Cognitive Decline Worsens With Memantine, ChEIs in Patients With Alzheimer’s

pills in senior woman's hand
pills in senior woman’s hand
The concomitant use of cholinesterase inhibitors or memantine was associated with an increased rate of cognitive decline in clinical trials of patients with Alzheimer disease.

Patients with Alzheimer disease (AD) who receive cholinesterase inhibitors (ChEIs) or memantine in clinical trials experience greater cognitive decline than patients who receive neither medication, according to study results published in JAMA Network Open.

A total of 10 clinical trials from the AD Cooperative Study and AD Neuroimaging Initiative of patients with AD were included. Across all studies, 2714 AD participants with a mean age of 75.0±8.2 years were analyzed. Patients in these trials were treated with ChEIs (n=906) or memantine (n=143) or both (n=923), or neither medication (n=742). The duration of each study was ≥6 months. Investigators estimated the annual rate of cognitive decline among participants according to the AD Assessment Scale-cognitive subscale.

In the meta-analysis of mixed-effects models that compared treatment with ChEIs or memantine or both vs no medication, patients who received ChEIs or memantine had a 1.4-point greater per-year decline in cognition (95% CI, 0.1-2.7). When the analysis was restricted to only randomized trials, the rate of decline for ChEIs or memantine vs neither medication use increased to 1.5 points per year (95% CI, 0.1-2.8). A faster decline rate of 2.0 points per year was observed for participants receiving memantine with or without ChEIs vs patients who received neither (95% CI, 1.3-2.7).

Limitations of the study included the researchers’ inability to determine indications for ChEIs and memantine use and the inclusion of mostly studies that were performed at large academic centers, which may limit generalizability of the findings.

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“The use of concomitant medications must specifically be accounted for in the design and analysis of trial data to prevent erroneous conclusions that could result from imbalances in the rates of these medications among trial participants,” the researchers concluded.


Kennedy RE, Cutter GR, Fowler ME, Schneider LS. Association of concomitant use of cholinesterase inhibitors or memantine with cognitive decline in Alzheimer clinical trials: a meta-analysis. JAMA Network Open. 2018;1(7):e184080.