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These pivotal discoveries and the subsequent genetic, pathological, and modeling studies supporting pivotal roles for tau and A\u03b2 aggregation and accumulation have provided firm rationale for a new generation of <jats:styled-content style=\"fixed-case\">AD<\/jats:styled-content> therapies designed not to just provide symptomatic benefit, but as disease modifying agents that would slow or even reverse the disease course. Indeed, over the last 20\u00a0years numerous therapeutic strategies for disease modification have emerged, been preclinically validated, and advanced through various stages of clinical testing. Unfortunately, no therapy has yet to show significant clinical disease modification. In this review, I describe 10 translational barriers to successful disease modification, highlight current efforts addressing some of these barriers, and discuss how the field could focus future efforts to overcome barriers that are not major foci of current research efforts.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13583-fig-0002-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>Seminal discoveries made over the past 25\u00a0years have provided firm rationale for a new generation of Alzheimer's disease (<jats:styled-content style=\"fixed-case\">AD<\/jats:styled-content>) therapies designed as disease modifying agents that would slow or even reverse the disease course. Unfortunately, no therapy has yet to show significant clinical disease modification. In this review, I describe 10 translational barriers to successful <jats:styled-content style=\"fixed-case\">AD<\/jats:styled-content> disease modification, highlight current efforts addressing some of these barriers, and discuss how the field could focus future efforts to overcome these barriers.<\/jats:p><jats:p><jats:bold>This article is part of the<\/jats:bold> <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/journal\/10.1111\/(ISSN)1471-4159\/homepage\/special_issues.htm\">60th Anniversary special issue<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13583","type":"journal-article","created":{"date-parts":[[2016,5,4]],"date-time":"2016-05-04T16:31:00Z","timestamp":1462379460000},"page":"224-236","source":"Crossref","is-referenced-by-count":28,"title":["Overcoming translational barriers impeding development of Alzheimer's disease modifying therapies"],"prefix":"10.1111","volume":"139","author":[{"given":"Todd E.","family":"Golde","sequence":"first","affiliation":[{"name":"Department of Neuroscience Center for Translational Research in Neurodegenerative Disease McKnight Brain Institute College of Medicine University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,5,4]]},"reference":[{"key":"e_1_2_15_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3050"},{"key":"e_1_2_15_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2015.02.003"},{"key":"e_1_2_15_4_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4637-04.2005"},{"key":"e_1_2_15_5_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genet.39.110304.095804"},{"key":"e_1_2_15_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08983"},{"key":"e_1_2_15_7_1","doi-asserted-by":"publisher","DOI":"10.1602\/neurorx.1.2.213"},{"key":"e_1_2_15_8_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006221"},{"key":"e_1_2_15_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(97)00056-0"},{"key":"e_1_2_15_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(96)12668-9"},{"key":"e_1_2_15_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1809"},{"key":"e_1_2_15_12_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3836-11.2011"},{"key":"e_1_2_15_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.02.011"},{"key":"e_1_2_15_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/alzrt98"},{"key":"e_1_2_15_15_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3672-12.2013"},{"key":"e_1_2_15_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/alzrt269"},{"key":"e_1_2_15_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-7-39"},{"key":"e_1_2_15_18_1","first-page":"23","article-title":"Recent advances in the neurochemistry of Alzheimer's disease","volume":"48","author":"Davies P.","year":"1987","journal-title":"J. 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