Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses
Identifieur interne : 000E86 ( Main/Corpus ); précédent : 000E85; suivant : 000E87Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses
Auteurs : Lars Bertram ; Rudolph E. TanziSource :
- Nature Reviews Neuroscience [ 1471-003X ] ; 2008-10.
Abstract
The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2)), and one genetic risk factor for late-onset AD (the gene that encodes apolipoprotein E (APOE)). A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades, collectively proposing or refuting the involvement of over 500 different gene candidates. Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk. This Review discusses the putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk factors.
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DOI: 10.1038/nrn2494
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ISTEX:9A457A2B8EE9D7085386C87B4511BADB2AA424C0Le document en format XML
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Tanzi</name><affiliation><mods:affiliation>Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, Massachusetts 02129, USA.</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:9A457A2B8EE9D7085386C87B4511BADB2AA424C0</idno><date when="2008" year="2008">2008</date><idno type="doi">10.1038/nrn2494</idno><idno type="url">https://api.istex.fr/document/9A457A2B8EE9D7085386C87B4511BADB2AA424C0/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">000E86</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses</title><author><name sortKey="Bertram, Lars" sort="Bertram, Lars" uniqKey="Bertram L" first="Lars" last="Bertram">Lars Bertram</name><affiliation><mods:affiliation>Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, Massachusetts 02129, USA.</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: bertram@helix.mgh.harvard.edu</mods:affiliation></affiliation></author><author><name sortKey="Tanzi, Rudolph E" sort="Tanzi, Rudolph E" uniqKey="Tanzi R" first="Rudolph E." last="Tanzi">Rudolph E. Tanzi</name><affiliation><mods:affiliation>Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, Massachusetts 02129, USA.</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Nature Reviews Neuroscience</title><idno type="ISSN">1471-003X</idno><idno type="eISSN">1471-0048</idno><imprint><publisher>Nature Publishing Group</publisher><date type="published" when="2008-10">2008-10</date><biblScope unit="volume">9</biblScope><biblScope unit="issue">10</biblScope><biblScope unit="page" from="768">768</biblScope><biblScope unit="page" to="778">778</biblScope></imprint><idno type="ISSN">1471-003X</idno></series><idno type="istex">9A457A2B8EE9D7085386C87B4511BADB2AA424C0</idno><idno type="DOI">10.1038/nrn2494</idno><idno type="ArticleID">nrn2494</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1471-003X</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="eng">The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2)), and one genetic risk factor for late-onset AD (the gene that encodes apolipoprotein E (APOE)). A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades, collectively proposing or refuting the involvement of over 500 different gene candidates. Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk. This Review discusses the putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk factors.</div></front></TEI><istex><corpusName>nature</corpusName><author><json:item><name>Lars Bertram</name><affiliations><json:string>Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, Massachusetts 02129, USA.</json:string><json:string>E-mail: bertram@helix.mgh.harvard.edu</json:string></affiliations></json:item><json:item><name>Rudolph E. 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Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk. 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After graduating from the medical school at Ruhr University Bochum (Bochum, North Rhine-Westphalia, Germany) in 1997, Bertram began his clinical training at the Alzheimer Centre of the Technical University in Munich (Germany). In 1999 he joined the Genetics and Aging Research Unit at Massachusetts General Hospital as a postdoctoral research fellow. There he received comprehensive training in a wide variety of molecular and statistical genetic techniques, and spearheaded the analyses that led to the identification of new Alzheimer's disease (AD) linkage regions on chromosomes 10 and 9. In 2004 he was appointed to the faculty of Harvard Medical School as Assistant Professor of Neurology. Bertram's main scientific interest is the genetics of neuropsychiatric disorders, in particular AD he is currently spearheading the follow-up of a recently completed 500K genome-wide association analysis in multiplex AD families in R.T.'s laboratory. In addition, he is a principal investigator on his own research projects, which are aimed at identifying and characterizing new early-onset AD genes. Recently Bertram has become interested in developing and applying new bioinformatics methodologies for the large-scale synthesis and meta-analysis of complex-disease genetics data. These projects, on which he is the principle investigator, led to the creation of several gene databases including data concerning AD, Parkinson's disease and schizophrenia.