Drug repositioning for Alzheimer's disease
Identifieur interne : 000A40 ( Istex/Corpus ); précédent : 000A39; suivant : 000A41Drug repositioning for Alzheimer's disease
Auteurs : Anne Corbett ; James Pickett ; Alistair Burns ; Jonathan Corcoran ; Stephen Dunnett ; Paul Edison ; Jim Hagan ; Clive Holmes ; Emma Jones ; Cornelius Katona ; Ian Kearns ; Patrick Kehoe ; Amrit Mudher ; Anthony Passmore ; Nicola Shepherd ; Frank Walsh ; Clive BallardSource :
- Nature Reviews Drug Discovery [ 1474-1776 ] ; 2012-11.
Abstract
Existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimer's-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimer's disease.
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DOI: 10.1038/nrd3869
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Drug repositioning for Alzheimer's disease</title><author><name sortKey="Corbett, Anne" sort="Corbett, Anne" uniqKey="Corbett A" first="Anne" last="Corbett">Anne Corbett</name><affiliation><mods:affiliation>Anne Corbett and Clive Ballard are at the Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.</mods:affiliation></affiliation><affiliation><mods:affiliation>A.C. and J.P. contributed equally to this work.</mods:affiliation></affiliation></author><author><name sortKey="Pickett, James" sort="Pickett, James" uniqKey="Pickett J" first="James" last="Pickett">James Pickett</name><affiliation><mods:affiliation>James Pickett is at the UK Alzheimer's Society, Devon House, 58 St Katharine's Way, London E1W 1LB, UK.</mods:affiliation></affiliation><affiliation><mods:affiliation>A.C. and J.P. contributed equally to this work.</mods:affiliation></affiliation></author><author><name sortKey="Burns, Alistair" sort="Burns, Alistair" uniqKey="Burns A" first="Alistair" last="Burns">Alistair Burns</name><affiliation><mods:affiliation>Alistair Burns is at the University of Manchester, Oxford Road, Manchester M13 9PT, UK.</mods:affiliation></affiliation></author><author><name sortKey="Corcoran, Jonathan" sort="Corcoran, Jonathan" uniqKey="Corcoran J" first="Jonathan" last="Corcoran">Jonathan Corcoran</name><affiliation><mods:affiliation>Jonathan Corcoran and Emma Jones are at the Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London SE1 1UL, UK.</mods:affiliation></affiliation></author><author><name sortKey="Dunnett, Stephen B" sort="Dunnett, Stephen B" uniqKey="Dunnett S" first="Stephen" last="Dunnett">Stephen Dunnett</name><affiliation><mods:affiliation>Stephen B. 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Hagan is at the Global Medical Excellence Cluster (GMEC), Hodgkin Building, Guy's Campus, King's College London, London SE1 1UL, UK.</mods:affiliation></affiliation></author><author><name sortKey="Holmes, Clive" sort="Holmes, Clive" uniqKey="Holmes C" first="Clive" last="Holmes">Clive Holmes</name><affiliation><mods:affiliation>Clive Holmes is at the University of Southampton, Southampton General Hospital, Mailpoint 801, South Academic Block, Tremona Road, Southampton SO16 6YD, UK.</mods:affiliation></affiliation></author><author><name sortKey="Jones, Emma" sort="Jones, Emma" uniqKey="Jones E" first="Emma" last="Jones">Emma Jones</name><affiliation><mods:affiliation>Jonathan Corcoran and Emma Jones are at the Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London SE1 1UL, UK.</mods:affiliation></affiliation></author><author><name sortKey="Katona, Cornelius" sort="Katona, Cornelius" uniqKey="Katona C" first="Cornelius" last="Katona">Cornelius Katona</name><affiliation><mods:affiliation>Cornelius Katona is at University College London, Mental Health Sciences Unit, Faculty of Brain Sciences, London WC1E 6BT, UK.</mods:affiliation></affiliation></author><author><name sortKey="Kearns, Ian" sort="Kearns, Ian" uniqKey="Kearns I" first="Ian" last="Kearns">Ian Kearns</name><affiliation><mods:affiliation>Ian Kearns is at AstraZeneca, 2 Kingdom Street, London W2 6BD, UK.</mods:affiliation></affiliation></author><author><name sortKey="Kehoe, Patrick" sort="Kehoe, Patrick" uniqKey="Kehoe P" first="Patrick" last="Kehoe">Patrick Kehoe</name><affiliation><mods:affiliation>Patrick Kehoe is at the University of Bristol, John James Laboratories, Frenchay Hospital, Bristol BS16 1LE, UK.</mods:affiliation></affiliation></author><author><name sortKey="Mudher, Amrit" sort="Mudher, Amrit" uniqKey="Mudher A" first="Amrit" last="Mudher">Amrit Mudher</name><affiliation><mods:affiliation>Amrit Mudher is at the University of Southampton, Life Sciences Building 85, University Road, Southampton SO17 1BJ, UK.</mods:affiliation></affiliation></author><author><name sortKey="Passmore, Anthony" sort="Passmore, Anthony" uniqKey="Passmore A" first="Anthony" last="Passmore">Anthony Passmore</name><affiliation><mods:affiliation>Anthony Passmore is at Queen's University Belfast, Centre for Public Health, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, UK.</mods:affiliation></affiliation></author><author><name sortKey="Shepherd, Nicola" sort="Shepherd, Nicola" uniqKey="Shepherd N" first="Nicola" last="Shepherd">Nicola Shepherd</name><affiliation><mods:affiliation>Nicola Shepherd is at the Wellcome Trust, Gibbs Building, 215 Euston Road, London NW1 2BE, UK.</mods:affiliation></affiliation></author><author><name sortKey="Walsh, Frank" sort="Walsh, Frank" uniqKey="Walsh F" first="Frank" last="Walsh">Frank Walsh</name><affiliation><mods:affiliation>Frank Walsh is at the Institute of Psychiatry, King's College London, London SE1 1UL, UK.</mods:affiliation></affiliation></author><author><name sortKey="Ballard, Clive" sort="Ballard, Clive" uniqKey="Ballard C" first="Clive" last="Ballard">Clive Ballard</name><affiliation><mods:affiliation>Anne Corbett and Clive Ballard are at the Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: clive.ballard@kcl.ac.uk</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:6A37E13CBEAD425373FA2EBBB3598916D2A6A7DB</idno><date when="2012" year="2012">2012</date><idno type="doi">10.1038/nrd3869</idno><idno type="url">https://api.istex.fr/document/6A37E13CBEAD425373FA2EBBB3598916D2A6A7DB/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000A40</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Drug repositioning for Alzheimer's disease</title><author><name sortKey="Corbett, Anne" sort="Corbett, Anne" uniqKey="Corbett A" first="Anne" last="Corbett">Anne Corbett</name><affiliation><mods:affiliation>Anne Corbett and Clive Ballard are at the Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.</mods:affiliation></affiliation><affiliation><mods:affiliation>A.C. and J.P. contributed equally to this work.</mods:affiliation></affiliation></author><author><name sortKey="Pickett, James" sort="Pickett, James" uniqKey="Pickett J" first="James" last="Pickett">James Pickett</name><affiliation><mods:affiliation>James Pickett is at the UK Alzheimer's Society, Devon House, 58 St Katharine's Way, London E1W 1LB, UK.</mods:affiliation></affiliation><affiliation><mods:affiliation>A.C. and J.P. contributed equally to this work.</mods:affiliation></affiliation></author><author><name sortKey="Burns, Alistair" sort="Burns, Alistair" uniqKey="Burns A" first="Alistair" last="Burns">Alistair Burns</name><affiliation><mods:affiliation>Alistair Burns is at the University of Manchester, Oxford Road, Manchester M13 9PT, UK.</mods:affiliation></affiliation></author><author><name sortKey="Corcoran, Jonathan" sort="Corcoran, Jonathan" uniqKey="Corcoran J" first="Jonathan" last="Corcoran">Jonathan Corcoran</name><affiliation><mods:affiliation>Jonathan Corcoran and Emma Jones are at the Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London SE1 1UL, UK.</mods:affiliation></affiliation></author><author><name sortKey="Dunnett, Stephen B" sort="Dunnett, Stephen B" uniqKey="Dunnett S" first="Stephen" last="Dunnett">Stephen Dunnett</name><affiliation><mods:affiliation>Stephen B. Dunnett is at the Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.</mods:affiliation></affiliation></author><author><name sortKey="Edison, Paul" sort="Edison, Paul" uniqKey="Edison P" first="Paul" last="Edison">Paul Edison</name><affiliation><mods:affiliation>Paul Edison is at Imperial College London, Cyclotron building, Hammersmith Campus, London W12 0NN, UK.</mods:affiliation></affiliation></author><author><name sortKey="Hagan, Jim J" sort="Hagan, Jim J" uniqKey="Hagan J" first="Jim" last="Hagan">Jim Hagan</name><affiliation><mods:affiliation>Jim J. Hagan is at the Global Medical Excellence Cluster (GMEC), Hodgkin Building, Guy's Campus, King's College London, London SE1 1UL, UK.</mods:affiliation></affiliation></author><author><name sortKey="Holmes, Clive" sort="Holmes, Clive" uniqKey="Holmes C" first="Clive" last="Holmes">Clive Holmes</name><affiliation><mods:affiliation>Clive Holmes is at the University of Southampton, Southampton General Hospital, Mailpoint 801, South Academic Block, Tremona Road, Southampton SO16 6YD, UK.</mods:affiliation></affiliation></author><author><name sortKey="Jones, Emma" sort="Jones, Emma" uniqKey="Jones E" first="Emma" last="Jones">Emma Jones</name><affiliation><mods:affiliation>Jonathan Corcoran and Emma Jones are at the Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London SE1 1UL, UK.</mods:affiliation></affiliation></author><author><name sortKey="Katona, Cornelius" sort="Katona, Cornelius" uniqKey="Katona C" first="Cornelius" last="Katona">Cornelius Katona</name><affiliation><mods:affiliation>Cornelius Katona is at University College London, Mental Health Sciences Unit, Faculty of Brain Sciences, London WC1E 6BT, UK.</mods:affiliation></affiliation></author><author><name sortKey="Kearns, Ian" sort="Kearns, Ian" uniqKey="Kearns I" first="Ian" last="Kearns">Ian Kearns</name><affiliation><mods:affiliation>Ian Kearns is at AstraZeneca, 2 Kingdom Street, London W2 6BD, UK.</mods:affiliation></affiliation></author><author><name sortKey="Kehoe, Patrick" sort="Kehoe, Patrick" uniqKey="Kehoe P" first="Patrick" last="Kehoe">Patrick Kehoe</name><affiliation><mods:affiliation>Patrick Kehoe is at the University of Bristol, John James Laboratories, Frenchay Hospital, Bristol BS16 1LE, UK.</mods:affiliation></affiliation></author><author><name sortKey="Mudher, Amrit" sort="Mudher, Amrit" uniqKey="Mudher A" first="Amrit" last="Mudher">Amrit Mudher</name><affiliation><mods:affiliation>Amrit Mudher is at the University of Southampton, Life Sciences Building 85, University Road, Southampton SO17 1BJ, UK.</mods:affiliation></affiliation></author><author><name sortKey="Passmore, Anthony" sort="Passmore, Anthony" uniqKey="Passmore A" first="Anthony" last="Passmore">Anthony Passmore</name><affiliation><mods:affiliation>Anthony Passmore is at Queen's University Belfast, Centre for Public Health, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, UK.</mods:affiliation></affiliation></author><author><name sortKey="Shepherd, Nicola" sort="Shepherd, Nicola" uniqKey="Shepherd N" first="Nicola" last="Shepherd">Nicola Shepherd</name><affiliation><mods:affiliation>Nicola Shepherd is at the Wellcome Trust, Gibbs Building, 215 Euston Road, London NW1 2BE, UK.</mods:affiliation></affiliation></author><author><name sortKey="Walsh, Frank" sort="Walsh, Frank" uniqKey="Walsh F" first="Frank" last="Walsh">Frank Walsh</name><affiliation><mods:affiliation>Frank Walsh is at the Institute of Psychiatry, King's College London, London SE1 1UL, UK.</mods:affiliation></affiliation></author><author><name sortKey="Ballard, Clive" sort="Ballard, Clive" uniqKey="Ballard C" first="Clive" last="Ballard">Clive Ballard</name><affiliation><mods:affiliation>Anne Corbett and Clive Ballard are at the Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: clive.ballard@kcl.ac.uk</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Nature Reviews Drug Discovery</title><idno type="ISSN">1474-1776</idno><idno type="eISSN">1474-1784</idno><imprint><publisher>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</publisher><date type="published" when="2012-11">2012-11</date><biblScope unit="volume">11</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="833">833</biblScope><biblScope unit="page" to="846">846</biblScope></imprint><idno type="ISSN">1474-1776</idno></series><idno type="istex">6A37E13CBEAD425373FA2EBBB3598916D2A6A7DB</idno><idno type="DOI">10.1038/nrd3869</idno><idno type="PublisherID">nrd3869</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1474-1776</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="eng">Existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimer's-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimer's disease.</div></front></TEI><istex><corpusName>nature</corpusName><author><json:item><name>Anne Corbett</name><affiliations><json:string>Anne Corbett and Clive Ballard are at the Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.</json:string><json:string>A.C. and J.P. contributed equally to this work.</json:string></affiliations></json:item><json:item><name>James Pickett</name><affiliations><json:string>James Pickett is at the UK Alzheimer's Society, Devon House, 58 St Katharine's Way, London E1W 1LB, UK.</json:string><json:string>A.C. and J.P. contributed equally to this work.</json:string></affiliations></json:item><json:item><name>Alistair Burns</name><affiliations><json:string>Alistair Burns is at the University of Manchester, Oxford Road, Manchester M13 9PT, UK.</json:string></affiliations></json:item><json:item><name>Jonathan Corcoran</name><affiliations><json:string>Jonathan Corcoran and Emma Jones are at the Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London SE1 1UL, UK.</json:string></affiliations></json:item><json:item><name>Stephen B. Dunnett</name><affiliations><json:string>Stephen B. Dunnett is at the Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.</json:string></affiliations></json:item><json:item><name>Paul Edison</name><affiliations><json:string>Paul Edison is at Imperial College London, Cyclotron building, Hammersmith Campus, London W12 0NN, UK.</json:string></affiliations></json:item><json:item><name>Jim J. Hagan</name><affiliations><json:string>Jim J. Hagan is at the Global Medical Excellence Cluster (GMEC), Hodgkin Building, Guy's Campus, King's College London, London SE1 1UL, UK.</json:string></affiliations></json:item><json:item><name>Clive Holmes</name><affiliations><json:string>Clive Holmes is at the University of Southampton, Southampton General Hospital, Mailpoint 801, South Academic Block, Tremona Road, Southampton SO16 6YD, UK.</json:string></affiliations></json:item><json:item><name>Emma Jones</name><affiliations><json:string>Jonathan Corcoran and Emma Jones are at the Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London SE1 1UL, UK.</json:string></affiliations></json:item><json:item><name>Cornelius Katona</name><affiliations><json:string>Cornelius Katona is at University College London, Mental Health Sciences Unit, Faculty of Brain Sciences, London WC1E 6BT, UK.</json:string></affiliations></json:item><json:item><name>Ian Kearns</name><affiliations><json:string>Ian Kearns is at AstraZeneca, 2 Kingdom Street, London W2 6BD, UK.</json:string></affiliations></json:item><json:item><name>Patrick Kehoe</name><affiliations><json:string>Patrick Kehoe is at the University of Bristol, John James Laboratories, Frenchay Hospital, Bristol BS16 1LE, UK.</json:string></affiliations></json:item><json:item><name>Amrit Mudher</name><affiliations><json:string>Amrit Mudher is at the University of Southampton, Life Sciences Building 85, University Road, Southampton SO17 1BJ, UK.</json:string></affiliations></json:item><json:item><name>Anthony Passmore</name><affiliations><json:string>Anthony Passmore is at Queen's University Belfast, Centre for Public Health, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, UK.</json:string></affiliations></json:item><json:item><name>Nicola Shepherd</name><affiliations><json:string>Nicola Shepherd is at the Wellcome Trust, Gibbs Building, 215 Euston Road, London NW1 2BE, UK.</json:string></affiliations></json:item><json:item><name>Frank Walsh</name><affiliations><json:string>Frank Walsh is at the Institute of Psychiatry, King's College London, London SE1 1UL, UK.</json:string></affiliations></json:item><json:item><name>Clive Ballard</name><affiliations><json:string>Anne Corbett and Clive Ballard are at the Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.</json:string><json:string>E-mail: clive.ballard@kcl.ac.uk</json:string></affiliations></json:item></author><language><json:string>eng</json:string></language><abstract>Existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimer's-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimer's disease.</abstract><qualityIndicators><score>8.108</score><pdfVersion>1.6</pdfVersion><pdfPageSize>595.276 x 782.362 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>962</abstractCharCount><pdfWordCount>12239</pdfWordCount><pdfCharCount>87864</pdfCharCount><pdfPageCount>14</pdfPageCount><abstractWordCount>134</abstractWordCount></qualityIndicators><title>Drug repositioning for Alzheimer's disease</title><genre><json:string>article</json:string></genre><host><volume>11</volume><pages><total>14</total><last>846</last><first>833</first></pages><issn><json:string>1474-1776</json:string></issn><issue>11</issue><genre></genre><language><json:string>unknown</json:string></language><eissn><json:string>1474-1784</json:string></eissn><title>Nature Reviews Drug Discovery</title></host><categories><wos><json:string>PHARMACOLOGY & PHARMACY</json:string><json:string>BIOTECHNOLOGY & APPLIED MICROBIOLOGY</json:string></wos></categories><publicationDate>2012</publicationDate><copyrightDate>2012</copyrightDate><doi><json:string>10.1038/nrd3869</json:string></doi><id>6A37E13CBEAD425373FA2EBBB3598916D2A6A7DB</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/6A37E13CBEAD425373FA2EBBB3598916D2A6A7DB/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/6A37E13CBEAD425373FA2EBBB3598916D2A6A7DB/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/6A37E13CBEAD425373FA2EBBB3598916D2A6A7DB/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Drug repositioning for Alzheimer's disease</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</publisher><date>2012-11-05</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Drug repositioning for Alzheimer's disease</title><author><persName><forename type="first">Anne</forename><surname>Corbett</surname></persName><note type="biography">Anne Corbett is lecturer of dementia research at King's College London, UK. She is an established author in the field. Her research interests include prevention of dementia, translational approaches to improving treatment and care, and clinical trials with a particular focus on behavioural and psychological symptoms and care home settings.</note><affiliation>Anne Corbett is lecturer of dementia research at King's College London, UK. She is an established author in the field. Her research interests include prevention of dementia, translational approaches to improving treatment and care, and clinical trials with a particular focus on behavioural and psychological symptoms and care home settings.</affiliation><affiliation>Anne Corbett and Clive Ballard are at the Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.</affiliation><affiliation>A.C. and J.P. contributed equally to this work.</affiliation></author><author><persName><forename type="first">James</forename><surname>Pickett</surname></persName><note type="biography">James Pickett is the senior research manager at the UK Alzheimer's Society the largest care and research charity for people with dementia in the United Kingdom. Previously, he worked for Diabetes UK and Nature Reviews Molecular Cell Biology. James completed his Ph.D. on exocytosis from University of Cambridge, UK, in 2006.</note><affiliation>James Pickett is the senior research manager at the UK Alzheimer's Society the largest care and research charity for people with dementia in the United Kingdom. Previously, he worked for Diabetes UK and Nature Reviews Molecular Cell Biology. James completed his Ph.D. on exocytosis from University of Cambridge, UK, in 2006.