
AU  - J. Xu
AU  - H. Farsad
AU  - C. J. Mummery
AU  - C. L. Masters
AU  - R. Sanchez-Valle
AU  - M. Masellis
AU  - G.-Y. R. Hsiung
AU  - S. Guthier
AU  - J. J. Lah
AU  - S. B. Berman
AU  - E. D. Roberson
AU  - G. Surti
AU  - L. S. Honig
AU  - R. Clarnette
AU  - P. Vitali
AU  - J. Ringman
AU  - T. D. Bird
AU  - W. S. Brook
AU  - N. C. Fox
AU  - K. Suzuki
AU  - S. E. Black
AU  - J. Levin
AU  - M. R. Farlow
AU  - J. Chhatwal
AU  - N. T. Aggarwal
AU  - M. Jucker
AU  - M. P. Frosch
AU  - J. K. Kofler
AU  - C. White
AU  - D. Keene
AU  - J. Chen
AU  - J. Glass
AU  - M. Gearing
AU  - N. S. Ryan
AU  - D. Aguillon
PY  - 2026
DA  - 2026/09/22
PB  - medRxiv
DO  - 10.64898/2026.09.22.26363432
UR  - https://www.medrxiv.org/content/10.64898/2026.09.22.26363432v1
AB  - 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.  Key SummaryO_ST_ABSQuestionC_ST_ABSHow do amyloid targeting treatments (ATT) affect the Alzheimer disease (AD)-related brain pathologies of soluble and aggregated amyloid-{beta} and tau proteoforms in postmortem tissue?  BackgroundExtracellular amyloid plaques and neurofibrillary tangles (NFTs) are the primary pathological hallmarks of AD. For the past three decades, active and passive immunization against cerebral amyloid-{beta} (A{beta}) has constituted one of the primary avenues of disease-modifying intervention in AD. Recently, passive immunizations using anti-A{beta} targeting antibodies have demonstrated slowing of cognitive decline in sporadic AD and possibly in dominantly inherited AD (DIAD). In these clinical trials, target engagement has been inferred from A{beta}-positron emission tomography (PET) and/or biofluid biomarkers during life. However, to confirm evidence of target engagement more directly, identify which pathological proteoforms are affected, quantify the dose dependent treatment effects of these treatments, and begin to evaluate their putative downstream effects on AD pathophysiology, quantitative biochemical comparisons of amyloid plaques and tau pathology (soluble and insoluble A{beta} and tau species) in postmortem brain tissue of treated and untreated AD are needed.  FindingsIn this study, using high resolution mass spectrometry we measured the soluble and insoluble A{beta} and tau proteoforms in the postmortem brain tissue homogenates from DIAN-TU-001 trial participants who were symptomatic and had been treated for [~] 4 years with gantenerumab (n=4) or solanezumab (n=4), two antibodies that bind to insoluble and soluble A{beta}, respectively. Intervals between treatment discontinuation and death ranged from 5 months to 3 years. Comparisons were made with postmortem brain tissue samples from untreated, symptomatic DIAD participants of the DIAN-Obs study (n=40) and from age-relevant, cognitively normal, non-DIAD controls with or without only modest burdens of diffuse A{beta} plaques (n=18). Consistent with antemortem A{beta}-PET findings in the clinical trial, gantenerumab significantly decreased specific A{beta} (A{beta}42, A{beta}40) proteoforms in the insoluble plaque associated pool (range: 60-80% reduction) compared to the untreated DIAD participants, but without reaching the levels found in the non-DIAD controls. Samples from gantenerumab treated participants also showed significantly lower amount of post-translationally modified A{beta} (A{beta}3pGlu) and regionally lower insoluble phosphorylated tau species (pT181, pT205 and pT208), without apparent differences in insoluble total tau levels. In contrast, solanezumab treatment did not show significant effect on the soluble or insoluble levels of A{beta} and tau proteoforms in comparison to samples from non-treated DIAD individuals.  SignificanceThese findings support that 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.
ER  -