Treatment Combinations for Alzheimer's Disease: Current and Future Pharmacotherapy Options

Abstract

Although Alzheimer's disease (AD) is the world's leading cause of dementia and the population of patients with AD continues to grow, no new therapies have been approved in more than a decade. Many clinical trials of single-agent therapies have failed to affect disease progression or symptoms compared with placebo. The complex pathophysiology of AD may necessitate combination treatments rather than monotherapy. The goal of this narrative literature review is to describe types of combination therapy, review the current clinical evidence for combination therapy regimens (both symptomatic and disease-modifying) in the treatment of AD, describe innovative clinical trial study designs that may be effective in testing combination therapy, and discuss the regulatory and drug development landscape for combination therapy. Successful combination therapies in other complex disorders, such as human immunodeficiency virus, may provide useful examples of a potential path forward for AD treatment.

Keywords: Alzheimer’s disease; cholinesterase inhibitor; dementia; disease-modifying; memantine; symptomatic; treatment combination.

Fig.1

Combination therapies in the AD drug development pipeline. 5-HT, 5-hydroxytryptamine (serotonin); Aβ, amyloid-β; AChE1, acetylcholinesterase inhibitor; AD, Alzheimer’s disease; BACE, aspartyl protease β-site amyloid precursor protein cleaving enzyme; GM-CSF, granulocyte-macrophage colony-stimulating factor; MAO, monoamine oxidase; NMDA, N-methyl-D-aspartate; PPAR, peroxisome-proliferator activated receptor; RAGE, receptor for advanced glycation end-products; rTMS, repetitive transcranial magnetic stimulation.

Fig.2

Combination drug development.