Background/Aims: We aimed to develop realistic definitions of clinical worsening in advanced Alzheimer's disease (AD) and to use them in a post hoc responder analysis of memantine. Methods: 2,340 patients with moderate to severe AD (Mini-Mental State Examination <20) were included from 9 multicentre, 16- to 28-week, randomised, double-blind, placebo-controlled studies of memantine 20 mg/day versus placebo. Responder meta-analyses were performed, with definitions of response based on minimally important differences (MIDs) on cognitive, functional, and global assessment scales. Validated or established MIDs were used where available; otherwise, MIDs were estimated by a data-driven approach, using data from our moderate to severe AD population. Results: Patients with moderate to severe AD treated with memantine had a lower incidence of worsening from baseline to endpoint than patients treated with placebo, in cognition [24.4 vs. 35.0%; odds ratio (OR) = 0.60; p < 0.001], function (38.1 vs. 43.4%; OR = 0.81; p = 0.01), global status (39.8 vs. 48.6%; OR = 0.70; p < 0.001), and in a combined ‘triple' worsening measure (9.4 vs. 16.1%; OR = 0.54; p < 0.001). Conclusions: New definitions of clinical worsening based on MIDs represent a more realistic functional decline in advanced stages of AD. Results of this new analysis show that memantine reduces the incidence of clinical worsening in key symptomatic domains in moderate to severe AD.

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This multicenter open-label clinical trial was designed to investigate the safety and efficacy of donepezil, a selective acetylcholinesterase inhibitor, in the treatment of Alzheimer’s disease (AD) in routine clinical practice in Germany. A total of 237 patients with mild-to-moderate AD were treated with donepezil for 24 weeks, 186 completed the study according to the protocol. In the completer group, mean MMSE score for efficacy showed an improvement from baseline of +1.6 points at week 12 (95% CI +1.1 to +2.1) and of +1.1 points at week 24 (95% CI +0.5 to +1.7). In more than 80% of the patients, global tolerability was rated to be very good or good. There were only insignificant effects on ECG parameters. This study confirms the results obtained in previous double-blind trials, which showed that donepezil is effective and well tolerated in patients with mild-to-moderately severe AD.

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