</note><affiliation>Lars Bertram is Assistant Professor of Neurology at Harvard Medical School (Boston, Massachusetts, USA) and Assistant in Genetics at Massachusetts General Hospital (Boston, Massachusetts, USA). After graduating from the medical school at Ruhr University Bochum (Bochum, North Rhine-Westphalia, Germany) in 1997, Bertram began his clinical training at the Alzheimer Centre of the Technical University in Munich (Germany). In 1999 he joined the Genetics and Aging Research Unit at Massachusetts General Hospital as a postdoctoral research fellow. There he received comprehensive training in a wide variety of molecular and statistical genetic techniques, and spearheaded the analyses that led to the identification of new Alzheimer's disease (AD) linkage regions on chromosomes 10 and 9. In 2004 he was appointed to the faculty of Harvard Medical School as Assistant Professor of Neurology. Bertram's main scientific interest is the genetics of neuropsychiatric disorders, in particular AD he is currently spearheading the follow-up of a recently completed 500K genome-wide association analysis in multiplex AD families in R.T.'s laboratory. In addition, he is a principal investigator on his own research projects, which are aimed at identifying and characterizing new early-onset AD genes. Recently Bertram has become interested in developing and applying new bioinformatics methodologies for the large-scale synthesis and meta-analysis of complex-disease genetics data. These projects, on which he is the principle investigator, led to the creation of several gene databases including data concerning AD, Parkinson's disease and schizophrenia.</affiliation><affiliation>Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, Massachusetts 02129, USA.</affiliation></author><author><persName><forename type="first">Rudolph E.</forename><surname>Tanzi</surname></persName><note type="biography">Rudolph Tanzi is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, and Director of the Genetics and Aging Research Unit at Massachusetts General Hospital. In 1980 he participated in the pioneering study that led to the chromosomal location of the Huntingtons' disease gene, the first autosomal disease gene to be localized using genetic markers. In 1987 he isolated the first familial Alzheimer's disease (AD) gene, amyloid precursor protein, and in 1995 he co-discovered the two other familial AD genes, presenilin 1 and presenilin 2. In 1993 Tanzi isolated the gene that is responsible for Wilson's disease, and he has collaborated on the identification of several other neurological-disease genes, including the gene that causes familial amyotrophic lateral sclerosis. Tanzi is also a co-founder of the 'metal hypothesis of Alzheimer's disease', which proposes that zinc and copper are necessary for the formation of neurotoxic assemblies of the AD-associated amyloid- protein. Tanzi has co-authored over 330 research articles and reviews, including 3 of the top 10 most-cited papers in AD research over the past decade. He is also co-author of the trade book Decoding Darkness: The Search for the Genetic Causes of Alzheimer's Disease. Tanzi has received several awards for his work, including The Metropolitan Life Foundation Award, The Potamkin Prize and the Reagan National Alzheimer's Disease Research Award. He is chairman of the Cure Alzheimer's Fund Research Consortium and serves on over 40 editorial and scientific advisory boards. Tanzi has also co-founded two biotechnology companies: Prana Biotechnology, LTD and TorreyPines Therapeutics, Inc., both of which are developing new therapeutics for treating AD.</note><affiliation>Rudolph Tanzi is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, and Director of the Genetics and Aging Research Unit at Massachusetts General Hospital. In 1980 he participated in the pioneering study that led to the chromosomal location of the Huntingtons' disease gene, the first autosomal disease gene to be localized using genetic markers. In 1987 he isolated the first familial Alzheimer's disease (AD) gene, amyloid precursor protein, and in 1995 he co-discovered the two other familial AD genes, presenilin 1 and presenilin 2. In 1993 Tanzi isolated the gene that is responsible for Wilson's disease, and he has collaborated on the identification of several other neurological-disease genes, including the gene that causes familial amyotrophic lateral sclerosis. Tanzi is also a co-founder of the 'metal hypothesis of Alzheimer's disease', which proposes that zinc and copper are necessary for the formation of neurotoxic assemblies of the AD-associated amyloid- protein. Tanzi has co-authored over 330 research articles and reviews, including 3 of the top 10 most-cited papers in AD research over the past decade. He is also co-author of the trade book Decoding Darkness: The Search for the Genetic Causes of Alzheimer's Disease. Tanzi has received several awards for his work, including The Metropolitan Life Foundation Award, The Potamkin Prize and the Reagan National Alzheimer's Disease Research Award. He is chairman of the Cure Alzheimer's Fund Research Consortium and serves on over 40 editorial and scientific advisory boards. Tanzi has also co-founded two biotechnology companies: Prana Biotechnology, LTD and TorreyPines Therapeutics, Inc., both of which are developing new therapeutics for treating AD.