</affiliation><affiliation>James Pickett is at the UK Alzheimer's Society, Devon House, 58 St Katharine's Way, London E1W 1LB, UK.</affiliation><affiliation>A.C. and J.P. contributed equally to this work.</affiliation></author><author><persName><forename type="first">Alistair</forename><surname>Burns</surname></persName><note type="biography">Alistair Burns is the National Clinical Director for Dementia in England at the UK Department of Health. He is Professor of Old Age Psychiatry and Vice Dean of the Faculty of Medical and Human Sciences at the University of Manchester, UK, Clinical Director for the Manchester Academic Health Science Centre (MAHSC) and an Honorary Consultant Old-Age Psychiatrist in the Manchester Mental Health and Social Care Trust (MMHSCT). He is editor of the International Journal of Geriatric Psychiatry, assistant editor of the British Journal of Psychiatry and is on the editorial boards of International Psychogeriatrics and Advances in Psychiatric Treatment. His research and clinical interests are in mental health problems of older people, particularly dementia and Alzheimer's disease. He has published over 300 papers and 25 books.</note><affiliation>Alistair Burns is the National Clinical Director for Dementia in England at the UK Department of Health. He is Professor of Old Age Psychiatry and Vice Dean of the Faculty of Medical and Human Sciences at the University of Manchester, UK, Clinical Director for the Manchester Academic Health Science Centre (MAHSC) and an Honorary Consultant Old-Age Psychiatrist in the Manchester Mental Health and Social Care Trust (MMHSCT). He is editor of the International Journal of Geriatric Psychiatry, assistant editor of the British Journal of Psychiatry and is on the editorial boards of International Psychogeriatrics and Advances in Psychiatric Treatment. His research and clinical interests are in mental health problems of older people, particularly dementia and Alzheimer's disease. He has published over 300 papers and 25 books.</affiliation><affiliation>Alistair Burns is at the University of Manchester, Oxford Road, Manchester M13 9PT, UK.</affiliation></author><author><persName><forename type="first">Jonathan</forename><surname>Corcoran</surname></persName><note type="biography">Jonathan Corcoran is professor of molecular neurobiology at King's College London. He is the director of the Neuroscience Drug Discovery Unit based in the Wolfson Centre for Age-Related Diseases, which carries out hit-to-lead and lead optimization using both in vitro and in vivo assays. His research interests include the development of orally available compounds for central nervous system (CNS) disorders.</note><affiliation>Jonathan Corcoran is professor of molecular neurobiology at King's College London. He is the director of the Neuroscience Drug Discovery Unit based in the Wolfson Centre for Age-Related Diseases, which carries out hit-to-lead and lead optimization using both in vitro and in vivo assays. His research interests include the development of orally available compounds for central nervous system (CNS) disorders.</affiliation><affiliation>Jonathan Corcoran and Emma Jones are at the Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London SE1 1UL, UK.</affiliation></author><author><persName><forename type="first">Stephen B.</forename><surname>Dunnett</surname></persName><note type="biography">Stephen B. Dunnett is a professor at Cardiff University, Wales, UK, and directs the Brain Repair Group in the School of Biosciences at Cardiff University. His research has pioneered the development of technologies for cell transplantation in animal models of neurodegenerative disease, with a particular focus on Alzheimer's, Parkinson's and Huntington's diseases. His laboratory has an international reputation for systematic behavioural analysis as the basis for refining the efficacy and understanding the mechanisms of action of cell transplantation in animal models of these diseases, and in developing primary embryonic and stem cell transplantation towards clinical application.</note><affiliation>Stephen B. Dunnett is a professor at Cardiff University, Wales, UK, and directs the Brain Repair Group in the School of Biosciences at Cardiff University. His research has pioneered the development of technologies for cell transplantation in animal models of neurodegenerative disease, with a particular focus on Alzheimer's, Parkinson's and Huntington's diseases. His laboratory has an international reputation for systematic behavioural analysis as the basis for refining the efficacy and understanding the mechanisms of action of cell transplantation in animal models of these diseases, and in developing primary embryonic and stem cell transplantation towards clinical application.</affiliation><affiliation>Stephen B. Dunnett is at the Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.</affiliation></author><author><persName><forename type="first">Paul</forename><surname>Edison</surname></persName><note type="biography">Paul Edison is a clinical senior lecturer in the Centre of Neuroscience at Imperial College London, UK. His research has focused on neuroimaging using novel molecular probes and magnetic resonance techniques for the study of pathophysiological changes associated with Alzheimer's disease and other forms of dementia. He has extensive experience in positron emission tomography (PET) imaging in amyloid, neuroinflammation, glucose metabolism and other neurotransporters in neurodegenerative and neuroinflammatory conditions. He is developing novel therapeutic strategies aimed at preventing the progression of the disease, and he is the chief investigator of large multicentre intervention studies. He also runs a dementia clinic at the Imperial College Healthcare NHS (National Health Service) trust.</note><affiliation>Paul Edison is a clinical senior lecturer in the Centre of Neuroscience at Imperial College London, UK. His research has focused on neuroimaging using novel molecular probes and magnetic resonance techniques for the study of pathophysiological changes associated with Alzheimer's disease and other forms of dementia. He has extensive experience in positron emission tomography (PET) imaging in amyloid, neuroinflammation, glucose metabolism and other neurotransporters in neurodegenerative and neuroinflammatory conditions. He is developing novel therapeutic strategies aimed at preventing the progression of the disease, and he is the chief investigator of large multicentre intervention studies. He also runs a dementia clinic at the Imperial College Healthcare NHS (National Health Service) trust.</affiliation><affiliation>Paul Edison is at Imperial College London, Cyclotron building, Hammersmith Campus, London W12 0NN, UK.</affiliation></author><author><persName><forename type="first">Jim J.</forename><surname>Hagan</surname></persName><note type="biography">Jim J. Hagan is CEO of GMEC (Global Medical Excellence Cluster), a company created to foster biomedical research between academia and industry. He sits on the board of Imanova, a research imaging company, and was previously vice president of Biology in the Psychiatry Centre of Excellence for Drug Discovery at GlaxoSmithKline. He has published extensively, including a recent volume on molecular and functional models of neuropsychiatric disorders.</note><affiliation>Jim J. Hagan is CEO of GMEC (Global Medical Excellence Cluster), a company created to foster biomedical research between academia and industry. He sits on the board of Imanova, a research imaging company, and was previously vice president of Biology in the Psychiatry Centre of Excellence for Drug Discovery at GlaxoSmithKline. He has published extensively, including a recent volume on molecular and functional models of neuropsychiatric disorders.</affiliation><affiliation>Jim J. Hagan is at the Global Medical Excellence Cluster (GMEC), Hodgkin Building, Guy's Campus, King's College London, London SE1 1UL, UK.</affiliation></author><author><persName><forename type="first">Clive</forename><surname>Holmes</surname></persName><note type="biography">Clive Holmes trained as a psychiatrist at Kings College London and the Maudsley Hospital, South London. His early research training was in the neurochemistry of Alzheimer's disease at the Institute of Neurology, London, followed by a Ph.D. in the genetics of the neuropsychiatric features of Alzheimer's disease at the Institute of Psychiatry, London. He is currently professor of biological psychiatry at the University of Southampton, UK, where his main interests are in the early diagnosis of dementia, neuropharmacology and the role of immunity in the development and treatment of Alzheimer's disease.</note><affiliation>Clive Holmes trained as a psychiatrist at Kings College London and the Maudsley Hospital, South London. His early research training was in the neurochemistry of Alzheimer's disease at the Institute of Neurology, London, followed by a Ph.D. in the genetics of the neuropsychiatric features of Alzheimer's disease at the Institute of Psychiatry, London. He is currently professor of biological psychiatry at the University of Southampton, UK, where his main interests are in the early diagnosis of dementia, neuropharmacology and the role of immunity in the development and treatment of Alzheimer's disease.</affiliation><affiliation>Clive Holmes is at the University of Southampton, Southampton General Hospital, Mailpoint 801, South Academic Block, Tremona Road, Southampton SO16 6YD, UK.</affiliation></author><author><persName><forename type="first">Emma</forename><surname>Jones</surname></persName><note type="biography">Emma Jones carried out her D.Phil. on microarray analysis of a model of ataxia under the supervision of Professor Kay Davies. Following this, she moved to King's College London and started analysing genetic factors that influence the onset of Alzheimer's disease in people with Down's syndrome. This project was continued during her time as a research fellow for the UK Alzheimer's Society, and she has also worked on clinical trials and biomarkers studies in dementia. She has recently started a post as a lecturer in translational stem cell biology at King's College London.</note><affiliation>Emma Jones carried out her D.Phil. on microarray analysis of a model of ataxia under the supervision of Professor Kay Davies. Following this, she moved to King's College London and started analysing genetic factors that influence the onset of Alzheimer's disease in people with Down's syndrome. This project was continued during her time as a research fellow for the UK Alzheimer's Society, and she has also worked on clinical trials and biomarkers studies in dementia. She has recently started a post as a lecturer in translational stem cell biology at King's College London.</affiliation><affiliation>Jonathan Corcoran and Emma Jones are at the Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London SE1 1UL, UK.</affiliation></author><author><persName><forename type="first">Cornelius</forename><surname>Katona</surname></persName><note type="biography">Cornelius Katona is Emeritus Professor of Psychiatry at the University of Kent, UK, and Honorary Professor of Psychiatry of the Elderly at University College London, UK. His main research interests are in dementia, mood disorders in old age and the mental health of asylum seekers. He has extensive experience of clinical trial work in dementia and in depression. He is the author of over 200 peer-reviewed articles as well as author and/or editor of 15 books. He is co-chair of the World Psychiatric Association section of affective disorders, Chair of the World Federation of Societies of Biological Psychiatry Taskforce on Old Age and co-founder and vice president of the International Society for Affective Disorders. He chaired the Dementia Clinical Studies Group within DeNDRoN (the Dementia and Neurodegenerative Disorders Network) between 2008 and 2012. He has been editor-in-chief of the Journal of Affective Disorders since 1994.</note><affiliation>Cornelius Katona is Emeritus Professor of Psychiatry at the University of Kent, UK, and Honorary Professor of Psychiatry of the Elderly at University College London, UK. His main research interests are in dementia, mood disorders in old age and the mental health of asylum seekers. He has extensive experience of clinical trial work in dementia and in depression. He is the author of over 200 peer-reviewed articles as well as author and/or editor of 15 books. He is co-chair of the World Psychiatric Association section of affective disorders, Chair of the World Federation of Societies of Biological Psychiatry Taskforce on Old Age and co-founder and vice president of the International Society for Affective Disorders. He chaired the Dementia Clinical Studies Group within DeNDRoN (the Dementia and Neurodegenerative Disorders Network) between 2008 and 2012. He has been editor-in-chief of the Journal of Affective Disorders since 1994.</affiliation><affiliation>Cornelius Katona is at University College London, Mental Health Sciences Unit, Faculty of Brain Sciences, London WC1E 6BT, UK.</affiliation></author><author><persName><forename type="first">Ian</forename><surname>Kearns</surname></persName><note type="biography">Ian Kearns is a clinical project manager of clinical trials. He has over 10 years of experience in setting up and conducting international clinical studies in a range of therapeutic areas within the pharmaceutical industry. He holds a B.Sc. degree in biochemistry/physiology from Sheffield University, UK, and a Ph.D. in the neurophysiology of memory and learning from Edinburgh University, Scotland, UK.</note><affiliation>Ian Kearns is a clinical project manager of clinical trials. He has over 10 years of experience in setting up and conducting international clinical studies in a range of therapeutic areas within the pharmaceutical industry. He holds a B.Sc. degree in biochemistry/physiology from Sheffield University, UK, and a Ph.D. in the neurophysiology of memory and learning from Edinburgh University, Scotland, UK.</affiliation><affiliation>Ian Kearns is at AstraZeneca, 2 Kingdom Street, London W2 6BD, UK.</affiliation></author><author><persName><forename type="first">Patrick</forename><surname>Kehoe</surname></persName><note type="biography">Patrick Kehoe has, for over a decade, been one of the earliest and biggest proponents of the 'angiotensin hypothesis' in the pathogenesis of Alzheimer's disease. Some of his seminal work has involved reporting positive genetic associations between the angiotensin-converting enzyme (ACE) gene and Alzheimer's disease risk, and he has followed this up with some of the largest haplotype and meta-analyses studies conducted to date. He has published widely on the importance of ACE and related vasoactive enzymes and cellular mechanisms as pathways contributing to the pathogenesis of Alzheimer's disease, and how a number of these already offer viable and potentially significant therapeutic targets for Alzheimer's disease.</note><affiliation>Patrick Kehoe has, for over a decade, been one of the earliest and biggest proponents of the 'angiotensin hypothesis' in the pathogenesis of Alzheimer's disease. Some of his seminal work has involved reporting positive genetic associations between the angiotensin-converting enzyme (ACE) gene and Alzheimer's disease risk, and he has followed this up with some of the largest haplotype and meta-analyses studies conducted to date. He has published widely on the importance of ACE and related vasoactive enzymes and cellular mechanisms as pathways contributing to the pathogenesis of Alzheimer's disease, and how a number of these already offer viable and potentially significant therapeutic targets for Alzheimer's disease.</affiliation><affiliation>Patrick Kehoe is at the University of Bristol, John James Laboratories, Frenchay Hospital, Bristol BS16 1LE, UK.</affiliation></author><author><persName><forename type="first">Amrit</forename><surname>Mudher</surname></persName><note type="biography">Amrit Mudher is a lecturer in neurosciences at the University of Southampton. Her D.Phil. (1998) at the University of Oxford, UK, was in rodent models of Alzheimer's disease. In 2001 she was awarded an independent fellowship to establish fruitfly models of tauopathies, which she still works on. She was appointed to her current position in 2004.</note><affiliation>Amrit Mudher is a lecturer in neurosciences at the University of Southampton. Her D.Phil. (1998) at the University of Oxford, UK, was in rodent models of Alzheimer's disease. In 2001 she was awarded an independent fellowship to establish fruitfly models of tauopathies, which she still works on. She was appointed to her current position in 2004.</affiliation><affiliation>Amrit Mudher is at the University of Southampton, Life Sciences Building 85, University Road, Southampton SO17 1BJ, UK.</affiliation></author><author><persName><forename type="first">Anthony</forename><surname>Passmore</surname></persName><note type="biography">Anthony Passmore is Professor of Ageing and Geriatric Medicine at Queen's University Belfast, Northern Ireland, UK. He trained in the Northern Ireland training scheme in Geriatrics and Clinical Pharmacology, spent a year as senior lecturer at Sydney University, Australia, and was appointed as senior lecturer in Belfast in 1993. He established the memory clinic at Belfast City Hospital and leads the local Dementia Research Programme. He has supervised a number of postdoctoral degrees and has been involved in many clinical trials. He has over 200 publications, including papers in the New England Journal of Medicine, Lancet and Stroke.</note><affiliation>Anthony Passmore is Professor of Ageing and Geriatric Medicine at Queen's University Belfast, Northern Ireland, UK. He trained in the Northern Ireland training scheme in Geriatrics and Clinical Pharmacology, spent a year as senior lecturer at Sydney University, Australia, and was appointed as senior lecturer in Belfast in 1993. He established the memory clinic at Belfast City Hospital and leads the local Dementia Research Programme. He has supervised a number of postdoctoral degrees and has been involved in many clinical trials. He has over 200 publications, including papers in the New England Journal of Medicine, Lancet and Stroke.</affiliation><affiliation>Anthony Passmore is at Queen's University Belfast, Centre for Public Health, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, UK.</affiliation></author><author><persName><forename type="first">Nicola</forename><surname>Shepherd</surname></persName><note type="biography">Nicola Shepherd is a business development manager in the Technology Transfer Division at the Wellcome Trust and is responsible for the Trust's Translation Fund. As well as managing a number of funded projects, her role involves contract negotiations, due diligence, monitoring patent prosecution and translation strategies leading to commercial exits.</note><affiliation>Nicola Shepherd is a business development manager in the Technology Transfer Division at the Wellcome Trust and is responsible for the Trust's Translation Fund. As well as managing a number of funded projects, her role involves contract negotiations, due diligence, monitoring patent prosecution and translation strategies leading to commercial exits.</affiliation><affiliation>Nicola Shepherd is at the Wellcome Trust, Gibbs Building, 215 Euston Road, London NW1 2BE, UK.</affiliation></author><author><persName><forename type="first">Frank</forename><surname>Walsh</surname></persName><note type="biography">Frank Walsh is Director of Research at the school of Biomedical and Health Sciences at King's College London and has held the positions of Executive Vice President of Discovery Research at Wyeth (including oversight of Alzheimer's disease research) and Senior Vice President at GlaxoSmithKline.