COMMENTARY

Controversy remains about the drug of choice for treating Alzheimer’s disease. This review by Trinh et al is therefore timely and appropriate. It complements another recent review by Cummings on the use of cholinesterase inhibitors.¹ Cholinesterase inhibitors are the most widely used treatment for Alzheimer’s disease. Four cholinesterase inhibitors were approved by the United States Food and Drug Administration after several large double blind randomised trials, but only donepezil, rivastigmine and galantamine are in common use. These drugs only appear to improve symptoms in people with mild to moderate Alzheimer’s disease.

Trinh et al focused studies of neuropsychiatric symptoms, functional outcomes, or both. The selection of these outcome measures is justifiable since they reflect clinical domains of practical significance to patients and their caregivers. Even small differences on activities of daily living (ADL) scales may be of great importance to families and caregivers. The findings suggest that cholinesterase inhibitors have significant effects in people with mild to moderate Alzheimer’s disease who have neuropsychiatric disturbances, and should be considered as a treatment option in psychiatric and behavioural disturbances.

The review focuses on a limited number of outcome measures, however. It is important to measure the effects of these drugs in multiple domains, including cognitive and global functioning. The review also provided limited explanations about differences in the results of various clinical trials. For example, the authors did not highlight the impact of differences in inclusion criteria. Some studies included relatively more severely affected or less affected participants, or patients with more or less comorbidities. Both of these factors may influence the magnitude of treatment effect. Moreover, the authors did not acknowledge the possibility that cholinesterase inhibitors may affect other currently developing targets for Alzheimer’s disease therapy, such as ApoE, amyloid peptides and tau proteins.²

Other unanswered questions include: (1) are there differences within types of cholinesterase inhibitors?; (2) what effects do gender and ERT have on outcomes?;³ (3) what are the effects of ApoE and other genotypes of patients?; and (4) what are the pharmacokinetic and pharmacodynamic differences of various cholinesterase inhibitors? It is reasonable to select studies for analysis as these reviewers have done, but it should be with full understanding of the similarities and differences of these drugs and how these characteristics limit comparisons of clinical significance and utility.