</affiliation><affiliation>Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, Massachusetts 02129, USA.</affiliation></author></analytic><monogr><title level="j">Nature Reviews Neuroscience</title><idno type="pISSN">1471-003X</idno><idno type="eISSN">1471-0048</idno><imprint><publisher>Nature Publishing Group</publisher><date type="published" when="2008-10"></date><biblScope unit="volume">9</biblScope><biblScope unit="issue">10</biblScope><biblScope unit="page" from="768">768</biblScope><biblScope unit="page" to="778">778</biblScope></imprint></monogr><idno type="istex">9A457A2B8EE9D7085386C87B4511BADB2AA424C0</idno><idno type="DOI">10.1038/nrn2494</idno><idno type="ArticleID">nrn2494</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2008</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2)), and one genetic risk factor for late-onset AD (the gene that encodes apolipoprotein E (APOE)). A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades, collectively proposing or refuting the involvement of over 500 different gene candidates. Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk. This Review discusses the putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk factors.</p></abstract></profileDesc><revisionDesc><change when="2008-10">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/9A457A2B8EE9D7085386C87B4511BADB2AA424C0/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus nature" 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:entity PUBLIC="-//NatureAmerica//FICI nrn2494-f1//EN" URL="//snapple/web_d/web/npg/nrn/journal/vaop/ncurrent/images/nrn2494-f1" NDATA="ITEM" name="figf1"></istex:entity><istex:entity PUBLIC="-//NatureAmerica//FICI nrn2494-i1//EN" URL="//snapple/web_d/web/npg/nrn/journal/vaop/ncurrent/images/nrn2494-i1" NDATA="ITEM" name="illus1"></istex:entity><istex:entity PUBLIC="-//NatureAmerica//FICI nrn2494-i2//EN" URL="//snapple/web_d/web/npg/nrn/journal/vaop/ncurrent/images/nrn2494-i2" NDATA="ITEM" name="illus2"></istex:entity><istex:entity PUBLIC="-//NatureAmerica//FICI nrn2494-t1//EN" URL="//snapple/web_d/web/npg/nrn/journal/vaop/ncurrent/images/nrn2494-t1" NDATA="ITEM" name="tbl1"></istex:entity><istex:entity PUBLIC="-//NatureAmerica//FICI nrn2494-t2//EN" URL="//snapple/web_d/web/npg/nrn/journal/vaop/ncurrent/images/nrn2494-t2" NDATA="ITEM" name="tbl2"></istex:entity></istex:docType><istex:document><article id="nrn2494" language="eng" publish="issue" relation="no" origsrc="yes"><!--nrn2494--><pubfm><jtl>Nature Reviews Neuroscience</jtl><vol>9</vol><iss>10</iss><idt>200810</idt><categ id="rv"></categ><pp><spn>768</spn><epn>778</epn><cnt>11</cnt></pp><issn type="print">1471-003X</issn><issn type="electronic">1471-0048</issn><cpg><cpy>2008</cpy><cpn>Nature Publishing Group</cpn></cpg><suppinfo id="s1"><suppobj extrefid="nrn2494-s1" format="pdf" filesize="137K"><title>Supplementary information S1 (table)</title><descrip><p>Thirty years of AD genetics</p></descrip></suppobj><suppobj extrefid="nrn2494-s2" format="pdf" filesize="199K"><title>Supplementary information S2 (box)</title><descrip><p>Thirty years of AD genetics</p></descrip></suppobj></suppinfo><doi>10.1038/nrn2494</doi></pubfm><fm><atl>Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses</atl><aug><cau><fnm>Lars</fnm><snm>Bertram</snm><inits>L</inits><orf rid="a1"></orf><corf rid="c1"></corf><bio><p>Lars Bertram is Assistant Professor of Neurology at Harvard Medical School (Boston, Massachusetts, USA) and Assistant in Genetics at Massachusetts General Hospital (Boston, Massachusetts, USA). After graduating from the medical school at Ruhr University Bochum (Bochum, North Rhine-Westphalia, Germany) in 1997, Bertram began his clinical training at the Alzheimer Centre of the Technical University in Munich (Germany). In 1999 he joined the Genetics and Aging Research Unit at Massachusetts General Hospital as a postdoctoral research fellow. There he received comprehensive training in a wide variety of molecular and statistical genetic techniques, and spearheaded the analyses that led to the identification of new Alzheimer's disease (AD) linkage regions on chromosomes 10 and 9. In 2004 he was appointed to the faculty of Harvard Medical School as Assistant Professor of Neurology. Bertram's main scientific interest is the genetics of neuropsychiatric disorders, in particular AD — he is currently spearheading the follow-up of a recently completed 500K genome-wide association analysis in multiplex AD families in R.T.'s laboratory. In addition, he is a principal investigator on his own research projects, which are aimed at identifying and characterizing new early-onset AD genes. Recently Bertram has become interested in developing and applying new bioinformatics methodologies for the large-scale synthesis and meta-analysis of complex-disease genetics data. These projects, on which he is the principle investigator, led to the creation of several gene databases including data concerning AD, Parkinson's disease and schizophrenia.