OBJECTIVES: For therapeutic augmentation of impaired cholinergic transmission in Alzheimer Disease (AD), Acetylcholine-Esterase-inhibitors (ACHE-I; galantamine, donepezil, rivastigmine) are approved therapies in mild to-moderate AD. The NMDA receptor partial antagonist (memantine) is licensed for therapy of moderate–severe AD. In order to inform clinical decision-making about efficacy, safety and broader non-cognitive outcomes, we identified evidence from comparative and non-comparative studies. METHODS: A comprehensive search was conducted on Medline, Embase, conference abstracts and the Cochrane Library aimed to identify all randomised, placebo controlled trials (RCTs) reporting efficacy and/or safety outcomes and randomised, controlled comparative trials. In a second step, trials with drug dosing outside the approved European Summary of Product Characteristics were excluded. Eligibility of trials was assessed by two blinded reviewers; quality of trials were assessed by CONSORT. Meta-analyses were performed, reporting fixed and random effects using comparative analytical techniques. RESULTS: Fifty – eight studies fulfilled the inclusion criteria. In 45 trials, ACHE-I were tested against placebo, in 9 trials against another ACHE-I. For memantine, 9 placebo-controlled trials were identified. In most trials, patients were treated between 12-30 weeks; 9 RCTs reported longer-term outcomes, up to 24 months. After critical appraisal, 33 studies were included in further analyses. Meta-analysis of effects on cognition (ADAS-cog, MMSE, SIB) showed superiority of at least one ACHE-I versus placebo at the 3 months, 6 months and longer-time timepoint. Results for memantine indicated non‑significant improvement at any assessed timepoint. Behavioural outcomes were less well reported but showed superiority versus placebo for galantamine and memantine measured by the Neuropsychiatric Inventory Scale. CONCLUSIONS: There is abundant evidence for the efficacy, safety and tolerability of ACHE-Is in the treatment of patients with mild to moderate AD. Data for improved behavioural functioning is limited though available for galantamine and memantine.