Findings  In this meta-analysis, participants receiving cholinesterase inhibitors or memantine had 1.4 points per year difference on the Alzheimer Disease Assessment Scale–cognitive subscale compared with those receiving neither medication, a significant difference that is roughly the same size as the expected effect of new therapeutic drugs being investigated in the clinical trials.

Meaning  Differences in the use of cholinesterase inhibitors and memantine between treatment and placebo groups of clinical trials may lead to the conclusion that a treatment is effective when it is not, or vice versa.

Importance  Clinical trials in Alzheimer disease (AD) generally allow participants to continue receiving concomitant medications, including cholinesterase inhibitors (ChEIs) and memantine, if the dose is stable. Previous analysis of observational studies indicates such individuals experience greater rate of decline on cognitive testing than those not receiving such medications.

Objective  To investigate whether concomitant use of ChEIs or memantine is associated with cognitive outcomes in AD clinical trials.

Data Sources  Meta-database of 18 studies from the Alzheimer Disease Cooperative Study and Alzheimer Disease Neuroimaging Initiative.

Study Selection  All studies with data on ChEI and memantine use that included assessment of specified outcome measures.

Data Extraction and Synthesis  The analysis estimated annual rate of decline on the Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-cog) using linear mixed-effects models, and compared rates for participants receiving ChEIs and memantine, alone and combined, with participants not receiving either medication using random-effects meta-analysis.

Main Outcomes and Measures  Annual rate of change on the ADAS-cog.

Results  Across 10 studies, of 2714 participants, the mean (SD) age was 75.0 (8.2) years, 58% were female, and 9% were racial/ethnic minorities. There were 906 participants (33.4%) receiving ChEIs, 143 (5.3%) receiving memantine, 923 (34.0%) receiving both, and 742 (27.3%) receiving neither. Meta-analysis showed those receiving ChEIs or memantine were associated with significantly greater annual rate of decline on the ADAS-cog than those receiving neither medication (1.4 points/y; 95% CI, 0.1-2.7).

Conclusions and Relevance  Similar to observational studies, many participants in AD clinical trials receiving ChEIs or memantine experience greater cognitive decline. This difference is nearly as large as the hypothesized effect sizes of the treatments investigated in the trials. Concomitant use of ChEIs or memantine may be confounded with outcomes on the ADAS-cog and should be considered in design of clinical trials of potential therapeutic agents for AD. Post hoc analyses stratifying by ChEIs or memantine must be interpreted cautiously given the potential for confounding.