</note><affiliation>Frank Walsh is Director of Research at the school of Biomedical and Health Sciences at King's College London and has held the positions of Executive Vice President of Discovery Research at Wyeth (including oversight of Alzheimer's disease research) and Senior Vice President at GlaxoSmithKline.</affiliation><affiliation>Frank Walsh is at the Institute of Psychiatry, King's College London, London SE1 1UL, UK.</affiliation></author><author><persName><forename type="first">Clive</forename><surname>Ballard</surname></persName><email>clive.ballard@kcl.ac.uk</email><note type="biography">Clive Ballard is Professor of Age-Related Diseases at King's College London, Institute of Psychiatry, where he is co-director of the Biomedical Research Unit for Dementia and the Wolfson Centre for Age-Related Diseases. He has published widely in the areas of clinical trials and systematic reviews pertaining to treatments for Alzheimer's disease and other forms of dementia as well as clinicopathological studies, including validation of diagnostic criteria particularly for vascular and synuclein dementias.</note><affiliation>Clive Ballard is Professor of Age-Related Diseases at King's College London, Institute of Psychiatry, where he is co-director of the Biomedical Research Unit for Dementia and the Wolfson Centre for Age-Related Diseases. He has published widely in the areas of clinical trials and systematic reviews pertaining to treatments for Alzheimer's disease and other forms of dementia as well as clinicopathological studies, including validation of diagnostic criteria particularly for vascular and synuclein dementias.</affiliation><affiliation>Anne Corbett and Clive Ballard are at the Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.</affiliation></author></analytic><monogr><title level="j">Nature Reviews Drug Discovery</title><idno type="pISSN">1474-1776</idno><idno type="eISSN">1474-1784</idno><imprint><publisher>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</publisher><date type="published" when="2012-11"></date><biblScope unit="volume">11</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="833">833</biblScope><biblScope unit="page" to="846">846</biblScope></imprint></monogr><idno type="istex">6A37E13CBEAD425373FA2EBBB3598916D2A6A7DB</idno><idno type="DOI">10.1038/nrd3869</idno><idno type="PublisherID">nrd3869</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2012-11-05</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimer's-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimer's disease.</p></abstract></profileDesc><revisionDesc><change when="2012-11-05">Created</change><change when="2012-11">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/6A37E13CBEAD425373FA2EBBB3598916D2A6A7DB/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0"</istex:xmlDeclaration><istex:docType PUBLIC="-//NPG//DTD XML Article//EN" URI="NPG_XML_Article.dtd" name="istex:docType"></istex:docType><istex:document><article id="nrd3869" language="eng" publish="issue" relation="no" origsrc="yes"><entity-declarations><entity id="tbl1" url="/nrd/journal/v11/n11/images/nrd3869-t1.jpg"></entity><entity id="tbl2" url="/nrd/journal/v11/n11/images/nrd3869-t2.jpg"></entity><entity id="tbl3" url="/nrd/journal/v11/n11/images/nrd3869-t3.jpg"></entity></entity-declarations><!--nrd3869--><pubfm><jtl>Nature Reviews Drug Discovery</jtl><vol>11</vol><iss>11</iss><idt>201211</idt><categ id="pe"></categ><subcateg id="op"></subcateg><pp><spn>833</spn><epn>846</epn><cnt>14</cnt></pp><issn type="print">1474-1776</issn><issn type="electronic">1474-1784</issn><cpg><cpy>2012</cpy><cpn>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</cpn></cpg><doi>10.1038/nrd3869</doi></pubfm><fm><atl>Drug repositioning for Alzheimer's disease</atl><aug><au><fnm>Anne</fnm><snm>Corbett</snm><inits>A</inits><orf rid="a1"></orf><orf rid="a16"></orf><bio><p>Anne Corbett is lecturer of dementia research at King's College London, UK. She is an established author in the field. Her research interests include prevention of dementia, translational approaches to improving treatment and care, and clinical trials with a particular focus on behavioural and psychological symptoms and care home settings.</p></bio></au><au><fnm>James</fnm><snm>Pickett</snm><inits>J</inits><orf rid="a2"></orf><orf rid="a16"></orf><bio><p>James Pickett is the senior research manager at the UK Alzheimer's Society — the largest care and research charity for people with dementia in the United Kingdom. Previously, he worked for Diabetes UK and Nature Reviews Molecular Cell Biology. James completed his Ph.D. on exocytosis from University of Cambridge, UK, in 2006.</p></bio></au><au><fnm>Alistair</fnm><snm>Burns</snm><inits>A</inits><orf rid="a3"></orf><bio><p>Alistair Burns is the National Clinical Director for Dementia in England at the UK Department of Health. He is Professor of Old Age Psychiatry and Vice Dean of the Faculty of Medical and Human Sciences at the University of Manchester, UK, Clinical Director for the Manchester Academic Health Science Centre (MAHSC) and an Honorary Consultant Old-Age Psychiatrist in the Manchester Mental Health and Social Care Trust (MMHSCT). He is editor of the International Journal of Geriatric Psychiatry, assistant editor of the British Journal of Psychiatry and is on the editorial boards of International Psychogeriatrics and Advances in Psychiatric Treatment. His research and clinical interests are in mental health problems of older people, particularly dementia and Alzheimer's disease. He has published over 300 papers and 25 books.</p></bio></au><au><fnm>Jonathan</fnm><snm>Corcoran</snm><inits>J</inits><orf rid="a4"></orf><bio><p>Jonathan Corcoran is professor of molecular neurobiology at King's College London. He is the director of the Neuroscience Drug Discovery Unit based in the Wolfson Centre for Age-Related Diseases, which carries out hit-to-lead and lead optimization using both in vitro and in vivo assays. His research interests include the development of orally available compounds for central nervous system (CNS) disorders.</p></bio></au><au><fnm>Stephen B.</fnm><snm>Dunnett</snm><inits>S B</inits><orf rid="a5"></orf><bio><p>Stephen B. Dunnett is a professor at Cardiff University, Wales, UK, and directs the Brain Repair Group in the School of Biosciences at Cardiff University. His research has pioneered the development of technologies for cell transplantation in animal models of neurodegenerative disease, with a particular focus on Alzheimer's, Parkinson's and Huntington's diseases. His laboratory has an international reputation for systematic behavioural analysis as the basis for refining the efficacy and understanding the mechanisms of action of cell transplantation in animal models of these diseases, and in developing primary embryonic and stem cell transplantation towards clinical application.</p></bio></au><au><fnm>Paul</fnm><snm>Edison</snm><inits>P</inits><orf rid="a6"></orf><bio><p>Paul Edison is a clinical senior lecturer in the Centre of Neuroscience at Imperial College London, UK. His research has focused on neuroimaging using novel molecular probes and magnetic resonance techniques for the study of pathophysiological changes associated with Alzheimer's disease and other forms of dementia. He has extensive experience in positron emission tomography (PET) imaging in amyloid, neuroinflammation, glucose metabolism and other neurotransporters in neurodegenerative and neuroinflammatory conditions. He is developing novel therapeutic strategies aimed at preventing the progression of the disease, and he is the chief investigator of large multicentre intervention studies. He also runs a dementia clinic at the Imperial College Healthcare NHS (National Health Service) trust.</p></bio></au><au><fnm>Jim J.</fnm><snm>Hagan</snm><inits>J J</inits><orf rid="a7"></orf><bio><p>Jim J. Hagan is CEO of GMEC (Global Medical Excellence Cluster), a company created to foster biomedical research between academia and industry. He sits on the board of Imanova, a research imaging company, and was previously vice president of Biology in the Psychiatry Centre of Excellence for Drug Discovery at GlaxoSmithKline. He has published extensively, including a recent volume on molecular and functional models of neuropsychiatric disorders.</p></bio></au><au><fnm>Clive</fnm><snm>Holmes</snm><inits>C</inits><orf rid="a8"></orf><bio><p>Clive Holmes trained as a psychiatrist at Kings College London and the Maudsley Hospital, South London. His early research training was in the neurochemistry of Alzheimer's disease at the Institute of Neurology, London, followed by a Ph.D. in the genetics of the neuropsychiatric features of Alzheimer's disease at the Institute of Psychiatry, London. He is currently professor of biological psychiatry at the University of Southampton, UK, where his main interests are in the early diagnosis of dementia, neuropharmacology and the role of immunity in the development and treatment of Alzheimer's disease.</p></bio></au><au><fnm>Emma</fnm><snm>Jones</snm><inits>E</inits><orf rid="a4"></orf><bio><p>Emma Jones carried out her D.Phil. on microarray analysis of a model of ataxia under the supervision of Professor Kay Davies. Following this, she moved to King's College London and started analysing genetic factors that influence the onset of Alzheimer's disease in people with Down's syndrome. This project was continued during her time as a research fellow for the UK Alzheimer's Society, and she has also worked on clinical trials and biomarkers studies in dementia. She has recently started a post as a lecturer in translational stem cell biology at King's College London.</p></bio></au><au><fnm>Cornelius</fnm><snm>Katona</snm><inits>C</inits><orf rid="a9"></orf><bio><p>Cornelius Katona is Emeritus Professor of Psychiatry at the University of Kent, UK, and Honorary Professor of Psychiatry of the Elderly at University College London, UK. His main research interests are in dementia, mood disorders in old age and the mental health of asylum seekers. He has extensive experience of clinical trial work in dementia and in depression. He is the author of over 200 peer-reviewed articles as well as author and/or editor of 15 books. He is co-chair of the World Psychiatric Association section of affective disorders, Chair of the World Federation of Societies of Biological Psychiatry Taskforce on Old Age and co-founder and vice president of the International Society for Affective Disorders. He chaired the Dementia Clinical Studies Group within DeNDRoN (the Dementia and Neurodegenerative Disorders Network) between 2008 and 2012. He has been editor-in-chief of the Journal of Affective Disorders since 1994.</p></bio></au><au><fnm>Ian</fnm><snm>Kearns</snm><inits>I</inits><orf rid="a10"></orf><bio><p>Ian Kearns is a clinical project manager of clinical trials. He has over 10 years of experience in setting up and conducting international clinical studies in a range of therapeutic areas within the pharmaceutical industry. He holds a B.Sc. degree in biochemistry/physiology from Sheffield University, UK, and a Ph.D. in the neurophysiology of memory and learning from Edinburgh University, Scotland, UK.</p></bio></au><au><fnm>Patrick</fnm><snm>Kehoe</snm><inits>P</inits><orf rid="a11"></orf><bio><p>Patrick Kehoe has, for over a decade, been one of the earliest and biggest proponents of the 'angiotensin hypothesis' in the pathogenesis of Alzheimer's disease. Some of his seminal work has involved reporting positive genetic associations between the angiotensin-converting enzyme (ACE) gene and Alzheimer's disease risk, and he has followed this up with some of the largest haplotype and meta-analyses studies conducted to date. He has published widely on the importance of ACE and related vasoactive enzymes and cellular mechanisms as pathways contributing to the pathogenesis of Alzheimer's disease, and how a number of these already offer viable and potentially significant therapeutic targets for Alzheimer's disease.</p></bio></au><au><fnm>Amrit</fnm><snm>Mudher</snm><inits>A</inits><orf rid="a12"></orf><bio><p>Amrit Mudher is a lecturer in neurosciences at the University of Southampton. Her D.Phil. (1998) at the University of Oxford, UK, was in rodent models of Alzheimer's disease. In 2001 she was awarded an independent fellowship to establish fruitfly models of tauopathies, which she still works on. She was appointed to her current position in 2004.</p></bio></au><au><fnm>Anthony</fnm><snm>Passmore</snm><inits>A</inits><orf rid="a13"></orf><bio><p>Anthony Passmore is Professor of Ageing and Geriatric Medicine at Queen's University Belfast, Northern Ireland, UK. He trained in the Northern Ireland training scheme in Geriatrics and Clinical Pharmacology, spent a year as senior lecturer at Sydney University, Australia, and was appointed as senior lecturer in Belfast in 1993. He established the memory clinic at Belfast City Hospital and leads the local Dementia Research Programme. He has supervised a number of postdoctoral degrees and has been involved in many clinical trials. He has over 200 publications, including papers in the New England Journal of Medicine, Lancet and Stroke.</p></bio></au><au><fnm>Nicola</fnm><snm>Shepherd</snm><inits>N</inits><orf rid="a14"></orf><bio><p>Nicola Shepherd is a business development manager in the Technology Transfer Division at the Wellcome Trust and is responsible for the Trust's Translation Fund. As well as managing a number of funded projects, her role involves contract negotiations, due diligence, monitoring patent prosecution and translation strategies leading to commercial exits.</p></bio></au><au><fnm>Frank</fnm><snm>Walsh</snm><inits>F</inits><orf rid="a15"></orf><bio><p>Frank Walsh is Director of Research at the school of Biomedical and Health Sciences at King's College London and has held the positions of Executive Vice President of Discovery Research at Wyeth (including oversight of Alzheimer's disease research) and Senior Vice President at GlaxoSmithKline.</p></bio></au><cau><fnm>Clive</fnm><snm>Ballard</snm><inits>C</inits><orf rid="a1"></orf><corf rid="c1"></corf><bio><p>Clive Ballard is Professor of Age-Related Diseases at King's College London, Institute of Psychiatry, where he is co-director of the Biomedical Research Unit for Dementia and the Wolfson Centre for Age-Related Diseases. He has published widely in the areas of clinical trials and systematic reviews pertaining to treatments for Alzheimer's disease and other forms of dementia as well as clinicopathological studies, including validation of diagnostic criteria — particularly for vascular and synuclein dementias.</p></bio></cau><aff><oid id="a1"></oid>Anne Corbett and Clive Ballard are at the <org>Wolfson Centre for Age-Related Diseases, King's College London</org>, <cty>London</cty><zip>SE1 1UL</zip>, <cny>UK</cny>.</aff><aff><oid id="a2"></oid>James Pickett is at the <org>UK Alzheimer's Society</org>, <street>Devon House, 58 St Katharine's Way</street>, <cty>London</cty><zip>E1W 1LB</zip>, <cny>UK</cny>.</aff><aff><oid id="a3"></oid>Alistair Burns is at the <org>University of Manchester</org>, <street>Oxford Road</street>, <cty>Manchester</cty><zip>M13 9PT</zip>, <cny>UK</cny>.</aff><aff><oid id="a4"></oid>Jonathan Corcoran and Emma Jones are at the <org>Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London</org>, <cty>London</cty><zip>SE1 1UL</zip>, <cny>UK</cny>.</aff><aff><oid id="a5"></oid>Stephen B. Dunnett is at the <org>Brain Repair Group, School of Biosciences, Cardiff University</org>, <street>Museum Avenue</street>, <cty>Cardiff</cty><zip>CF10 3AX</zip>, <cny>UK</cny>.</aff><aff><oid id="a6"></oid>Paul Edison is at <org>Imperial College London</org>, <street>Cyclotron building, Hammersmith Campus</street>, <cty>London</cty><zip>W12 0NN</zip>, <cny>UK</cny>.</aff><aff><oid id="a7"></oid>Jim J. Hagan is at the <org>Global Medical Excellence Cluster (GMEC), Hodgkin Building, Guy's Campus, King's College London</org>, <cty>London</cty><zip>SE1 1UL</zip>, <cny>UK</cny>.</aff><aff><oid id="a8"></oid>Clive Holmes is at the <org>University of Southampton, Southampton General Hospital</org>, <street>Mailpoint 801, South Academic Block, Tremona Road</street>, <cty>Southampton</cty><zip>SO16 6YD</zip>, <cny>UK</cny>.</aff><aff><oid id="a9"></oid>Cornelius Katona is at <org>University College London, Mental Health Sciences Unit, Faculty of Brain Sciences</org>, <cty>London</cty><zip>WC1E 6BT</zip>, <cny>UK</cny>.</aff><aff><oid id="a10"></oid>Ian Kearns is at <org>AstraZeneca</org>, <street>2 Kingdom Street</street>, <cty>London</cty><zip>W2 6BD</zip>, <cny>UK</cny>.</aff><aff><oid id="a11"></oid>Patrick Kehoe is at the <org>University of Bristol, John James Laboratories, Frenchay Hospital</org>, <cty>Bristol</cty><zip>BS16 1LE</zip>, <cny>UK</cny>.</aff><aff><oid id="a12"></oid>Amrit Mudher is at the <org>University of Southampton</org>, <street>Life Sciences Building 85, University Road</street>, <cty>Southampton</cty><zip>SO17 1BJ</zip>, <cny>UK</cny>.</aff><aff><oid id="a13"></oid>Anthony Passmore is at <org>Queen's University Belfast, Centre for Public Health</org>, <street>Whitla Medical Building, 97 Lisburn Road</street>, <cty>Belfast</cty><zip>BT9 7BL</zip>, <cny>UK</cny>.</aff><aff><oid id="a14"></oid>Nicola Shepherd is at the <org>Wellcome Trust</org>, <street>Gibbs Building, 215 Euston Road</street>, <cty>London</cty><zip>NW1 2BE</zip>, <cny>UK</cny>.</aff><aff><oid id="a15"></oid>Frank Walsh is at the <org>Institute of Psychiatry, King's College London</org>, <cty>London</cty><zip>SE1 1UL</zip>, <cny>UK</cny>.</aff><aff><oid id="a16"></oid>A.C. and J.P. contributed equally to this work.</aff><caff><coid id="c1"></coid><email>clive.ballard@kcl.ac.uk</email></caff></aug><hst><pubdate type="iss" year="2012" month="11" day="05"></pubdate></hst><websumm>Preclinical research indicates that various drugs approved for indications such as hypertension and diabetes could also have potentially beneficial effects in Alzheimer's disease, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. This article presents a formal consensus evaluation of these drug repositioning opportunities, and highlights several compounds for which sufficient evidence is available to encourage further investigation and potential progression to clinical trials in Alzheimer's disease.</websumm><abs><p>Existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimer's-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimer's disease.</p></abs></fm><bdy><p><bi>Alzheimer's disease.</bi> Dementia affects 35 million people worldwide, the majority of whom have Alzheimer's disease — a devastating condition leading to progressive cognitive decline, functional impairment and loss of independence. Alzheimer's disease affects 5% of individuals over the age of 65, 20% over the age of 80 and more than a third of those over the age of 90 (Ref. <bibrinl rid="b1">1</bibrinl>), and its prevalence will therefore continue to increase substantially as life expectancy increases, with current best estimates indicating that there will be more than 115 million people with dementia worldwide by 2050 (Ref. <bibrinl rid="b1">1</bibrinl>). Alzheimer's disease incurs an enormous personal cost to those affected, and the worldwide financial cost in 2010 was estimated at US$604 billion<bibr rid="b1"></bibr>. It therefore represents a major and rising public health concern and there is an urgent need to develop more effective therapies to treat and delay the onset of the disease.