Amyloid‐Related Imaging Abnormalities in the DIAN‐TU‐001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease
Authors: Joseph‐Mathurin Nelly , Llibre‐Guerra Jorge J. , Li Yan , McCullough Austin A. , Hofmann Carsten , Wojtowicz Jakub , Park Ethan , Wang Guoqiao , Preboske Gregory M. , Wang Qing , Gordon Brian A. , Chen Charles D. , Flores Shaney , Aggarwal Neelum T. , Berman Sarah B. , Bird Thomas D. , Black Sandra E. , Borowski Bret , Brooks William S. , Chhatwal Jasmeer P. , Clarnette Roger , Cruchaga Carlos , Fagan Anne M. , Farlow Martin , Fox Nick C. , Gauthier Serge , Hassenstab Jason , Hobbs Diana A. , Holdridge Karen C. , Honig Lawrence S. , Hornbeck Russ C. , Hsiung Ging‐Yuek R. , Jack Clifford R. , Jimenez‐Velazquez Ivonne Z. , Jucker Mathias , Klein Gregory , Levin Johannes , Mancini Michele , Masellis Mario , McKay Nicole S. , Mummery Catherine J. , Ringman John M. , Shimada Hiroyuki , Snider B. Joy , Suzuki Kazushi , Wallon David , Xiong Chengjie , Yaari Roy , McDade Eric , Perrin Richard J. , Bateman Randall J. , Salloway Stephen P. , Benzinger Tammie L.S. , Clifford David B. ,   For the Dominantly Inherited Alzheimer Network Trials Unit
Published: September 2022

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