Context Cholinesterase inhibitors are the primary treatment for the cognitive
symptoms of Alzheimer disease (AD). Cholinergic dysfunction is also associated
with neuropsychiatric and functional deficits, but results from randomized
controlled trials of cholinesterase inhibitors are conflicting.
Objective To conduct a systematic review and meta-analysis to quantify the efficacy
of cholinesterase inhibitors for neuropsychiatric and functional outcomes
in patients with mild to moderate AD.
Data Sources We performed a literature search of trials using MEDLINE (January 1966–December
2001), Dissertations Abstracts On-line, PSYCHINFO, BIOSIS, PubMed, and the
Cochrane Controlled Trials Register. We retrieved English- and non–English-language
articles for review and collected references from bibliographies of reviews,
original research articles, and other articles of interest. We searched for
both published and unpublished trials, contacting researchers and pharmaceutical
Study Selection We included 29 parallel-group or crossover randomized, double-blind,
placebo-controlled trials of outpatients who were diagnosed as having mild
to moderate probable AD and were treated for at least 1 month with a cholinesterase
inhibitor. Sixteen trials included neuropsychiatric and 18 included functional
Data Extraction Two investigators (N.H.T. and J.H.) independently extracted study methods,
sources of bias, and outcomes. Neuropsychiatric outcomes were measured with
the Neuropsychiatric Inventory (NPI, 0-120 points) and the Alzheimer Disease
Assessment Scale, noncognitive (ADAS-noncog, 0-50 points) and were analyzed
with the weighted mean difference method. Functional outcomes were measured
with several activities of daily living (ADL) and instrumental activities
of daily living (IADL) scales and analyzed with the standardized mean difference
Data Synthesis For neuropsychiatric outcomes, 10 trials included the ADAS-noncog and
6 included the NPI. Compared with placebo, patients randomized to cholinesterase
inhibitors improved 1.72 points on the NPI (95% confidence interval [CI],
0.87-2.57 points), and 0.03 points on the ADAS-noncog (95% CI, 0.00-0.05 points).
For functional outcomes, 14 trials used ADL and 13 trials used IADL scales.
Compared with placebo, patients randomized to cholinesterase inhibitors improved
0.1 SDs on ADL scales (95% CI, 0.00-0.19 SDs), and 0.09 SDs on IADL scales
(95% CI, 0.01 to 0.17 SDs). There was no difference in efficacy among various
Conclusions These results indicate that cholinesterase inhibitors have a modest
beneficial impact on neuropsychiatric and functional outcomes for patients
with AD. Future research should focus on how such improvements translate into
long-term outcomes such as patient quality of life, institutionalization,
and caregiver burden.