Combination Therapy for Alzheimer’s Disease: Perspectives of the Eu/Us Ctad Task Force

Abstract

Combination therapy is expected to play an important role for the treatment of Alzheimer’s disease (AD). In October 2018, the European Union-North American Clinical Trials in Alzheimer’s Disease Task Force (EU/US CTAD Task Force) met to discuss scientific, regulatory, and logistical challenges to the development of combination therapy for AD and current efforts to address these challenges. Task Force members unanimously agreed that successful treatment of AD will likely require combination therapy approaches that target multiple mechanisms and pathways. They further agreed on the need for global collaboration and sharing of data and resources to accelerate development of such approaches.

Alzheimer Disease: An Update on Pathobiology and Treatment Strategies

“…The AMBAR trial, a current phase 2b/3 trial, is testing this hypothesis by assessing the effect of monthly plasma exchange with albumin replacement on mild-to-moderate AD (Boada et al, 2019). Combination Therapies Using the example of treatment paradigms for other chronic diseases, such as hypertension, congestive heart failure, epilepsy, HIV, and others, a combinatorial treatment strategy for AD seems more likely to yield clinical successes than monotherapy (Gauthier et al, 2019;Morris, 2019;Stephenson et al, 2015). Many of the diseases just listed are only effectively managed when multiple medications spanning different drug classes are employed.…”

The informed road map to prevention of Alzheimer Disease: A call to arms

“…A combination therapy for AD might address different points in the pathway leading to deposits of aggregated Aβ-42, such as a monoclonal antibody directed toward Aβ-42 and a β-secretase (β-site APP cleaving enzyme 1, or BACE) inhibitor to both remove deposited amyloid via the antibody and reduce the generation of new amyloidogenic isoforms with the BACE inhibitor. Unexpected cognitive worsening, as well as other potential adverse effects (e.g., hepatotoxicity, weight loss or neuropsychiatric symptoms), with BACE inhibitors in phase 2/3 trials have halted their therapeutic development in AD [ 11 , 12 , 151 ], but the model targeting the amyloid pathway at different stages remains a viable strategy, and may be facilitated by next generation gamma secretase modulators [ 152 , 153 ]. Another approach to combination therapy is to target two (or more) pathogenic pathways.…”

Simulating the outcome of amyloid treatments in Alzheimer's disease from imaging and clinical data

“…It is worth noting that recent works ventured the idea to combine drugs targeting multiple mechanisms at the same time. 53 For instance, pathologists have shown tau deposition in brainstem nuclei in adolescents and children, 54 and clinicians are currently investigating the pathological effect of early tau spreading on Alzheimer’s disease progression, 55 raising crucial questions about its relationship with amyloid accumulation, and the impact on cognitive impairment. 56 In this study, 190 subjects underwent at least one Tau-PET scan.…”