Reversibility of cognitive worsening observed with BACE inhibitor umibecestat in the Alzheimer's Prevention Initiative (API) Generation Studies

• Published in: Alzheimer's & dementia 2024-11, Vol.20 (11), p.7745-7761
• Main Authors: Tariot, Pierre N., Riviere, Marie‐Emmanuelle, Salloway, Stephen, Burns, Jeffrey M., Snaedal, Jón G., Borowsky, Beth, Lopez, Cristina Lopez, Liu, Fonda, Rouzade‐Dominguez, Marie‐Laure, Cazorla, Pilar, Mousseau, Marie‐Catherine, Arkuszewski, Michal, Ricart, Javier, Viglietta, Vissia, Sui, Yihan, Caputo, Angelika, Langbaum, Jessica B., Reiman, Eric M., Graf, Ana
• Format: Article
• Language: English
• Subjects: Aged; Alzheimer Disease - drug therapy; Alzheimer Disease - prevention & control; Alzheimer's disease (AD) prevention; amyloid beta lowering; Amyloid Precursor Protein Secretases - antagonists & inhibitors; APOE; Apolipoprotein E4 - genetics; Aspartic Acid Endopeptidases - antagonists & inhibitors; BACE inhibitors; biomarkers; Cognitive Dysfunction - prevention & control; Double-Blind Method; Female; Humans; imaging; Male; Middle Aged; Neuropsychological Tests - statistics & numerical data
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.14237

INTRODUCTION The Alzheimer's Prevention Initiative (API) Generation Studies evaluated the BACE inhibitor umibecestat for Alzheimer's disease (AD) prevention. The studies were terminated early, and the reversibility of umibecestat's side effects was assessed. METHODS Cognitively unimpaired 60‐ to 75‐year‐old apolipoprotein E (APOE) ε4 homozygotes and heterozygotes (the latter with elevated brain amyloid deposition) (n = 1556) received umibecestat (50 or 15 mg daily) or placebo for 7 months on average and were followed for a median (interquartile range) of 4 (3 to 6) months after washout. RESULTS Compared to placebo, umibecestat‐treated participants had small, non‐progressive, but statistically significant decline in performance on certain cognitive batteries including Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and API Preclinical Composite Cognitive test, but not Clinical Dementia Rating‐Sum of Boxes. RBANS differences were no longer significant at the end of follow‐up. DISCUSSION In people at genetic risk for AD, high‐dose beta‐site amyloid precursor protein cleaving enzyme (BACE) inhibition was associated with early mild cognitive worsening, which reversed shortly after washout, suggesting a symptomatic side effect not associated with neurodegeneration. Fully anonymized data, images, and samples are available upon request for further research on BACE inhibition. Highlights This is the first trial with blinded assessment of reversibility of BACE inhibitor side effects. Umibecestat was tested in cognitively unimpaired persons at genetic risk for AD. Umibecestat led to early mild cognitive decline that reversed shortly after washout. This suggests a potentially manageable effect not associated with neurodegeneration. Further research may determine the future of BACE inhibition in AD prevention.