</p><p>The key pathological hallmarks of Alzheimer's disease are the accumulation of amyloid-β peptide (Aβ)-enriched neuritic plaques and neurofibrillary tangles composed of the microtubule-associated protein tau, synaptic and neuronal dysfunction as well as loss, in combination with the associated neurochemical changes in the brain. The sequence of events leading to different pathologies and the exact pathways involved continue to be a source of debate, and the relative importance of different pathological entities as neurotoxic substrates remains controversial<bibr rid="b2"></bibr>. The prevailing hypothesis is that Aβ fragments aggregate, initially to form toxic soluble oligomers and eventually to form insoluble neuritic plaques. Neurofibrillary tangles develop as a result of hyperphosphorylation of intracellular tau, leading to disruption of cytoskeletal integrity. Although there is probably a pathological link between the amyloid cascade and tau phosphorylation, the pathways have not been definitively identified. Recent work suggests that higher levels of total tau may potentiate the toxic effects of Aβ<bibr rid="b3"></bibr>. Other factors such as inflammatory processes and mitochondrial function, as well as the protection and regeneration of neurons, are also likely to have an important role<bibr rid="b4"></bibr>.</p><p>Providing high-quality support, services and information can make an enormous difference in enabling patients to live with Alzheimer's disease, and is a key part of treatment. In addition, there are currently four approved pharmacotherapies that provide symptomatic benefit. Three acetylcholinesterase inhibitors (donepezil, rivastigmine and galanthamine) are licensed for the treatment of patients with mild to moderate Alzheimer's disease; and memantine, an NMDA (<i>N</i>-methyl-d-aspartate) receptor antagonist, is licensed for the treatment of patients with moderate to severe Alzheimer's disease. Meta-analyses and cost-effectiveness evaluations have demonstrated that these treatments confer moderate symptomatic benefits and are cost-effective<bibr rid="b5"></bibr>. For example, acetylcholinesterase inhibitors improve cognition to above pre-treatment performance for ∼6–12 months. The availability of these drugs has substantially advanced the treatment of patients with Alzheimer's disease, but there is a pressing need to build on our increasing understanding of disease pathogenesis to develop more effective symptomatic treatments and disease-modifying therapies.</p><p>Efforts to develop more effective therapies have so far been unsuccessful, with several high-profile clinical trials failing to demonstrate benefit. The reasons for this are probably multifactorial. The majority of putative disease-modifying therapies that have been evaluated have targeted amyloid pathology. This lack of breadth in treatment approaches has been criticized, and some commentators have argued that a more sophisticated knowledge of disease pathways is needed before we can develop more effective candidate therapies. In addition, most randomized clinical trials have focused on patients with mild to moderate Alzheimer's disease, at which point the disease process may already be too advanced for intervention to be effective, particularly for amyloid-targeted therapies<bibr rid="b2"></bibr>.</p><p>It is also evident, in retrospect, that a number of candidate therapies progressed to Phase III trials based on over-optimistic interpretation of Phase II trial data or without adequate proof of concept regarding the impact of the selected doses on the proposed mechanism of action. For example, Phase II trials of tarenflurbil only provided a suggestion of benefit in a post-hoc subgroup analysis<bibr rid="b6"></bibr>; the putative mechanism of action via <deflistr rid="df13">γ-secretase</deflistr> modulation and its related impact on amyloid pathology was never confirmed in patients with Alzheimer's disease. Subsequent Phase III trials had clearly negative outcomes<bibr rid="b7"></bibr>.</p><p>Although the results of a Phase II trial of dimebon were much more favourable than of tarenflurbil, it seems that the significant benefit seen in the treatment group was driven by a larger-than-expected deterioration in the group receiving placebo treatment, and the mechanism of action was not well characterized. Several possible beneficial mechanisms of action for dimebon were postulated. Of these, mitochondria-mediated neuroprotection was the most prominently discussed<bibr rid="b8"></bibr>, but inhibition of the toxic effects of amyloid, direct actions at glutamate and monoamine receptors as well as acetylcholinesterase inhibition were also suggested as potential mechanisms of action. Unfortunately, the magnitude of the impact of these putative actions on key disease processes was not robustly clarified in preclinical studies and there was no target validation in patients with Alzheimer's disease. Again, Phase III trials were unsuccessful.</p><p>For semagacestat, the mechanism of action via γ-secretase inhibition was better understood. However, although preclinical studies demonstrated a modest short-term impact on hippocampal Aβ levels in transgenic mouse models of Alzheimer's disease, 5 months of treatment at doses comparable to those used in the clinical trials did not result in sustained Aβ suppression or a reduction in plaque deposition<bibr rid="b9"></bibr>. Phase III trials did not demonstrate clear benefit.</p><p>Immunotherapy approaches have also generated tremendous enthusiasm that has so far not translated into clinical benefit. Active immunotherapy, using fragments of the Aβ protein, was effective in transgenic animal models, resulting in clearance of Aβ and behavioural improvements<bibr rid="b10"></bibr>. However, results in humans were mixed; clearance of Aβ plaques was still evident but encephalitis was a worrying adverse effect, and the clinical benefit was less clear-cut<bibr rid="b11"></bibr>. Subsequently, passive immunotherapy using antibodies against Aβ was shown to confer some benefit in transgenic animals<bibr rid="b12"></bibr> but the benefits were less clear in Phase II trials<bibr rid="b13"></bibr>. Recently completed Phase III trials of the passive immunotherapy agents bapineuzumab and solanezumab have been unsuccessful. Although an impact on amyloid levels was reported in the Phase II trials of both bapineuzumab and solanezumab, the mechanism of action is not clear as only a small proportion of the antibody crosses the blood–brain barrier, and other possible mechanisms of action — such as the <deflistr rid="df7">'peripheral sink' hypothesis</deflistr> — have not been verified.</p><p>The results of these studies are disappointing but it still needs to be determined whether these treatment approaches are ineffective or whether the therapies have just been administered too late in the disease process, when the damage related to the proposed amyloid cascade is already irreversible. For this reason, several trials currently in progress or planned are focusing on early-stage preclinical Alzheimer's disease (for example, an ongoing Phase III trial of the humanized monoclonal antibody crenezumab in early-stage Alzheimer's disease) or on individuals carrying genes for familial Alzheimer's disease (such as the DIAN study).</p><p>In order to maximize the chances of success in future drug discovery programmes for Alzheimer's disease, it will be essential to learn from the lessons of failed trials. To ensure that the trial design is optimized, more rigour is needed in understanding and verifying the mechanisms of action of candidate drugs and in establishing the dose that is most likely to be effective. Importantly, there are promising developments in specific and sensitive diagnostic criteria for use in clinical trials in Alzheimer's disease. A combination of the neuropsychological identification of mild amnestic deficits and the detection of changes in biomarkers that are consistent with disease progression is enabling putative disease-modifying therapies to be evaluated at earlier stages in the Alzheimer's disease process<bibr rid="b14"></bibr>. As noted above, several new clinical trials utilizing these criteria are now — or will shortly be — underway.</p><p>Nevertheless, at present there are only 21 Phase II or Phase III trials of investigational medicinal products to treat cognition, function or disease modification in Alzheimer's disease that are registered as being in progress on the <weblink url="http://clinicaltrials.gov/">ClinicalTrials.gov</weblink> website or <weblink url="http://isrctn.org/">ISRCTN Register</weblink>, compared to approximately 1,700 trials of cancer therapies<bibr rid="b15"></bibr>. Despite the enormous commercial value of an effective disease-modifying therapy for Alzheimer's disease, this area is understandably considered as high-risk within the pharmaceutical industry owing to the high cost of these trials and the lack of any positive disease-modifying studies to date. There are, therefore, potential advantages of strategies that could complement the traditional drug discovery approach, provided that strict methodological rigour is maintained.<pullquoter rid="pq1"></pullquoter></p><p><bi>Drug repositioning.</bi> Drug repositioning, sometimes known as drug repurposing, has been defined as “the application of established drug compounds to new therapeutic indications”<bibr rid="b16"></bibr> and offers a drug development route that is accessible to academic centres, research council programmes and not-for-profit organizations, as well as pharmaceutical and biotechnology companies. Drug repositioning has been the basis of successful therapies in many areas including cancer, cardiovascular disease, stress incontinence, irritable bowel syndrome, obesity, erectile dysfunction, smoking cessation, psychosis, attention deficit disorder and Parkinson's disease<bibr rid="b17 b18"></bibr>. The established safety of the candidate compounds provides several advantages compared with the development of novel therapeutic compounds. The time and cost required to advance a candidate treatment into clinical trials can be substantially reduced because <i>in vitro</i> and <i>in vivo</i> screening, chemical optimization, toxicology studies, bulk manufacturing and formulation development have, in many cases, already been completed and can therefore be bypassed (<bxr rid="bx1">Box 1</bxr>)<bibr rid="b17"></bibr>. Furthermore, for some compounds there will already be clinical evidence of potential efficacy from epidemiological cohort studies, open-treatment studies and preliminary clinical trials, offering an added dimension to the available evidence regarding the candidate therapies.</p><p>Various approaches to drug repositioning have been reported in the literature, with some studies focusing on the identification of novel therapeutic targets for established drugs and others utilizing a broader interpretation that includes the investigation of drugs for additional applications that may be based on activity at the same target (or targets) as those underlying their efficacy in indications for which they are already licensed. However, an approach focused on investigating licensed drugs in the hope of uncovering additional or different biological activities relevant to other diseases — for example, through phenotypic screening in disease models —has the potential advantage of identifying unanticipated novel therapeutic strategies.</p><p><bi>Review methodology.</bi> The available evidence to support the repositioning of individual compounds for Alzheimer's disease treatment includes postulated theoretical mechanisms and biological plausibility, <i>in vitro</i> and <i>in vivo</i> studies as well as clinical data. This article discusses the outcomes of a comprehensive assessment of the published literature, systematic evaluation and a formal consensus process by an expert panel to identify licensed drugs with the most robust breadth of evidence to be considered as potential candidates for repositioning in Alzheimer's disease. Fifteen licensed drug candidates were identified by consensus based on candidate therapies proposed by the expert panel, including putative symptomatic and disease-modifying therapies as well as natural products with a published rationale for efficacy. A summary of the preclinical, epidemiological and clinical evidence for each candidate was compiled based on a full literature review. Search terms and parameters are detailed in <bxr rid="bx2">Box 2</bxr>.</p><p>Drug candidates were then shortlisted based on the strength of evidence using a two-stage <deflistr rid="df3">Delphi-type process</deflistr>. A full list of excluded drugs is available in <tablr rid="t1">Table 1</tablr>. The shortlist was then reviewed by industry experts to provide insight into the viability of each candidate and requirements for additional preclinical evidence; key points raised included issues related to dosage and brain penetration. A more detailed review of each identified priority candidate was then undertaken, guided by these recommendations. Insight from patients was also sought through consulting patients with dementia and their carers to understand the perception of acceptable risk–benefit ratios. A final prioritization process was then undertaken. The high-priority candidates are presented below and summarized in <tablr rid="t2">Table 2</tablr>.</p><crosshd>Priority compounds for repositioning</crosshd><p>Various possible therapies were highlighted through the review process, most of which were not considered as high-priority candidates following a careful review of the evidence. Although symptomatic therapies were within the scope of the evaluation, none of the potential symptomatic therapies was considered to meet the required level of evidence for inclusion in the subsequent stages of the consensus process. Examples of some of the proposed therapies excluded at this stage of the consensus process (along with the related evidence) are summarized in <tablr rid="t1">Table 1</tablr>. Priority candidate treatments for which there was considered to be a higher level of supportive evidence, such as antihypertensives, antibiotics, antidiabetic drugs and retinoid therapy (as well as the related existing evidence base), are summarized in <tablr rid="t2">Table 2</tablr> and described in more detail below.</p><crosshd>Antihypertensives</crosshd><p>Longitudinal cohort studies have established that there is a significant link between mid-life hypertension and Alzheimer's disease<bibr rid="b19 b20 b21 b22"></bibr>, highlighting a potentially modifiable risk factor for the prevention of the disease. However, the relationship between Alzheimer's disease and hypertension is complex, and the risk associated with hypertension does not appear to be as significant in later life<bibr rid="b23"></bibr>. In addition, hypertension often occurs concomitantly with other vascular risk factors, vascular dysfunction and associated cerebrovascular pathologies such as small-vessel subcortical vascular disease, which has been implicated in both the aetiology and progression of Alzheimer's disease<bibr rid="b24"></bibr>. Concurrent vascular pathology in patients with Alzheimer's disease also has an additive impact on the severity of cognitive and functional impairments<bibr rid="b25"></bibr>.</p><p>In addition to their direct effects on blood pressure, some classes of antihypertensives have also been proposed as neuroprotective agents through independent mechanisms of action. In particular, it has been suggested that neuroprotection and cognitive benefits in Alzheimer's disease might be mediated through angiotensin receptor blocker (ARB)- and calcium channel blocker (CCB)-related mechanisms.</p><p><bi>Angiotensin receptor blockers.</bi> Centrally acting angiotensin II has a key role in the release of inflammatory mediators, vasoconstriction, mitochondrial dysfunction and inhibition of acetylcholine release at central synapses, all of which are proposed to be relevant to Alzheimer's disease and are potential targets for therapeutic intervention<bibr rid="b26 b27"></bibr>. It has also been proposed that ARBs may confer symptomatic benefits on cognition through two possible mechanisms: either through direct blockade of the angiotensin II type 1 receptor (AT<sub>1</sub>), or through increased processing of angiotensin II to angiotensin III and angiotensin IV, enabling angiotensin IV to act via the angiotensin IV receptor (also known as insulin-regulated aminopeptidase) to mediate cognitive improvement<bibr rid="b28"></bibr>. However, this has not been directly investigated in <i>in vivo</i> studies.</p><p>A crucial characteristic of drugs for Alzheimer's disease is the extent of their brain penetration. ARBs differ in their ability to cross the blood–brain barrier. Losartan, irbesartan, telmisartan and candesartan have all been shown to attenuate the central effects of angiotensin II (increases in mean arterial pressure, thirst and the release of vasopressin) in a dose-dependent manner<bibr rid="b29"></bibr>. Candesartan is the most potent of these, achieving 24-hour blockade at doses 5–10 times lower than losartan or irbesartan. Telmisartan is more lipophilic than losartan and irbesartan, and is also more potent at blocking central AT<sub>1</sub> when administered systemically.</p><p>A large-scale screen of 55 antihypertensive drugs identified the ARB valsartan as the only compound that was able to reduce Aβ accumulation in cultured neurons and inhibit Aβ aggregation <i>in vitro</i><bibr rid="b30"></bibr>. Wang and colleagues<bibr rid="b30"></bibr> then demonstrated reduced plaque burden as well as improved learning and memory in cognitive tests (including the Morris water maze task) following 5 months of treatment with valsartan in 6-month-old <deflistr rid="df9">Tg2576 transgenic mice</deflistr>; the greatest benefits were seen at a dose of 40 mg per kg per day, which is equivalent to 1.5 times the maximum recommended dose for treating patients with hypertension. However, a further study of valsartan using a dose of 40 mg per kg per day in 3- to 4-month-old <deflistr rid="df10">triple-transgenic mice</deflistr> (known as 3xTg-AD mice) that were treated for 2 months did not demonstrate any significant impact on intraneuronal Aβ accumulation, amyloid precursor protein (APP) levels or Aβ oligomers<bibr rid="b31"></bibr>. The effect on cognition was not measured. No significant effect on blood pressure was detected in either study. Hemming <i>et al</i>.<bibr rid="b32"></bibr> also reported no benefit on Aβ levels or plaque burden following treatment of older <deflistr rid="df4">J20 mice</deflistr> with losartan for 1 month.</p><p>Using another ARB, olmesartan, Takeda <i>et al</i>.<bibr rid="b33"></bibr> demonstrated that daily treatment of young <deflistr rid="df1">APP23 mice</deflistr> for 1 month improved cerebral blood flow without affecting Aβ<sub>1–40</sub> and Aβ<sub>1–42</sub> levels. In the Aβ<sub>1–40</sub>-injected mouse model, in which Aβ fragments are injected intracranially to generate deficits, pre-treatment with telmisartan increased cerebral blood flow and inhibited plaque deposition<bibr rid="b34"></bibr>. However, the physiological relevance of this model is unclear.</p><p>Perhaps the most striking preclinical evidence comes from a study in which losartan was administered intranasally to <deflistr rid="df2">APP/PSEN1 mice</deflistr>, at a dose much lower than that mediating hypotensive effects; losartan led to a 3.7-fold reduction in Aβ plaques compared to vehicle-treated mice but also reduced levels of pro-inflammatory mediators and increased levels of the anti-inflammatory mediator interleukin-10 (IL-10) in the serum of these animals<bibr rid="b35"></bibr>. Overall, the body of preclinical research on ARBs provides some evidence of benefit with longer periods of treatment, but most studies only included one ARB drug at a single dose, which makes interpretation of the data difficult.</p><p>There is also some epidemiological evidence to support the potential of ARBs in Alzheimer's disease. Li and colleagues<bibr rid="b36"></bibr> reported the results of a substantial study based on the analysis of more than 800,000 records of patients over the age of 65 without dementia and over 12,000 patients with dementia, with an average follow-up period of 4 years. The study compared people taking ARBs with people taking comparator cardiovascular drugs. To meet the inclusion criteria, patients had to have taken the medication for at least 80% of the first 6 months of the study period. Overall, there were significant reductions in the incidence of dementia in the patients taking ARBs compared to those taking the comparator cardiovascular drugs (hazard ratio: 0.76; 95% confidence interval: 0.69–0.84) and those taking the angiotensin-converting enzyme (ACE) inhibitor lisinopril (hazard ratio: 0.81; 95% confidence interval: 0.73–0.90). In addition, patients taking ARBs were at a significantly lower risk of being admitted into nursing homes (hazard ratio: 0.51; 95% confidence interval: 0.36–0.72) and had a lower mortality rate (hazard ratio: 0.83; 95% confidence interval: 0.71–0.92) than patients in the comparator group. There were some imbalances between groups — a higher rate of diabetes in the ARB group and a greater proportion of patients with cardiovascular comorbidity in the comparator group — but these were adjusted for in the analyses. It should also be noted that both groups were predominantly male. A similar study based on primary records from general practices around the United Kingdom, with an 8-year follow-up period, found ARBs to be associated with an almost 50% reduction in the incidence of Alzheimer's disease<bibr rid="b37"></bibr>.</p><p>Two large, randomized controlled trials to evaluate the efficacy of ramipril plus telmisartan (ONTARGET study) or telmisartan alone (TRANSCEND study) in reducing cardiovascular disease have been undertaken in people over 55 years of age who have cardiovascular disease or diabetes with end-organ damage<bibr rid="b38"></bibr>. The trials included comprehensive cognitive outcome measurements. The ONTARGET study compared telmisartan (80 mg) and the ACE inhibitor ramipril in ∼16,000 patients, whereas the TRANSCEND trial compared telmisartan (80 mg) with placebo in just over 5,000 patients. In the ONTARGET study, there was a trend towards a reduction in the number of patients whose <deflistr rid="df5">mini mental state examination</deflistr> (MMSE) scores deteriorated to 23 or less (odds ratio (OR): 0.9; 95% confidence interval: 0.8–1.01; <i>P</i> = 0.06) and a significant reduction in the number of patients whose MMSE scores deteriorated to 18 or less (OR: 0.84, 95% confidence interval: 0.71–0.99; <i>P</i> = 0.04) with telmisartan compared to ramipril. In the TRANSCEND trial, however, there were no significant benefits on cognitive deterioration with telmisartan compared to placebo<bibr rid="b38"></bibr>.</p><p>In a further study, known as the SCOPE trial, 4,937 patients were randomized to receive candesartan (8–16 mg once daily) or placebo, with a mean follow-up of 3.5–3.7 years. Additional antihypertensive treatment was permitted as clinically indicated. Candesartan had a significantly greater effect than placebo on blood pressure, cerebrovascular events and mortality, but MMSE scores remained stable in both treatment arms, showing no benefit in favour of candesartan<bibr rid="b39"></bibr>. A sub-analysis was subsequently reported, focusing on the 2,020 patients with lower levels of cognitive function (MMSE scores of 24–28). In this analysis, there was a smaller decline in the MMSE scores in the group receiving candesartan than in the control group (mean difference: 0.49; 95% confidence interval: 0.02–0.97; <i>P</i> = 0.04)<bibr rid="b40"></bibr>.</p><p>Although the evidence for the potential of ARBs in Alzheimer's disease is conflicting and difficult to interpret, in our view there is a sufficient indication of potential benefit to merit further <i>in vivo</i> work to clarify the relative importance of different mechanisms, the optimal dose and the optimal agent, which could lead to a proof-of-concept study in patients with Alzheimer's disease. The best evidence from <i>in vitro</i> and <i>in vivo</i> studies points to either losartan or valsartan as the preferred candidate ARBs, with some animal studies also highlighting olmesartan as a potential candidate. However, there is an unfortunate disconnect between the <i>in vivo</i> and clinical studies, as no formal studies to provide direct clinical evidence have so far been conducted on any of the most promising candidates.</p><p><bi>Calcium channel blockers.</bi> CCBs of the dihydropyridine class are widely used to treat hypertension and angina through their vasodilatory activity on smooth muscle vasculature. Most of the drugs in this class have good blood–brain barrier penetration and induce cerebral vasodilatation and increased cerebral blood flow in animals and humans<bibr rid="b41 b42 b43"></bibr>. In contrast to other drugs considered in this article, the clinical data for CCBs have largely preceded preclinical studies, but have led to further studies to establish plausible mechanisms of action for CCBs in Alzheimer's disease as well as dosages and differences among individual drugs within the class.</p><p><i>In vitro</i> research has indicated that certain CCBs reduce Aβ production, oligomerization and accumulation, rescue Aβ-induced neurotoxicity and improve cell survival in the presence of Aβ<bibr rid="b44 b45 b46"></bibr>. CCBs have also been shown to reduce glutamate-induced cell death and levels of intracellular calcium<bibr rid="b47"></bibr>. The ability of nine CCBs (of both the dihydropyridine and non-dihydropyridine class) to prevent Aβ<sub>1–40</sub> and Aβ<sub>1–42</sub> production was investigated <i>in vitro</i> in Chinese hamster ovary cells, and amlodipine and nilvadipine were identified as the only agents that inhibited Aβ production<bibr rid="b48"></bibr>. However, the concentrations studied were several-fold higher than can be achieved therapeutically.</p><p>The activities observed <i>in vitro</i> have been reflected in <i>in vivo</i> studies, which have reported reduced Aβ production, increased Aβ clearance and improved cell survival in transgenic rodent models of Alzheimer's disease treated with CCBs<bibr rid="b44 b45 b46"></bibr>. There have been several high-quality studies that, importantly, have compared various CCBs in the same model systems. In APP/PSEN1 double-transgenic animals, nilvadipine reduced soluble Aβ levels (by 30–40%) and improved Aβ clearance across the blood–brain barrier over 4 days of treatment. Longer-term treatment also resulted in a 40–60% reduction in Aβ plaques and reversed memory and learning deficits (including performance on the Morris water maze task)<bibr rid="b48"></bibr>. In further studies of induced damage in the <deflistr rid="df12">Wistar rat</deflistr> model, nilvadipine (but not amlodipine) was shown to protect against neuronal apoptosis in the hippocampus and to have a restorative effect on spatial memory induced by a combination of ischaemia and Aβ injection<bibr rid="b49"></bibr>. Improved brain clearance of Aβ and improved performance in the Morris water maze task was also achieved by administering nilvadipine to 5-month-old wild-type mice treated with intracranial Aβ<sub>1–42</sub> injections. The dose of nilvadipine used in these studies varied from 2 mg per kg to 3.2 mg per kg, which would be equated to a dose of ∼15 mg per day in humans — close to the maximum recommended dose for clinical use.</p><p>Elsewhere, isradipine was shown to have a neuroprotective effect against Aβ-induced apoptosis in a neuroblastoma MG65 cell line, a protective effect in a <i>Drosophila melanogaster</i> model of Aβ-induced neurotoxicity, and is brain-penetrant in the 3xTg-AD mouse model of Alzheimer's disease<bibr rid="b46 b50"></bibr>. The differential effects of CCBs indicate that their potential benefits in Alzheimer's disease are probably independent of their antihypertensive activity and may be specific to individual drugs within this class. Dihydropyridines seem to be more effective than compounds with different chemical structures (such as verapamil or diltiazem), with evidence from preclinical studies highlighting nilvadipine as the best candidate therapy.</p><p>There is some clinical evidence regarding the potential benefit of the CCB nimodipine in patients with clinically significant dementia. The evidence has been summarized in a Cochrane review<bibr rid="b51"></bibr> of 15 nimodipine trials in more than 3,000 patients with dementia. The review reported that the treatment showed efficacy in improving cognition, but not activities of daily living, at doses of 90 mg per day<bibr rid="b51"></bibr>. However, the evidence is limited by the small size and duration (mostly 12 weeks) of the trials as well as the lack of operational diagnostic criteria for Alzheimer's disease or vascular dementia. Additionally, these trials did not evaluate the effect of treatment on Alzheimer's disease pathology, so the disease-modifying effect is unknown. Importantly, only two of these trials focused specifically on patients with Alzheimer's disease: Branconnier <i>et al</i>.<bibr rid="b52"></bibr> evaluated the effect of nimodipine in a randomized controlled trial of 227 patients (MMSE scores: 4–23; mean age 69), and Morich <i>et al</i>.<bibr rid="b53"></bibr> undertook a larger randomized controlled trial of nimodipine with more than 1,000 patients who had Alzheimer's disease (mean MMSE score: 18; mean age 72).</p><p>The overall meta-analysis undertaken as part of the Cochrane review<bibr rid="b51"></bibr> indicated that 12-week treatment with nimodipine (90 mg per day) resulted in a significant improvement in cognitive function (<deflistr rid="df8">standardized mean difference</deflistr> (SMD): 0.61; 95% confidence interval: 0.12–1.10; <i>P</i> = 0.01) and overall clinical improvement (clinical global impression, <deflistr rid="df11">weighted mean difference</deflistr> (WMD): −1.34; 95% confidence interval: −1.84 to −0.84; <i>P</i> < 0.00001) in comparison with placebo. Over a 24-week period, there was significant benefit with nimodipine compared to placebo in measures of cognitive function (SMD: 0.19; 95% confidence interval: 0.06–0.31) at a dose of 180 mg per day, but there was no overall clinical benefit and no significant benefit with 24 weeks of treatment at a dose of 90 mg per day. Functional outcomes were not significantly improved at either 12 weeks or 24 weeks.</p><p>An open-label, 6-week Phase II trial of 56 patients taking nilvadipine demonstrated that the drug was safe and well tolerated in patients with Alzheimer's disease<bibr rid="b54"></bibr>. Short-term study benefits on cognition and executive function were observed, with preliminary analysis suggesting that the improvements were greater in <deflistr rid="df6">non-APOE4 carriers</deflistr><bibr rid="b55"></bibr>. These promising findings will now be followed up in a large, multicentre, Phase III randomized controlled trial known as NILVAD.</p><p>There is also evidence to support the efficacy of CCBs in reducing the risk of incident Alzheimer's disease. The Cache County Study, a longitudinal epidemiological study, provided some initial evidence for the potential protective effect of CCBs<bibr rid="b56"></bibr>. More than 3,000 participants with a mean age of 74 were followed up for 3 years. Over this period, 105 participants developed incident Alzheimer's disease. Overall treatment with antihypertensives led to a significant reduction in the risk of incident Alzheimer's disease (hazard ratio: 0.64; 95% confidence interval: 0.41–0.98), but this effect was greater with the dihydropyridine class of CCBs (hazard ratio: 0.53; 95% confidence interval: 0.16–1.34). Of note, there was no observed benefit with non-dihydropyridine CCBs. The dosage was not specifically described but CCBs were used as clinically indicated for the treatment of hypertension.</p><p>The SYST-EUR study provided further evidence of a potential protective effect of CCBs on the development of incident dementia. SYST-EUR was a 2-year randomized controlled trial that compared CCBs to placebo, with extended follow-up for up to 3.9 years<bibr rid="b57"></bibr>. Eligible participants had no dementia, were over the age of 60 and had a systolic blood pressure of 160–219 mm Hg, with a diastolic blood pressure of less than 95 mm Hg. Therapy was started immediately after randomization in the active treatment group but only after termination of the double-blind trial in the control group. Treatment consisted of nitrendipine (10–40 mg per day), with the possible addition of enalapril maleate (5–20 mg per day), hydrochlorothiazide (12.5–25 mg per day) or both add-on drugs. In the original trial, active treatment (<i>n</i> = 1,238) reduced the incidence of dementia by 50%, from 7.7 to 3.8 cases per 1,000 patient-years (21 versus 11 patients, <i>P</i> = 0.05).</p><p>Over the extended follow-up period, the number of patients with dementia doubled from 32 to 64, 41 of whom had Alzheimer's disease. Throughout the follow-up period, systolic blood pressure was 7.0 mm Hg higher and diastolic blood pressure 3.2 mm Hg higher in the 1,417 control individuals than in the 1,485 individuals randomized to receive CCB. Compared with the controls, long-term CCB treatment reduced the risk of dementia by 55%, from 7.4 to 3.3 cases per 1,000 patient-years (43 versus 21 cases, <i>P</i> <0.001)<bibr rid="b57"></bibr>. After adjustment for sex, age, education and entry blood pressure, the hazard ratio associated with the use of nitrendipine was 0.38 (95% confidence interval: 0.23–0.64; <i>P</i> <0.001).</p><p>There seems to be strong evidence regarding the potential value of CCBs in reducing incident Alzheimer's disease (and dementia in general). There is also evidence of benefit in the treatment of established Alzheimer's disease, although this is modest in size and not sustained. There has only been one small open-label trial of the CCB that appears to be most effective in preclinical studies — nivaldipine — which might therefore potentially confer greater treatment benefits. Furthermore, it is not clear to what extent any benefits may be attributed to the general antihypertensive effects of CCBs in addition to other disease-specific mechanisms. The best candidates emerging from preclinical and clinical studies are probably nitrendipine, nimodipine and nilvadipine, which have effects at dose ranges within those prescribed in the clinic. Further preclinical and clinical studies are needed to address key questions regarding the differential mechanisms of action and benefits of these agents as well as the optimal doses. With this caveat, the currently available evidence highlights these specific CCBs as potential novel therapies for the prevention and treatment of Alzheimer's disease.<pullquoter rid="pq2"></pullquoter></p><crosshd>GLP1 analogues</crosshd><p>Type 2 diabetes has been identified as a risk factor for Alzheimer's disease<bibr rid="b58"></bibr>. Insulin signalling is impaired in type 2 diabetes, and studies have shown that insulin signalling is also desensitized in the brains of patients with Alzheimer's disease<bibr rid="b59"></bibr>. Apart from controlling blood glucose levels, insulin has the general physiological profile of a growth factor. The neuronal insulin receptors have been shown to induce dendritic sprouting, neuronal stem cell activation as well as general cell growth and repair<bibr rid="b60 b61 b62 b63 b64 b65"></bibr>. Furthermore, insulin and the related insulin-like growth factor 1 are potent neuroprotective factors and are known to regulate levels of phosphorylated tau<bibr rid="b66 b67"></bibr>. Treatment with insulin has been shown to improve brain function — including attention, memory and cognition — in humans<bibr rid="b68 b69 b70 b71"></bibr>.</p><p>A study evaluating the intranasal delivery of insulin showed that this more direct application of insulin to the brain resulted in clear beneficial effects on attention and memory formation<bibr rid="b70 b72 b73"></bibr>. In a Phase II trial, intranasal insulin delivery improved several of the main biomarkers of mild cognitive impairment or early Alzheimer's disease in patients. There was an improvement in cognition and glucose uptake in the cortex, as well as in markers of amyloid and tau in the cerebrospinal fluid (CSF)<bibr rid="b74"></bibr>. This proof-of-concept study indicates that enhancing insulin signalling does lead to improvements in patients with Alzheimer's disease, although in this instance it was associated with significant hypoglycaemia.</p><p>A more indirect route to address this aspect of Alzheimer's disease pathology is to explore compounds that influence insulin release. The glucagon-like peptide 1 (GLP1) analogues exenatide and liraglutide are approved for the treatment of diabetes as agents that promote insulin secretion. They may also act on several pathways related to pathological processes in Alzheimer's disease. <i>In vitro</i>, GLP1 analogues reduce intracellular APP, Aβ and Fe<super>2+</super>-induced impairment of neuronal function and cell death<bibr rid="b75 b76"></bibr>. This appears to be achieved through a mechanism involving glycogen synthase kinase 3β (GSK3β) and reduced tau phosphorylation<bibr rid="b77"></bibr>. These agents may also confer protection against oxidative stress, apoptotic mechanisms mediated by caspase 3, BAX and B cell lymphoma 2 (BCL-2), glutamate toxicity and Aβ-induced neurotoxicity<bibr rid="b76 b77 b78 b79"></bibr>.</p><p>GLP1 analogues have shown neuroprotective effects in mouse models of Alzheimer's disease. The GLP1 analogue Val(8)GLP-1 was tested in a model that overexpresses the human Swedish mutated form of APP and a human mutated form of presenilin 1, which results in rapid development of Aβ plaques in the cortex and hippocampus, starting at 2–3 months of age<bibr rid="b80"></bibr>. Treatment with intraperitoneal injections of Val(8)GLP-1 daily for 3 weeks resulted in protection of synaptic plasticity in the hippocampus from the effects of Aβ plaque formation. In addition, the number of Congo-red-positive dense-core amyloid plaques in the brain was reduced. Long-term potentiation (LTP) was also protected in aged wild-type mice compared to saline-injected wild-type mice, indicating that Val(8)GLP-1 also protects from age-related synaptic degenerative processes<bibr rid="b81"></bibr>.</p><p>A further study evaluated the effect of liraglutide in the APP/PSEN1 mouse model; a decrease in cognitive defects, synapse loss and Alzheimer's disease neuropathology was observed when liraglutide was injected once daily for 8 weeks at a dose comparable to the dose received by patients with diabetes<bibr rid="b82"></bibr>. A further potential benefit of this approach is that liraglutide may promote neurogenesis. The study showed enhanced neuronal progenitor cell proliferation in the dentate gyrus, and an increase in the number of young neurons in the dentate gyrus, indicating that additional repair processes were activated in the brain<bibr rid="b83"></bibr>.</p><p>Brain penetration has been established for GLP1 analogues. Several studies have shown that native GLP1 and long-lasting GLP1 analogues, such as liraglutide, exendin-4 and Val(8)GLP-1, cross the blood–brain barrier<bibr rid="b84 b85"></bibr>. These analogues not only cross the blood–brain barrier after peripheral injection but — most importantly — they also show physiological effects in the brain by increasing neuronal progenitor cell proliferation, enhancing LTP in the hippocampus, improving learning and reducing plaque formation and inflammation in the brain, and even increasing neurogenesis<bibr rid="b86"></bibr>.