In this issue, Gauthier and colleagues from the European Union-North America Clinical Trials in Alzheimer Disease Task Force (EU/US CTAD Task Force) provide a compelling argument for the implementation of clinical trials in persons with Alzheimer disease (AD) dementia that utilize combinations of experimental anti-Alzheimer therapies (1). The rationale for combination therapy in AD rests on the appreciation that AD pathophysiology is complex and involves many pathogenic pathways (2). The EU/US CTAD Task Force recommends that combination therapies should include therapies that target various aspects of the process wherein amyloid precursor protein undergoes proteolytic cleavage to produce amyloidogenic peptides. That anti-amyloid monotherapy alone is insufficient to provide clinical benefit with AD dementia has been underscored once again by the recent decision of Biogen and Eisai to discontinue Phase 3 studies of aducanumab, a human monoclonal antibody that targets aggregated forms of amyloid-beta, because futility analyses indicated that the trials were unlikely to meet their primary endpoint (3); similarly, Roche has announced discontinuation of trials of crenezumab (4). The EU/US CTAD Task Force nonetheless recommends that therapies that target amyloid-beta should be considered for inclusion in combination clinical trials in AD dementia, given the preponderance of evidence that disruptions in amyloid-beta production, clearance, or processing are very likely to be involved with, or even initiate, AD pathogenesis (5).
Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease