TY - JOUR
T1 - Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab
T2 - Lessons from a Trial in Dominantly Inherited Alzheimer Disease
AU - For the Dominantly Inherited Alzheimer Network Trials Unit
AU - Friedrichsen, Nelly
AU - Llibre-Guerra, Jorge
AU - Li, Yan
AU - McCullough, Austin A.
AU - Hofmann, Carsten
AU - Wojtowicz, Jakub
AU - Park, Ethan
AU - Wang, Guoqiao
AU - Preboske, Gregory M.
AU - Wang, Qing
AU - Gordon, Brian
AU - Chen, Charles D.
AU - Flores, Shaney
AU - Aggarwal, Neelum T.
AU - Berman, Sarah B.
AU - Bird, Thomas D.
AU - Black, Sandra E.
AU - Borowski, Bret
AU - Brooks, William S.
AU - Chhatwal, Jasmeer P.
AU - Clarnette, Roger
AU - Cruchaga, Carlos
AU - Niven, Anne
AU - Farlow, Martin
AU - Fox, Nick C.
AU - Gauthier, Serge
AU - Hassenstab, Jason
AU - Hobbs, Diana A.
AU - Holdridge, Karen C.
AU - Honig, Lawrence S.
AU - Hornbeck, Russ C.
AU - Hsiung, Ging Yuek R.
AU - Jack, Clifford R.
AU - Jimenez-Velazquez, Ivonne Z.
AU - Jucker, Mathias
AU - Klein, Gregory
AU - Levin, Johannes
AU - Mancini, Michele
AU - Masellis, Mario
AU - McKay, Nicole S.
AU - Mummery, Catherine J.
AU - Ringman, John M.
AU - Shimada, Hiroyuki
AU - Snider, Joy
AU - Suzuki, Kazushi
AU - Wallon, David
AU - Xiong, Chengjie
AU - Yaari, Roy
AU - McDade, Eric
AU - Perrin, Richard
AU - Bateman, Randall
AU - Salloway, Stephen P.
AU - Benzinger, Tammie
AU - Clifford, David
N1 - Publisher Copyright:
© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2022/11
Y1 - 2022/11
N2 - Objective: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). Methods: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. Results: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. Interpretation: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729–744.
AB - Objective: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). Methods: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. Results: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. Interpretation: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729–744.
UR - http://www.scopus.com/inward/record.url?scp=85140097709&partnerID=8YFLogxK
U2 - 10.1002/ana.26511
DO - 10.1002/ana.26511
M3 - Article
C2 - 36151869
AN - SCOPUS:85140097709
SN - 0364-5134
VL - 92
SP - 729
EP - 744
JO - Annals of neurology
JF - Annals of neurology
IS - 5
ER -