</p><p>There is currently no epidemiological or clinical evidence pertaining to the use of GLP1 analogues in Alzheimer's disease, mainly because these treatments have only been recently approved. However, several Phase II trials are underway and results are expected to be reported in 2013–2014 (<tablr rid="t3">Table 3</tablr>). It is of interest that GLP1 analogues are safe in normoglycaemic individuals and, unlike some other classes of antidiabetic agents, do not cause hypoglycaemia. Consequently, liraglutide is currently under development as a treatment for individuals who are obese but do not have diabetes. In a clinical trial that involved 564 non-diabetic obese individuals with a body mass index of 30–40 kg per m², each person was assigned to one of four liraglutide doses (1.2 mg, 1.8 mg, 2.4 mg or 3.0 mg; <i>n</i> = 90–95) or to placebo (<i>n</i> = 98) subcutaneously administered once a day. Apart from mild nausea, the drug was well tolerated and no significant effects on blood sugar levels were observed<bibr rid="b87"></bibr>.</p><p>In summary, there is evidence to indicate that antidiabetic therapies provide a potential opportunity for the treatment of Alzheimer's disease, with promising data from <i>in vitro</i> studies and <i>in vivo</i> studies highlighting potential mechanisms of action along with both behavioural and pathological benefits at doses equivalent to those used for the treatment of patients with diabetes. Liraglutide has been tested in non-diabetic populations<bibr rid="b87"></bibr>, but it has not been evaluated in older, frailer populations that would be more representative of an Alzheimer's disease trial, and there may be specific safety concerns linked to this age group. Reflecting the potential promise of this drug class, several Phase II trials are already underway.<pullquoter rid="pq3"></pullquoter></p><crosshd>Minocycline</crosshd><p>Tetracycline antibiotics are widely used to treat bacterial infections and are well tolerated in older people, but most of the treatment data pertain to short-term periods of exposure. Studies related to Alzheimer's disease have predominantly focused on minocycline because it is the most lipophilic tetracycline, with greater blood–brain barrier penetration than other agents in this class.</p><p>With regard to preclinical studies, minocycline has been shown to reduce Aβ<sub>1–42</sub> aggregation and promote disassembly of pre-formed fibrils in <i>in vitro</i> studies<bibr rid="b88"></bibr>. Various groups have independently shown that minocycline reduces levels of pro-inflammatory mediators and microglial activation in a range of mouse models of Alzheimer's disease<bibr rid="b89 b90 b91 b92 b93 b94"></bibr>. In addition, two of the three studies using transgenic mouse models of Alzheimer's disease for 28 days or more of treatment have shown a significant decrease in cerebral Aβ accumulation and improvements in behavioural outcomes<bibr rid="b93 b95"></bibr>. One of these studies used 8-month-old 3xTg-AD mice and reported reductions in cortical amyloid levels following 4 months of minocycline treatment, but no changes in tau pathology were observed<bibr rid="b93"></bibr>. The third study reported no benefit with respect to amyloid accumulation or behaviour over a treatment period of 12 months<bibr rid="b96"></bibr>.</p><p>An additional study in a rat model of diabetes demonstrated a reduction in Aβ<sub>1–40</sub> and Aβ<sub>1–42</sub> levels and associated improvements in behavioural outcomes over 8 weeks of treatment<bibr rid="b94"></bibr>. Various other studies in transgenic mouse models of Alzheimer's disease have not identified any significant reduction in Aβ<sub>1–40</sub> and Aβ<sub>1–42</sub> levels following less than 28 days of treatment<bibr rid="b90 b91 b97"></bibr>; however, the only one of these studies to measure behavioural outcomes did report that treatment with minocycline rescued performance on a spatial learning maze task<bibr rid="b90"></bibr>. However, the evidence indicates that at least 28 days of treatment are probably needed to confer a significant reduction in Aβ levels.</p><p>These studies have only tested minocycline at doses between 40 mg per kg per day and 50 mg per kg per day; dose–response relationships and the shape of the dose–response curve in animals have not yet been established. Furthermore, of clinical importance, this dose range broadly equates to about 4 mg per kg in humans<bibr rid="b98"></bibr>, which is about 1.25–1.45-fold higher than the recommended maximum clinical dose.</p><p>There have been no clinical trials of minocycline in Alzheimer's disease, although trials have been undertaken in other neurodegenerative diseases. Results so far are variable and suggest that minocycline does not provide neuroprotection against all mechanisms of neurodegeneration. For example, minocycline was examined as a therapy for amyotrophic lateral sclerosis in a trial completed by 310 individuals<bibr rid="b99"></bibr> and was found to cause a greater deterioration in measures of disease than placebo. Two open-label trials of minocycline in patients with Huntington's disease (<i>n</i> = 14 and <i>n</i> = 30) showed no improvement in cognition<bibr rid="b100 b101 b102"></bibr>, and the most recent study indicates that further trials are not warranted<bibr rid="b103"></bibr>. However, pilot studies in Parkinson's disease indicate that further trials of minocycline are justified, as the study reached the required futility threshold and did not adversely affect symptoms and treatment response, and have shown that minocycline has an acceptable safety profile, although reduced tolerability was observed<bibr rid="b104"></bibr>.</p><p>Overall, minocycline — and possibly other tetracyclines — could warrant further investigation for development as treatments for Alzheimer's disease. Although the required dose may be slightly higher than that used clinically for treating bacterial infections, these compounds are generally well tolerated and toxicology information is already available for this dose range.</p><crosshd>Retinoid therapy</crosshd><p>Drugs that activate retinoic acid receptors (RARs) are used to treat several skin-related conditions such as acne and psoriasis. Retinoic acid is also vital for normal nerve function and repair, and there is genomic and epidemiological evidence to suggest that impaired retinoic acid signalling may contribute to the aetiology of Alzheimer's disease<bibr rid="b105"></bibr>. Chronic deprivation of retinoic acid in rats leads to deposition of Aβ in the vasculature<bibr rid="b106"></bibr> and dysregulation of amyloid processing in the cortex<bibr rid="b107"></bibr>. Husson <i>et al</i>.<bibr rid="b107"></bibr> showed that administration of all-<i>trans</i> retinoic acid reversed this dysregulation.</p><p><i>In vivo</i> studies with double-transgenic APP mice have indicated that intraperitoneal injection of all-<i>trans</i> retinoic acid substantially reduces neuropathology, inflammation, Aβ plaque burden and tau phosphorylation, and improves performance in behavioural testing, including in the Morris water maze task<bibr rid="b108"></bibr>. This provides a useful proof of concept, but high levels of all-<i>trans</i> retinoic acid exhibit too many side effects to be clinically useful. Tippman <i>et al</i>.<bibr rid="b109"></bibr> reported that a single intracerebral injection of acitretin, a synthetic retinoid currently used to treat severe psoriasis, led to upregulation of the α-secretase ADAM10 (disintegrin and metalloproteinase domain-containing protein 10) and significant reductions in Aβ<sub>1–40</sub> and Aβ<sub>1–42</sub> levels. Jarvis <i>et al</i>.<bibr rid="b110"></bibr> built on this study by demonstrating that oral and intraperitoneal administration of a specific RARα agonist, am580, in Tg2576 mice (over a period of 4 months) led to upregulation of ADAM10 and non-amyloidogenic processing of APP mediated by the α-isoform of RAR (RARα). Specific agonists of RARβ and RARγ did not confer the same benefit. Therefore, RAR activation, specifically through RARα, may have beneficial effects on APP processing by altering the relative ratio of α- to β-secretase activity and promoting non-amyloidogenic processing of APP. In a further study, Kawahara <i>et al</i>.<bibr rid="b111"></bibr> demonstrated that tamibarotene, another orally active synthetic retinoid, reduced insoluble Aβ<sub>1–40</sub> and Aβ<sub>1–42</sub> levels in transgenic APP mice over 14 weeks of treatment. This study did not identify any behavioural benefits.</p><p>More recently, it has been shown that treatment with the RXR agonist bexarotene, which is approved for the treatment of cutaneous T cell lymphoma, leads to pathological and behavioural improvements in transgenic mouse models of Alzheimer's disease. Acute treatment with bexarotene (lasting less than 14 days) caused a rapid 25% reduction in Aβ<sub>1–40</sub> and Aβ<sub>1–42</sub> levels and in Aβ plaque burden in both young and old APP/PSEN1 mice<bibr rid="b112"></bibr>. Chronic 90-day treatment resulted in a sustained 30% reduction in soluble Aβ levels. There was also reversal of cognitive and behavioural deficits, including performance in the Morris water maze task, although there was intriguingly no reduction in overall Aβ plaque burden. The dose used in the study (100 mg per kg per day) equates to approximately three times the dose used in the clinic. Clearance of Aβ was shown to be dependent on the apolipoprotein E (<i>APOE</i>) gene, the most influential risk factor gene for late-onset Alzheimer's disease. Bexarotene resulted in the upregulation of components of the high-density lipoprotein (HDL) pathway such as APOE, which promotes the proteolytic degradation of Aβ<bibr rid="b113"></bibr>.</p><p>Further potential mechanisms of action for retinoids may include the upregulation of enzymes involved in amyloid clearance, such as the insulin degrading enzyme<bibr rid="b114"></bibr> and components of the APOE pathway<bibr rid="b112"></bibr>. Retinoids may also induce potentially beneficial changes related to insulin signalling and increased neurogenesis, and promote neuronal differentiation of progenitor cells<bibr rid="b115 b116"></bibr>. <i>In vitro</i>, retinoids also act as antioxidants (by regulating superoxide dismutases and inhibiting glutathione depletion to reduce mitochondrial damage) and as anti-inflammatory agents (for example, by reducing production of IL-6). Both of these activities have potential importance in Alzheimer's disease pathology<bibr rid="b117 b118"></bibr>. There is, therefore, a strong mechanistic rationale for the potential benefit of retinoid therapies beyond amyloid modulation, but there is a need to further clarify the impact of treatment on these pathways through <i>in vivo</i> studies.</p><p>Overall, studies in the literature indicate that retinoids have strong potential mechanistic plausibility as therapies for Alzheimer's disease owing to their effects on APP processing, Aβ clearance, insulin signalling and neurogenesis. RARα agonists might confer additional benefits over non-selective RAR activators, but none is currently approved for use. Out of the approved drugs, data for bexarotene have provided proof of concept for the potential of retinoid therapies as candidate treatments for Alzheimer's disease in preclinical studies, as noted above, whereas acitretin — which is known to penetrate tissue including the brain — may also be a promising candidate<bibr rid="b119"></bibr>. In taking forward the development of acitretin for Alzheimer's disease, work is required to confirm functional activity at currently approved doses and to establish the effects of this agent on the HDL–APOE pathway — as shown for bexarotene<bibr rid="b112"></bibr>. However, there are currently no clinical data to support this approach in humans.</p><p>There is a need to establish the safety of long-term therapy with currently available retinoids in older adults with Alzheimer's disease. The side-effect profile of bexarotene is extensive and potentially problematic for older patients with Alzheimer's disease, particularly as the effective dose in animal studies was threefold higher than that used in the clinical setting. Fortunately, one of the major safety concerns associated with retinoid therapy, teratogenesis, is not a major consideration for the treatment of patients with Alzheimer's disease. Mucosal drying, including the membranes of the eye and nose, and severe thirst are common and potentially unpleasant adverse effects. Some of the other common adverse effects of bexarotene are also seen with acitretin and include impaired liver function, skin exfoliation, headache, myalgia and abnormal levels of lipids. Acitretin is currently being tested in patients with Alzheimer's disease in a small Phase II trial (<tablr rid="t3">Table 3</tablr>), and establishing whether the treatment has acceptable tolerability is a key priority.</p><crosshd>Views of patients and carers</crosshd><p>The opinions of patients with dementia and their carers were sought to supplement the prioritization process undertaken for this article. This was particularly important owing to the potential side-effect profiles of some of the priority treatment candidates. Consultation with these individuals facilitated an understanding of the level of risk that is considered to be acceptable by people affected by the condition, as well as their perception of the potential benefit conferred. Key desirable aspects of a treatment were as follows: convenient administration, ideally orally, through dosing once or twice daily.</p><p>Drug repositioning was welcomed as many of the candidate treatments identified are already in routine clinical use and are generally considered to have tolerable side-effect profiles. The potential adverse effects of retinoid therapy were highlighted as a potential concern, particularly the drying of mucosal layers. Patients also expressed concerns that the long-term use of antibiotics could increase the risk of infection or reduce treatment options should infection occur. However, none of the priority candidates was dismissed as having unacceptable side-effect profiles.</p><crosshd>Summary</crosshd><p>The robust consensus process described above has identified a number of drug candidates for which there is encouraging evidence to support their potential as treatments for Alzheimer's disease. The process has also identified a number of discrepancies and issues with the current evidence, particularly where there is no supporting clinical evidence or where there are inconsistencies in drug choice between preclinical and clinical studies. Gaps have been highlighted that should enable key issues — pertaining to confirming mechanisms of action and optimal doses — to be clarified for individual candidate treatments. Promisingly, doses used in the preclinical literature are reasonably consistent with clinical dosing, indicating that current findings from animal models may be translatable to the clinical setting. The most promising evidence appears to be for CCBs, for which there are very consistent preclinical and clinical data to support their benefit in Alzheimer's disease. There are also strong <i>in vivo</i> data for GLP1 analogues, minocycline and retinoid therapy. However, the considerable safety and tolerability issues surrounding retinoid therapy may preclude the further development of candidates in this class. The evidence for ARBs is less consistent, and further work is required to elucidate their effect.</p><p>In conclusion, there are some promising drug candidates for repositioning in Alzheimer's disease, and this article has indicated where additional work is required — particularly regarding the mechanism of action, dose and choice of agent — to take them forward in clinical trials. It is important to emphasize that rigour is needed in such assessments in order to reduce the likelihood of failures such as those observed with the various investigational disease-modifying drugs discussed above, which may have partly been due to premature progression of flawed candidates. Although some of the drugs discussed here appear to be good candidates for further investigation, it is far from certain whether any of them will emerge as successful therapies for Alzheimer's disease, and a more systematic approach is needed towards the screening of approved drugs and analysis of epidemiological and clinical data to identify new potential candidates for repositioning in Alzheimer's disease. Depending on the mechanisms of action of the emerging candidates, it will also be important to consider the optimal stage of the disease to instigate therapy and to determine whether trials should focus on patients with preclinical early-stage Alzheimer's disease.<pullquoter rid="pq4"></pullquoter></p><crosshd>Author contributions</crosshd><p>Clive Ballard conceived the initial project and contributed at each stage of the protocol design, consensus meetings and data interpretation. He also led several of the systematic reviews, contributed to each version of the manuscript and had final sign off on the submitted version of the manuscript. Anne Corbett and James Pickett worked with Clive Ballard to develop the protocol, contributed several of the systematic reviews, led the consumer review panel and took a lead on interpreting the data and writing the manuscript. Ian Kearns project-managed the consensus process, including the systematic reviews, and wrote a summary report of the consensus findings. Emma Jones wrote a number of the systematic reviews for individual candidate drugs and contributed to the final version of the manuscript. The other authors contributed to the identification of candidate drugs, had an active role in each stage of the consensus process and data interpretation, and contributed to the final version of the manuscript.</p></bdy><bm><objects><deflist id="df1"><term>APP23 mice</term><defn><p>Transgenic mice carrying the double Swedish mutation (K670N/M671L) of amyloid precursor protein (APP), which leads to familial Alzheimer's disease. These animals overexpress APP by about sevenfold and develop amyloid deposits and behavioural deficits as they age.</p></defn></deflist><deflist id="df2"><term>APP/PSEN1 mice</term><defn><p>A transgenic mouse model of Alzheimer's disease carrying both human amyloid precursor protein (APP) with the Swedish mutation (K670N/M671L) and the presenilin 1 (PSEN1) A246E mutation. These mice develop amyloid deposits and behavioural deficits at a younger age than the APP transgenic animals (K670N/M671L models alone).</p></defn></deflist><deflist id="df3"><term>Delphi-type process</term><defn><p>A structured technique to achieve consensus from a panel of experts using a systematic method, usually using two or more stages to share and discuss the emerging consensus in order to achieve the best overall consensus from the expert group.</p></defn></deflist><deflist id="df4"><term>J20 mice</term><defn><p>A transgenic mouse model of Alzheimer's disease. These mice express a mutant form of human amyloid precursor protein (APP) bearing both the Swedish (K670N/M671L) and the Indiana (V717F) mutations of familial Alzheimer's disease. These mice develop amyloid deposits and behavioural deficits as they age.</p></defn></deflist><deflist id="df5"><term>Mini mental state examination</term><defn><p>(MMSE). A brief and widely used 30-point neuropsychological assessment evaluating a number of cognitive domains. A score of 25 or less is indicative of a degree of cognitive deficit requiring further evaluation. In patients with Alzheimer's disease, an MMSE score <10 indicates severe dementia, 10–20 indicates moderate dementia and >20 indicates mild dementia.</p></defn></deflist><deflist id="df6"><term>Non-APOE4 carriers</term><defn><p>Individuals who do not carry the E4 allele of the gene encoding apolipoprotein E (<i>APOE</i>); APOE4 is a known risk factor for the development of late-onset Alzheimer's disease; 25% of the population and 50% of patients with Alzheimer's disease carry at least one E4 allele.</p></defn></deflist><deflist id="df7"><term>'Peripheral sink' hypothesis</term><defn><p>A hypothesis stating that antibodies bind to amyloid-β in the bloodstream, shifting the distribution of amyloid-β between the brain and the peripheral circulatory system and thereby leading to a net efflux of amyloid-β from the central nervous system to plasma, where it is degraded.