</p></bio></cau><au><fnm>Rudolph E.</fnm><snm>Tanzi</snm><inits>R E</inits><orf rid="a1"></orf><bio><p>Rudolph Tanzi is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, and Director of the Genetics and Aging Research Unit at Massachusetts General Hospital. In 1980 he participated in the pioneering study that led to the chromosomal location of the Huntingtons' disease gene, the first autosomal disease gene to be localized using genetic markers. In 1987 he isolated the first familial Alzheimer's disease (AD) gene, amyloid precursor protein, and in 1995 he co-discovered the two other familial AD genes, presenilin 1 and presenilin 2. In 1993 Tanzi isolated the gene that is responsible for Wilson's disease, and he has collaborated on the identification of several other neurological-disease genes, including the gene that causes familial amyotrophic lateral sclerosis. Tanzi is also a co-founder of the 'metal hypothesis of Alzheimer's disease', which proposes that zinc and copper are necessary for the formation of neurotoxic assemblies of the AD-associated amyloid-β protein. Tanzi has co-authored over 330 research articles and reviews, including 3 of the top 10 most-cited papers in AD research over the past decade. He is also co-author of the trade book <i>Decoding Darkness: The Search for the Genetic Causes of Alzheimer's Disease</i>. Tanzi has received several awards for his work, including The Metropolitan Life Foundation Award, The Potamkin Prize and the Reagan National Alzheimer's Disease Research Award. He is chairman of the Cure Alzheimer's Fund Research Consortium and serves on over 40 editorial and scientific advisory boards. Tanzi has also co-founded two biotechnology companies: Prana Biotechnology, LTD and TorreyPines Therapeutics, Inc., both of which are developing new therapeutics for treating AD.</p></bio></au><aff><oid id="a1"></oid><org>Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital</org>, <street>114 16th Street</street>, <cty>Charlestown</cty>, <st>Massachusetts</st> <zip>02129</zip>, <cny>USA</cny>.</aff><caff><coid id="c1"></coid><email>bertram@helix.mgh.harvard.edu</email></caff></aug><execsumm><p><list id="l1" type="bullet"><li>Alzheimer's disease (AD) is a highly heritable disorder, the genetic underpinnings of which remain incompletely understood despite intense research over the past 30 years.</li><li>Over 1,000 individual genetic-association studies have been published in the field of AD; these studies are exhaustively annotated and systematically meta-analysed in a continuously updated online database called AlzGene.</li><li>Genome-wide association (GWA) studies, which have the potential to pinpoint new pathogenetic pathways by simultaneously testing thousands of genetic markers in a largely hypothesis-free fashion, are becoming increasingly available for AD.</li><li>Over 20 genetic loci currently show evidence for a significant role in modifying risk for AD in the AlzGene meta-analyses. One-third of these were originally described in GWA studies.</li><li>The potential functional and pathogenetic implications of some of the most interesting of these genes (angiotensin I converting enzyme (<i>ACE</i>); cholesterol 25-hydroxylase (<i>CH25H</i>); cholinergic receptor, nicotinic, β2 (<i>CHRNB2</i>); cystatin C (<i>CST3</i>); GRB2-associated binding protein 2 (<i>GAB2</i>); lamin A/C (<i>LMNA</i>); microtubule-associated protein tau (<i>MAPT</i>); prion protein (<i>PRNP</i>); sortilin-related receptor, L(DLR class) A repeats-containing (<i>SORL1</i>) and transferrin (<i>TF</i>)) can now be summarized.</li></list></p></execsumm><websumm>Studies of the genetic causes of Alzheimer's disease have yielded a bewildering array of candidate genes. Bertram and Tanzi describe the results of ongoing systematic meta-analyses of these studies and discuss how some of the risk factors identified might contribute to disease pathology.</websumm><abs><p>The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein (<i>APP</i>) and the presenilins (<i>PSEN1</i> and <i>PSEN2</i>)), and one genetic risk factor for late-onset AD (the gene that encodes apolipoprotein E (<i>APOE</i>)). A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades, collectively proposing or refuting the involvement of over 500 different gene candidates. Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk. This Review discusses the putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk factors.