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Background  Approximately 35 million people world-wide have Alzheimer’s disease and this is projected to nearly double by 2030. Cognitive enhancers, including cholinesterase inhibitors (for example, donepezil, galantamine and rivastigmine) and memantine (N-methyl-D-aspartic acid (NMDA) receptor antagonist) have been approved for the treatment of Alzheimer’s disease in many countries. Our objective is to evaluate the comparative effectiveness, safety, and cost of cognitive enhancers for Alzheimer’s disease through a systematic review.    Methods/design  Studies examining the efficacy, safety, and cost of cognitive enhancers compared to placebo, supportive care, and other cognitive enhancers for Alzheimer’s patients will be included. The primary outcome is cognition and secondary outcomes include function, behavior, quality of life, safety, and cost. Experimental studies (randomized controlled trials, quasi-randomized controlled trials, controlled clinical trials), quasi-experimental studies (controlled before-after, interrupted time series), and observational studies (cohort, case–control studies) will be eligible for inclusion. Inclusion will not be limited by publication status, time period or language of dissemination.  We will search electronic databases (for example, MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, Ageline) from inception onwards. The electronic database search will be supplemented by searching for grey literature (for example, conference proceedings, searches in Google and relevant organization websites). Two reviewers will independently screen the studies for inclusion using the eligibility criteria established  a priori  and independently extract data. Risk of bias will be assessed using the Cochrane Risk of Bias tool for experimental and quasi-experimental studies and the Newcastle Ottawa Scale for observational studies. If deemed appropriate, meta-analysis and network (that is, indirect comparisons) meta-analysis will be conducted.    Discussion  Our systematic review will inform the decision of healthcare providers, policy-makers, Alzheimer’s patients and family members about the use of cognitive enhancers, by improving their understanding of the costs, benefits and harms that are associated with these agents.    PROSPERO registry number  CRD42012001948

Efficacy of cognitive enhancers for Alzheimer’s disease: protocol for a systematic review and network meta-analysis