</p></defn></deflist><deflist id="df8"><term>Standardized mean difference</term><defn><p>(SMD). A statistical method for calculating a standardizing coefficient to quantify differences between treatment groups based on mean changes and standard deviation to enable comparison of outcomes across studies that have used different outcome measures.</p></defn></deflist><deflist id="df9"><term>Tg2576 transgenic mice</term><defn><p>Transgenic mice expressing abnormal variants of the human genes encoding amyloid precursor protein (APP) that are a rare cause of familial Alzheimer's disease. These mice exhibit a fivefold increase in APP levels in the brain and develop amyloid deposits and behavioural deficits as they age.</p></defn></deflist><deflist id="df10"><term>Triple-transgenic mice</term><defn><p>(3xTg-AD mice). A novel mouse model of Alzheimer's disease, incorporating human genes that lead to abnormal processing of amyloid-β and tau. This mouse model is the only model to exhibit both amyloid-β and tau pathology, and therefore mimics human Alzheimer's disease more closely than other mouse models.</p></defn></deflist><deflist id="df11"><term>Weighted mean difference</term><defn><p>(WMD). A statistical method for calculating a standardizing coefficient to quantify differences between treatment groups based on mean changes and standard deviation to enable comparison of outcomes across studies that have used different outcome measures to enable them to be combined in meta-analyses; this method makes the calculation based on the size of the individual studies.</p></defn></deflist><deflist id="df12"><term>Wistar rat</term><defn><p>A breed of non-transgenic rat that has been widely used for experimental studies.</p></defn></deflist><deflist id="df13"><term>γ-secretase</term><defn><p>An intramembrane protease complex that cleaves the transmembrane amyloid precursor protein to produce amyloid-β.</p></defn></deflist><linkgrp><linkset name="FURTHER INFORMATION"><weblink url="http://clinicaltrials.gov/">ClinicalTrials.gov website</weblink><weblink url="http://isrctn.org/">ISRCTN Register</weblink></linkset></linkgrp><pullquote id="pq1">Despite the enormous commercial value of an effective disease-modifying therapy for Alzheimer's disease, this area is understandably considered as high-risk within <newline></newline>the pharmaceutical industry.</pullquote><pullquote id="pq2">There seems to be strong evidence regarding the potential value of CCBs in reducing incident Alzheimer's disease.</pullquote><pullquote id="pq3">In summary, there is evidence to indicate that antidiabetic therapies provide a potential opportunity for the treatment of Alzheimer's disease.</pullquote><pullquote id="pq4">a more systematic approach is needed towards the screening of approved drugs and analysis of epidemiological and clinical data to identify new potential candidates for repositioning in Alzheimer's disease.</pullquote><table id="t1" tocentry="0" frame="topbot" colsep="0" rowsep="0" orient="port" pgwide="0" tabcols="3"><title>Potential candidate drugs or drug classes excluded on the basis of the consensus process</title><tgroup cols="3" colsep="0" rowsep="0" align="left"><colspec colnum="1" colname="1" align="left" colwidth="1*"></colspec><colspec colnum="2" colname="2" align="left" colwidth="1*"></colspec><colspec colnum="3" colname="3" align="left" colwidth="1*"></colspec><spanspec namest="1" nameend="3" spanname="1"></spanspec><thead valign="top"><row><entry>Candidates</entry><entry>Current approved indications</entry><entry>Summary of evidence</entry></row></thead><tbody valign="top"><row><entry spanname="1"><bi>Symptomatic targets</bi></entry></row><row><entry>SSRIs</entry><entry>Major depressive disorder</entry><entry>There is evidence for benefit on overall neurological function <i>in vitro</i> and improved behavioural symptoms; however, clinical and preclinical evidence for benefit in cognition is limited and conflicting<bibr rid="b120"></bibr></entry></row><row><entry>Sage oil</entry><entry>Unlicensed: health supplement</entry><entry>There is limited preliminary <i>in vitro</i> evidence to support pathological effect; some limited promising evidence from initial clinical work requiring more in-depth preclinical study<bibr rid="b121"></bibr></entry></row><row><entry spanname="1"><bi>Same functional targets</bi></entry></row><row><entry>ACE inhibitors</entry><entry>Hypertension</entry><entry>There is tentative evidence for mechanism of action to reduce amyloid aggregation, although current evidence indicates that antihypertensive effect is most likely; limited clinical evidence and meta-analysis of treatment studies have reported no benefit<bibr rid="b122"></bibr></entry></row><row><entry>NSAIDs</entry><entry>Pain, inflammation</entry><entry>There is good <i>in vitro</i> evidence for an effect on reducing amyloid accumulation, supported by limited epidemiological studies; conflicting clinical data do not provide strong enough rationale for benefit<bibr rid="b6 b123"></bibr>; a recent Cochrane review based on 15 studies concluded that NSAIDs could not be recommended for the treatment of Alzheimer's disease<bibr rid="b124"></bibr></entry></row><row><entry>TNF inhibitors</entry><entry>Autoimmune disorders</entry><entry>Proposed mechanism of action is based on evidence of TNF-related synapse loss and cognitive impairment; initial evidence of benefit in cognition was observed following perispinal administration of etanercept in one small cohort study<bibr rid="b125"></bibr>; etanercept does not have brain-penetrative properties but there is evidence that peripheral blockade may have a protective effect in some positive open-label studies<bibr rid="b126"></bibr>; a Phase II randomized controlled trial of peripheral administration of etanercept is in progress</entry></row><row><entry spanname="1"><bi>Novel functional targets</bi></entry></row><row><entry>B vitamins</entry><entry>Unlicensed: health supplements</entry><entry>Evidence of benefit is controversial and conflicting; B vitamins may have some benefit in patients with elevated homocysteine levels<bibr rid="b127"></bibr></entry></row><row><entry>Cannabinoids</entry><entry>Multiple sclerosis (nabiximols); chemotherapy-related nausea and vomiting (nabilone)</entry><entry>Proposed mechanism of action is unclear owing to conflicting preclinical evidence and no well-designed clinical studies to date<bibr rid="b128"></bibr></entry></row><row><entry>Guanosine analogue antivirals</entry><entry>Viral infections, including herpes simplex virus type 1 (HSV1)</entry><entry>Evidence for a potential mechanism of action in Alzheimer's disease is controversial and limited to pathological observations of HSV1 colocalization in post-mortem brain tissue of patients with Alzheimer's disease<bibr rid="b129"></bibr>; no preclinical or clinical evidence is currently available<bibr rid="b130"></bibr></entry></row><row><entry>Lithium</entry><entry>Bipolar disorder</entry><entry>Lithium has an established effect in reducing tau pathology, although there is conflicting evidence regarding its effect on amyloid pathology and cognitive function; despite promising initial epidemiological studies and a feasibility study showing an acceptable side-effect profile, no benefit was observed in one small randomized controlled trial<bibr rid="b131 b132 b133"></bibr></entry></row><row><entry>Metformin</entry><entry>Type 2 diabetes</entry><entry>There is established <i>in vitro</i> evidence for effectiveness in increasing amyloid clearance and reducing tau phosphorylation, with related benefits in rodent models of diabetes; limited epidemiological and clinical evidence is restricted to benefit in patients with diabetes and related risk factors; initial clinical studies are required in patients with mild cognitive impairment and Alzheimer's disease<bibr rid="b134 b135"></bibr></entry></row><row><entry>Rifamycins (antibiotics)</entry><entry>Tuberculosis, leprosy</entry><entry>Established effects on reducing amyloid accumulation <i>in vitro</i> provide putative mechanism of action; very limited clinical evidence and no epidemiological evidence is available<bibr rid="b136"></bibr></entry></row><row><entry>Sodium valproate</entry><entry>Anticonvulsant and mood stabilizer: for example, in epilepsy, anorexia and bipolar disorder</entry><entry>Sodium valproate has an established effect as a GSK3 inhibitor with neuroprotective properties; recent randomized controlled trial showed no benefit — increased deterioration and brain atrophy was observed in the treatment group<bibr rid="b137"></bibr></entry></row><row><entry>Taxanes</entry><entry>Chemotherapy</entry><entry>There is some initial evidence that the microtubule-stabilizing function reduces tau and amyloid pathology in transgenic mice; mechanism of action is unclear; no clinical evidence is available and few taxanes penetrate the brain<bibr rid="b133"></bibr></entry></row><row><entry>PPARγ agonists</entry><entry>Type 2 diabetes and metabolic syndrome</entry><entry>Initial enthusiasm from animal studies has been dampened by unsuccessful Phase III studies of rosiglitazone<bibr rid="b138"></bibr>; there have been subsequent suggestions that there may be a subgroup of responders, and a small pilot study of patients with Alzheimer's disease in the context of diabetes provided a suggestion of benefit with pioglitazone<bibr rid="b139"></bibr>; although there is some potential for further development of PPARγ agonists as therapeutics (perhaps for specific subgroups of patients with Alzheimer's disease), in the context of a failed Phase III trial this was not considered to be a high-priority candidate</entry></row><row><entry spanname="1"> ACE, angiotensin-converting enzyme; GSK3, glycogen synthase kinase 3; NSAID, non-steroidal anti-inflammatory drug; PPARγ, peroxisome proliferator-activated receptor-γ; SSRI, selective serotonin reuptake inhibitor; TNF, tumour necrosis factor. </entry></row></tbody></tgroup><!--nrd3869-t1--></table><table id="t2" tocentry="0" frame="topbot" colsep="0" rowsep="0" orient="port" pgwide="0" tabcols="5"><title>Priority candidate drugs for repositioning in Alzheimer's disease</title><tgroup cols="5" colsep="0" rowsep="0" align="left"><colspec colnum="1" colname="1" align="left" colwidth="1*"></colspec><colspec colnum="2" colname="2" align="left" colwidth="1*"></colspec><colspec colnum="3" colname="3" align="left" colwidth="1*"></colspec><colspec colnum="4" colname="4" align="left" colwidth="1*"></colspec><colspec colnum="5" colname="5" align="left" colwidth="1*"></colspec><spanspec namest="1" nameend="5" spanname="1"></spanspec><thead valign="top"><row><entry>Drugs (or drug classes)</entry><entry>Proposed candidates</entry><entry>Proposed mechanism of action</entry><entry>Summary of evidence</entry><entry>Remaining work required</entry></row></thead><tbody valign="top"><row><entry>Angiotensin receptor blockers (ARBs)</entry><entry>Valsartan</entry><entry>• Inhibition of inflammation, vasoconstriction and mitochondrial dysfunction, and promotion of acetylcholine release<newline></newline>• Direct blockade of AT<sub>1</sub> or processing of angiotensin II<bibr rid="b28"></bibr></entry><entry>• <i>In vitro</i> and <i>in vivo</i> evidence of reduced Aβ burden and improved cognitive function, and some conflicting outcomes observed with different drugs<bibr rid="b30 b31 b32 b33 b34"></bibr><newline></newline>• Established brain penetration<bibr rid="b35"></bibr><newline></newline>• Some epidemiological evidence for reduction of incident dementia<bibr rid="b36 b37"></bibr><newline></newline>• Two out of three randomized controlled trials showed some benefit with ARB treatment compared to placebo<bibr rid="b38 b39"></bibr></entry><entry>• Clarification of mechanism of action and the need to distinguish direct effect of treatment from indirect effects on blood pressure and other cardiovascular factors<newline></newline>• Clinical work required to link evidence from preclinical work with individual drugs<newline></newline>• Clarification of optimal dosage<newline></newline>• Confirmation of priority agent<newline></newline>• Proof-of-concept study required in patients with Alzheimer's disease</entry></row><row><entry>Calcium channel blockers</entry><entry>Nitrendipine, nimodipine and nilvadipine</entry><entry>• Reduction of Aβ production, burden and neurotoxicity<bibr rid="b44 b45 b46"></bibr><newline></newline>• Specific mechanism of action unclear but differential effects indicate a novel mechanism independent of antihypertensive properties</entry><entry>• <i>In vitro</i> evidence of reduction of Aβ pathology and improved cell survival, with associated cognitive improvement and reduction in disease pathology <i>in vivo</i> in rodent and <i>Drosophila melanogaster</i> models<bibr rid="b44 b45 b46 b47 b48 b49 b50"></bibr><newline></newline>• Established clinical evidence of benefit in patients with dementia, but limited in patients with Alzheimer's disease<newline></newline>• Meta-analysis of randomized controlled trials shows clinical benefit on cognition in initial trials<bibr rid="b51 b52 b53 b54 b55"></bibr></entry><entry>• Preclinical work required to refine mechanism of action, obtain further data on the effect on pathology and optimize dose<newline></newline>• Clinical work needed to identify effect on Alzheimer's disease pathology in humans<newline></newline>• Clarification of optimal dosage<newline></newline>• Confirmation of priority agent<newline></newline>• Proof-of-concept study in patients with Alzheimer's disease<newline></newline>• Further clinical evidence required to support risk reduction for incident Alzheimer's disease<bibr rid="b56"></bibr></entry></row><row><entry>GLP1 analogues</entry><entry>Liraglutide</entry><entry>• Neuroprotective properties involving GSK3β and tau phosphorylation<bibr rid="b80 b81"></bibr><newline></newline>• Additional effects on oxidative stress and apoptotic pathways<bibr rid="b82"></bibr></entry><entry>• Established <i>in vitro</i> evidence for reduction of intracellular APP, Aβ and Fe2+-related neurodegeneration<bibr rid="b80"></bibr><newline></newline>• <i>In vivo</i> evidence of improved synaptic plasticity and cognitive function, and reduced Alzheimer's disease pathology<bibr rid="b82"></bibr><newline></newline>• Established brain penetration<bibr rid="b84 b85"></bibr><newline></newline>• No epidemiological or clinical evidence<newline></newline>• Phase II trials underway</entry><entry>• Clinical and/or epidemiological evidence needed<newline></newline>• Clarification of optimal dosage<newline></newline>• Proof-of-concept study in patients with Alzheimer's disease</entry></row><row><entry>Tetracycline antibiotics</entry><entry>Minocycline</entry><entry>• Reduction of Aβ aggregation, promotion of Aβ clearance and reduction of pro-inflammatory markers<bibr rid="b89 b90 b91 b92"></bibr><newline></newline>• Specific mechanism of action unclear</entry><entry>• <i>In vitro</i> and <i>in vivo</i> evidence for effect on Alzheimer's disease pathology and related inflammatory markers, including microglial activation, with some associated benefit to cognitive function, although this is conflicting<newline></newline>• Benefit seen only with treatment lasting longer than 28 days<bibr rid="b89 b90 b91 b92"></bibr><newline></newline>• No clinical evidence but some promising findings from studies in other neurological conditions<bibr rid="b99 b100 b101"></bibr></entry><entry>• Clinical and/or epidemiological evidence needed<newline></newline>• Clarification of optimal dosage<newline></newline>• Evidence of safety with long-term use<newline></newline>• Proof-of-concept study in patients with Alzheimer's disease</entry></row><row><entry>Retinoid therapy</entry><entry>Acitretin</entry><entry>• Direct effect on APP processing mediated by RXR<bibr rid="b108"></bibr><newline></newline>• Upregulation of amyloid-clearing enzymes<bibr rid="b109"></bibr><newline></newline>• Antioxidant regulation<bibr rid="b118"></bibr></entry><entry>• Established evidence suggesting that impaired retinoic acid signalling may lead to Alzheimer's disease pathology<bibr rid="b105 b106 b107"></bibr><newline></newline>• <i>In vitro</i> evidence for overall mechanistic effect<bibr rid="b107"></bibr><newline></newline>• <i>In vivo</i> evidence for reduction in inflammation, Aβ burden and tau phosphorylation with associated cognitive benefit, although studies are conflicting<bibr rid="b110 b111 b112"></bibr><newline></newline>• No clinical data, but Phase II trial is underway<newline></newline>• Significant safety concerns</entry><entry>• Further <i>in vivo</i> work required to clarify mechanism of action and effect on cognition and behaviour<newline></newline>• Clinical evidence<newline></newline>• Evidence of safety with long-term use<newline></newline>• Clarification of optimal dosage</entry></row><row><entry spanname="1"> Aβ, amyloid-β; APP, amyloid precursor protein; AT<sub>1</sub>, angiotensin II type 1 receptor; GLP1, glucagon-like peptide 1; GSK3β, glycogen synthase kinase 3β; RXR, retinoid X receptor. </entry></row></tbody></tgroup><!--nrd3869-t2--></table><table id="t3" tocentry="0" frame="topbot" colsep="0" rowsep="0" orient="port" pgwide="0" tabcols="6"><title>Ongoing trials in Alzheimer's disease related to priority candidates discussed in this article<super>*</super></title><tgroup cols="6" colsep="0" rowsep="0" align="left"><colspec colnum="1" colname="1" align="left" colwidth="1*"></colspec><colspec colnum="2" colname="2" align="left" colwidth="1*"></colspec><colspec colnum="3" colname="3" align="left" colwidth="1*"></colspec><colspec colnum="4" colname="4" align="left" colwidth="1*"></colspec><colspec colnum="5" colname="5" align="left" colwidth="1*"></colspec><colspec colnum="6" colname="6" align="left" colwidth="1*"></colspec><spanspec namest="1" nameend="6" spanname="1"></spanspec><thead valign="top"><row><entry>Drug</entry><entry>Phase and location</entry><entry>Study description</entry><entry>Status</entry><entry>Estimated completion date</entry><entry>ClinicalTrials.gov identifier</entry></row></thead><tbody valign="top"><row><entry>Acitretin</entry><entry>II Germany</entry><entry>28 days of acitretin treatment (30 mg) in patients with mild to moderate Alzheimer's disease; primary objective is to measure the change in APPsα levels in the CSF</entry><entry>Recruiting<super>‡</super></entry><entry>April 2011<super>‡</super></entry><entry>NCT01078168</entry></row><row><entry>Exenatide</entry><entry>II United States</entry><entry>Drug administered to patients with early Alzheimer's disease or MCI, with planned follow-up using sum of boxes and ADAS-cog for 36 months following treatment; MRI and CSF biomarkers used as secondary measures</entry><entry>Recruiting</entry><entry>January 2013</entry><entry>NCT01255163</entry></row><row><entry>Liraglutide</entry><entry>II Denmark</entry><entry>26 weeks of treatment with liraglutide (intravenously administered) or placebo in patients with mild Alzheimer's disease; primary outcome is amyloid load measured by <super>11</super>C-PiB–PET imaging</entry><entry>Recruiting</entry><entry>June 2013</entry><entry>NCT01469351</entry></row><row><entry>Nilvadipine</entry><entry>III Europe</entry><entry>18-month randomized placebo-controlled trial in 500 patients with Alzheimer's disease across 18 European sites (funded by the European Union)</entry><entry>Finalizing protocol</entry><entry>To be confirmed</entry><entry>To be confirmed</entry></row><row><entry spanname="1"><super>13</super>C-PiB, <super>13</super>C -labelled Pittsburgh compound B; ADAS-cog, Alzheimer's Disease Assessment Scale-cognitive subscale; APPsα, secreted form of amyloid precursor protein (cleaved by α-secretase); CSF, cerebrospinal fluid; MCI, mild cognitive impairment; MRI, magnetic resonance imaging; PET, positron emission tomography. <super>*</super>Based on information in the ClinicalTrials.gov database; accessed October 2012. <super>‡</super>Last verified in September 2010. </entry></row></tbody></tgroup><!