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Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>lzheimer's disease during the past 30\u00a0years, considering the drugs, potential targets, late\u2010stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late\u2010stage <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>lzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta\u2010analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild\u2010to\u2010moderate <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>lzheimer's disease criteria, recently extending to early or prodromal <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>lzheimer disease or \u2018mild cognitive impairment due to <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>lzheimer's disease\u2019, for drugs considered to be disease modifying. The duration of trials has remained at 6\u201312\u00a0months for drugs intended to improve symptoms; 18\u2010 to 24\u2010month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early\u2010stage <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>lzheimer's disease trial samples using biomarkers and phase\u2010specific outcomes. In conclusion, validated drug targets for <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>lzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late\u2010phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.<\/jats:p>","DOI":"10.1111\/joim.12191","type":"journal-article","created":{"date-parts":[[2014,3,8]],"date-time":"2014-03-08T22:34:56Z","timestamp":1394318096000},"page":"251-283","source":"Crossref","is-referenced-by-count":611,"title":["Clinical trials and late\u2010stage drug development for <scp>A<\/scp>lzheimer's disease: an appraisal from 1984 to 2014"],"prefix":"10.1111","volume":"275","author":[{"given":"L. 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