--nrd3869-t3--></table><bx id="bx1" placement="external" type="reg"><bxtitle>Box 1 | Requirements for preclinical investigation prior to Phase III trial</bxtitle><p><list id="l1" type="bullet"><li>Determination of dose–response relationships in animal models of Alzheimer's disease</li><li>Determination of the highest dose that can be safely administered on the basis of current preclinical and clinical data</li><li>Understanding the effects and safety associated with chronic administration of the drug</li><li>Understanding pharmacokinetics and pharmacodynamics in animal models and their relationship to humans</li><li>Understanding the course of disease progression and when the optimal time to commence treatment may be to gain maximum efficacy</li><li>Obtaining detailed intra-class comparability data for drug classes for which more than one agent in the class is available</li><li>Measurement of suitable biomarker changes in Phase II clinical trials: <list id="l2" type="bullet"><li>Measuring changes in cerebrospinal fluid (CSF) biomarkers (such as Aβ<sub>1–40</sub>, Aβ<sub>1–42</sub>, phosphorylated tau and inflammatory markers);</li><li>Measuring changes in amyloid load using <super>13</super>C-PCB–PET (<super>13</super>C-labelled Pittsburgh compound B positron emission tomography) imaging;</li><li>Measuring changes in microglial activation and glucose metabolism in the brain using PET imaging;</li><li>Measuring changes in hippocampal atrophy using serial magnetic resonance imaging (MRI);</li><li>Measuring changes in inflammatory markers in blood and CSF.</li></list></li></list></p></bx><bx id="bx2" placement="external" type="reg"><bxtitle>Box 2 | Search terms and parameters</bxtitle><p>Searches were performed in EMBASE, PsycINFO, MEDLINE and Cochrane databases for papers published after 1950. Search terms were as follows: generic class OR specific drug names OR any known alternative name (obtained from the electronic Medicines Compendium (eMC) and the British National Formulary (BNF)) AND Dement<super>*</super> OR Alzheim<super>*</super> OR Cognitive Declin<super>*</super> OR Cognitive Dysfunc<super>*</super> OR Cognitive Impairmen<super>*</super> OR Neuropsych<super>*</super> test<super>*</super>.</p></bx></objects><ack><p>The authors thank: the UK Alzheimer's Society for supporting this work; I. Testad and E. Perry for their contributions to the consensus process; and the UK National Institute for Health Research (NIHR) Biomedical Research Unit at South London and Maudsley UK National Health Service (NHS) Trust/King's College London for supporting the involvement of C.B. in this work.</p></ack><audecl conflct="yes"><explanatory>Clive Holmes is in receipt of a grant from Pfizer to investigate peripherally administered etanercept. 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Aging</jtl><vid>32</vid>, <ppf>1626</ppf>–<ppl>1633</ppl> (<cd year="2011">2011</cd>).</reftxt></bib></bibl></bm></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="eng"><title>Drug repositioning for Alzheimer's disease</title></titleInfo><titleInfo type="alternative" lang="eng" contentType="CDATA"><title>Drug repositioning for Alzheimer's disease</title></titleInfo><name type="personal"><namePart type="given">Anne</namePart><namePart type="family">Corbett</namePart><affiliation>Anne Corbett and Clive Ballard are at the Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.</affiliation><affiliation>A.C. and J.P. contributed equally to this work.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Anne Corbett is lecturer of dementia research at King's College London, UK. She is an established author in the field. Her research interests include prevention of dementia, translational approaches to improving treatment and care, and clinical trials with a particular focus on behavioural and psychological symptoms and care home settings.</description></name><name type="personal"><namePart type="given">James</namePart><namePart type="family">Pickett</namePart><affiliation>James Pickett is at the UK Alzheimer's Society, Devon House, 58 St Katharine's Way, London E1W 1LB, UK.</affiliation><affiliation>A.C. and J.P. contributed equally to this work.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>James Pickett is the senior research manager at the UK Alzheimer's Society the largest care and research charity for people with dementia in the United Kingdom. Previously, he worked for Diabetes UK and Nature Reviews Molecular Cell Biology. James completed his Ph.D. on exocytosis from University of Cambridge, UK, in 2006.</description></name><name type="personal"><namePart type="given">Alistair</namePart><namePart type="family">Burns</namePart><affiliation>Alistair Burns is at the University of Manchester, Oxford Road, Manchester M13 9PT, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Alistair Burns is the National Clinical Director for Dementia in England at the UK Department of Health. He is Professor of Old Age Psychiatry and Vice Dean of the Faculty of Medical and Human Sciences at the University of Manchester, UK, Clinical Director for the Manchester Academic Health Science Centre (MAHSC) and an Honorary Consultant Old-Age Psychiatrist in the Manchester Mental Health and Social Care Trust (MMHSCT). He is editor of the International Journal of Geriatric Psychiatry, assistant editor of the British Journal of Psychiatry and is on the editorial boards of International Psychogeriatrics and Advances in Psychiatric Treatment. His research and clinical interests are in mental health problems of older people, particularly dementia and Alzheimer's disease. He has published over 300 papers and 25 books.</description></name><name type="personal"><namePart type="given">Jonathan</namePart><namePart type="family">Corcoran</namePart><affiliation>Jonathan Corcoran and Emma Jones are at the Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London SE1 1UL, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Jonathan Corcoran is professor of molecular neurobiology at King's College London. He is the director of the Neuroscience Drug Discovery Unit based in the Wolfson Centre for Age-Related Diseases, which carries out hit-to-lead and lead optimization using both in vitro and in vivo assays. His research interests include the development of orally available compounds for central nervous system (CNS) disorders.</description></name><name type="personal"><namePart type="given">Stephen B.</namePart><namePart type="family">Dunnett</namePart><affiliation>Stephen B. Dunnett is at the Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Stephen B. Dunnett is a professor at Cardiff University, Wales, UK, and directs the Brain Repair Group in the School of Biosciences at Cardiff University. His research has pioneered the development of technologies for cell transplantation in animal models of neurodegenerative disease, with a particular focus on Alzheimer's, Parkinson's and Huntington's diseases. His laboratory has an international reputation for systematic behavioural analysis as the basis for refining the efficacy and understanding the mechanisms of action of cell transplantation in animal models of these diseases, and in developing primary embryonic and stem cell transplantation towards clinical application.</description></name><name type="personal"><namePart type="given">Paul</namePart><namePart type="family">Edison</namePart><affiliation>Paul Edison is at Imperial College London, Cyclotron building, Hammersmith Campus, London W12 0NN, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Paul Edison is a clinical senior lecturer in the Centre of Neuroscience at Imperial College London, UK. His research has focused on neuroimaging using novel molecular probes and magnetic resonance techniques for the study of pathophysiological changes associated with Alzheimer's disease and other forms of dementia. He has extensive experience in positron emission tomography (PET) imaging in amyloid, neuroinflammation, glucose metabolism and other neurotransporters in neurodegenerative and neuroinflammatory conditions. He is developing novel therapeutic strategies aimed at preventing the progression of the disease, and he is the chief investigator of large multicentre intervention studies. He also runs a dementia clinic at the Imperial College Healthcare NHS (National Health Service) trust.</description></name><name type="personal"><namePart type="given">Jim J.</namePart><namePart type="family">Hagan</namePart><affiliation>Jim J. Hagan is at the Global Medical Excellence Cluster (GMEC), Hodgkin Building, Guy's Campus, King's College London, London SE1 1UL, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Jim J. Hagan is CEO of GMEC (Global Medical Excellence Cluster), a company created to foster biomedical research between academia and industry. He sits on the board of Imanova, a research imaging company, and was previously vice president of Biology in the Psychiatry Centre of Excellence for Drug Discovery at GlaxoSmithKline. He has published extensively, including a recent volume on molecular and functional models of neuropsychiatric disorders.</description></name><name type="personal"><namePart type="given">Clive</namePart><namePart type="family">Holmes</namePart><affiliation>Clive Holmes is at the University of Southampton, Southampton General Hospital, Mailpoint 801, South Academic Block, Tremona Road, Southampton SO16 6YD, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Clive Holmes trained as a psychiatrist at Kings College London and the Maudsley Hospital, South London. His early research training was in the neurochemistry of Alzheimer's disease at the Institute of Neurology, London, followed by a Ph.D. in the genetics of the neuropsychiatric features of Alzheimer's disease at the Institute of Psychiatry, London. He is currently professor of biological psychiatry at the University of Southampton, UK, where his main interests are in the early diagnosis of dementia, neuropharmacology and the role of immunity in the development and treatment of Alzheimer's disease.</description></name><name type="personal"><namePart type="given">Emma</namePart><namePart type="family">Jones</namePart><affiliation>Jonathan Corcoran and Emma Jones are at the Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London SE1 1UL, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Emma Jones carried out her D.Phil. on microarray analysis of a model of ataxia under the supervision of Professor Kay Davies. Following this, she moved to King's College London and started analysing genetic factors that influence the onset of Alzheimer's disease in people with Down's syndrome. This project was continued during her time as a research fellow for the UK Alzheimer's Society, and she has also worked on clinical trials and biomarkers studies in dementia. She has recently started a post as a lecturer in translational stem cell biology at King's College London.</description></name><name type="personal"><namePart type="given">Cornelius</namePart><namePart type="family">Katona</namePart><affiliation>Cornelius Katona is at University College London, Mental Health Sciences Unit, Faculty of Brain Sciences, London WC1E 6BT, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Cornelius Katona is Emeritus Professor of Psychiatry at the University of Kent, UK, and Honorary Professor of Psychiatry of the Elderly at University College London, UK. His main research interests are in dementia, mood disorders in old age and the mental health of asylum seekers. He has extensive experience of clinical trial work in dementia and in depression. He is the author of over 200 peer-reviewed articles as well as author and/or editor of 15 books. He is co-chair of the World Psychiatric Association section of affective disorders, Chair of the World Federation of Societies of Biological Psychiatry Taskforce on Old Age and co-founder and vice president of the International Society for Affective Disorders. He chaired the Dementia Clinical Studies Group within DeNDRoN (the Dementia and Neurodegenerative Disorders Network) between 2008 and 2012. He has been editor-in-chief of the Journal of Affective Disorders since 1994.</description></name><name type="personal"><namePart type="given">Ian</namePart><namePart type="family">Kearns</namePart><affiliation>Ian Kearns is at AstraZeneca, 2 Kingdom Street, London W2 6BD, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Ian Kearns is a clinical project manager of clinical trials. He has over 10 years of experience in setting up and conducting international clinical studies in a range of therapeutic areas within the pharmaceutical industry. He holds a B.Sc. degree in biochemistry/physiology from Sheffield University, UK, and a Ph.D. in the neurophysiology of memory and learning from Edinburgh University, Scotland, UK.</description></name><name type="personal"><namePart type="given">Patrick</namePart><namePart type="family">Kehoe</namePart><affiliation>Patrick Kehoe is at the University of Bristol, John James Laboratories, Frenchay Hospital, Bristol BS16 1LE, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Patrick Kehoe has, for over a decade, been one of the earliest and biggest proponents of the 'angiotensin hypothesis' in the pathogenesis of Alzheimer's disease. Some of his seminal work has involved reporting positive genetic associations between the angiotensin-converting enzyme (ACE) gene and Alzheimer's disease risk, and he has followed this up with some of the largest haplotype and meta-analyses studies conducted to date. He has published widely on the importance of ACE and related vasoactive enzymes and cellular mechanisms as pathways contributing to the pathogenesis of Alzheimer's disease, and how a number of these already offer viable and potentially significant therapeutic targets for Alzheimer's disease.</description></name><name type="personal"><namePart type="given">Amrit</namePart><namePart type="family">Mudher</namePart><affiliation>Amrit Mudher is at the University of Southampton, Life Sciences Building 85, University Road, Southampton SO17 1BJ, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Amrit Mudher is a lecturer in neurosciences at the University of Southampton. Her D.Phil. (1998) at the University of Oxford, UK, was in rodent models of Alzheimer's disease. In 2001 she was awarded an independent fellowship to establish fruitfly models of tauopathies, which she still works on. She was appointed to her current position in 2004.</description></name><name type="personal"><namePart type="given">Anthony</namePart><namePart type="family">Passmore</namePart><affiliation>Anthony Passmore is at Queen's University Belfast, Centre for Public Health, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Anthony Passmore is Professor of Ageing and Geriatric Medicine at Queen's University Belfast, Northern Ireland, UK. He trained in the Northern Ireland training scheme in Geriatrics and Clinical Pharmacology, spent a year as senior lecturer at Sydney University, Australia, and was appointed as senior lecturer in Belfast in 1993. He established the memory clinic at Belfast City Hospital and leads the local Dementia Research Programme. He has supervised a number of postdoctoral degrees and has been involved in many clinical trials. He has over 200 publications, including papers in the New England Journal of Medicine, Lancet and Stroke.</description></name><name type="personal"><namePart type="given">Nicola</namePart><namePart type="family">Shepherd</namePart><affiliation>Nicola Shepherd is at the Wellcome Trust, Gibbs Building, 215 Euston Road, London NW1 2BE, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Nicola Shepherd is a business development manager in the Technology Transfer Division at the Wellcome Trust and is responsible for the Trust's Translation Fund. As well as managing a number of funded projects, her role involves contract negotiations, due diligence, monitoring patent prosecution and translation strategies leading to commercial exits.</description></name><name type="personal"><namePart type="given">Frank</namePart><namePart type="family">Walsh</namePart><affiliation>Frank Walsh is at the Institute of Psychiatry, King's College London, London SE1 1UL, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Frank Walsh is Director of Research at the school of Biomedical and Health Sciences at King's College London and has held the positions of Executive Vice President of Discovery Research at Wyeth (including oversight of Alzheimer's disease research) and Senior Vice President at GlaxoSmithKline.</description></name><name type="personal"><namePart type="given">Clive</namePart><namePart type="family">Ballard</namePart><affiliation>Anne Corbett and Clive Ballard are at the Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.</affiliation><affiliation>E-mail: clive.ballard@kcl.ac.uk</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Clive Ballard is Professor of Age-Related Diseases at King's College London, Institute of Psychiatry, where he is co-director of the Biomedical Research Unit for Dementia and the Wolfson Centre for Age-Related Diseases. He has published widely in the areas of clinical trials and systematic reviews pertaining to treatments for Alzheimer's disease and other forms of dementia as well as clinicopathological studies, including validation of diagnostic criteria particularly for vascular and synuclein dementias.</description></name><typeOfResource>text</typeOfResource><genre type="article">Perspectives</genre><originInfo><publisher>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</publisher><dateIssued encoding="w3cdtf">2012-11</dateIssued><dateCreated encoding="w3cdtf">2012-11-05</dateCreated><copyrightDate encoding="w3cdtf">2012</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="eng">Existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimer's-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimer's disease.</abstract><relatedItem type="host"><titleInfo><title>Nature Reviews Drug Discovery</title></titleInfo><identifier type="ISSN">1474-1776</identifier><identifier type="eISSN">1474-1784</identifier><part><date>2012</date><detail type="volume"><caption>vol.</caption><number>11</number></detail><detail type="issue"><caption>no.</caption><number>11</number></detail><extent unit="pages"><start>833</start><end>846</end><total>14</total></extent></part></relatedItem><identifier type="istex">6A37E13CBEAD425373FA2EBBB3598916D2A6A7DB</identifier><identifier type="DOI">10.1038/nrd3869</identifier><identifier type="PublisherID">nrd3869</identifier><accessCondition type="use and reproduction" contentType="copyright">©2012 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</accessCondition><recordInfo><recordOrigin>NATURE</recordOrigin><recordIdentifier>/nrd/journal/v11/n11/images/nrd3869-t1.jpg</recordIdentifier><recordIdentifier>/nrd/journal/v11/n11/images/nrd3869-t2.jpg</recordIdentifier><recordIdentifier>/nrd/journal/v11/n11/images/nrd3869-t3.jpg</recordIdentifier></recordInfo></mods></metadata><annexes><json:item><original>true</original><mimetype>application/vnd.ms-powerpoint</mimetype><extension>ppt</extension><uri>https://api.istex.fr/document/6A37E13CBEAD425373FA2EBBB3598916D2A6A7DB/annexes/ppt</uri></json:item></annexes><enrichments><istex:catWosTEI uri="https://api.istex.fr/document/6A37E13CBEAD425373FA2EBBB3598916D2A6A7DB/enrichments/catWos"><teiHeader><profileDesc><textClass><classCode scheme="WOS">PHARMACOLOGY & PHARMACY</classCode><classCode scheme="WOS">BIOTECHNOLOGY & APPLIED MICROBIOLOGY</classCode></textClass></profileDesc></teiHeader></istex:catWosTEI></enrichments><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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