</p></abs></fm></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="eng"><title>Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses</title></titleInfo><titleInfo type="alternative" lang="eng" contentType="CDATA"><title>Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses</title></titleInfo><name type="personal"><namePart type="given">Lars</namePart><namePart type="family">Bertram</namePart><affiliation>Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, Massachusetts 02129, USA.</affiliation><affiliation>E-mail: bertram@helix.mgh.harvard.edu</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Lars Bertram is Assistant Professor of Neurology at Harvard Medical School (Boston, Massachusetts, USA) and Assistant in Genetics at Massachusetts General Hospital (Boston, Massachusetts, USA). After graduating from the medical school at Ruhr University Bochum (Bochum, North Rhine-Westphalia, Germany) in 1997, Bertram began his clinical training at the Alzheimer Centre of the Technical University in Munich (Germany). In 1999 he joined the Genetics and Aging Research Unit at Massachusetts General Hospital as a postdoctoral research fellow. There he received comprehensive training in a wide variety of molecular and statistical genetic techniques, and spearheaded the analyses that led to the identification of new Alzheimer's disease (AD) linkage regions on chromosomes 10 and 9. In 2004 he was appointed to the faculty of Harvard Medical School as Assistant Professor of Neurology. Bertram's main scientific interest is the genetics of neuropsychiatric disorders, in particular AD he is currently spearheading the follow-up of a recently completed 500K genome-wide association analysis in multiplex AD families in R.T.'s laboratory. In addition, he is a principal investigator on his own research projects, which are aimed at identifying and characterizing new early-onset AD genes. Recently Bertram has become interested in developing and applying new bioinformatics methodologies for the large-scale synthesis and meta-analysis of complex-disease genetics data. These projects, on which he is the principle investigator, led to the creation of several gene databases including data concerning AD, Parkinson's disease and schizophrenia.</description></name><name type="personal"><namePart type="given">Rudolph E.</namePart><namePart type="family">Tanzi</namePart><affiliation>Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, Massachusetts 02129, USA.</affiliation><role><roleTerm type="text">author</roleTerm></role><description>Rudolph Tanzi is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, and Director of the Genetics and Aging Research Unit at Massachusetts General Hospital. In 1980 he participated in the pioneering study that led to the chromosomal location of the Huntingtons' disease gene, the first autosomal disease gene to be localized using genetic markers. In 1987 he isolated the first familial Alzheimer's disease (AD) gene, amyloid precursor protein, and in 1995 he co-discovered the two other familial AD genes, presenilin 1 and presenilin 2. In 1993 Tanzi isolated the gene that is responsible for Wilson's disease, and he has collaborated on the identification of several other neurological-disease genes, including the gene that causes familial amyotrophic lateral sclerosis. Tanzi is also a co-founder of the 'metal hypothesis of Alzheimer's disease', which proposes that zinc and copper are necessary for the formation of neurotoxic assemblies of the AD-associated amyloid- protein. Tanzi has co-authored over 330 research articles and reviews, including 3 of the top 10 most-cited papers in AD research over the past decade. He is also co-author of the trade book Decoding Darkness: The Search for the Genetic Causes of Alzheimer's Disease. Tanzi has received several awards for his work, including The Metropolitan Life Foundation Award, The Potamkin Prize and the Reagan National Alzheimer's Disease Research Award. He is chairman of the Cure Alzheimer's Fund Research Consortium and serves on over 40 editorial and scientific advisory boards. Tanzi has also co-founded two biotechnology companies: Prana Biotechnology, LTD and TorreyPines Therapeutics, Inc., both of which are developing new therapeutics for treating AD.</description></name><typeOfResource>text</typeOfResource><genre type="review-article" displayLabel="Review"></genre><originInfo><publisher>Nature Publishing Group</publisher><dateIssued encoding="w3cdtf">2008-10</dateIssued><copyrightDate encoding="w3cdtf">2008</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">The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2)), and one genetic risk factor for late-onset AD (the gene that encodes apolipoprotein E (APOE)). A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades, collectively proposing or refuting the involvement of over 500 different gene candidates. Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk. This Review discusses the putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk factors.</abstract><note type="additional physical form">Supplementary information S1 (table) : Thirty years of AD genetics [nrn2494-s1]</note><note type="additional physical form">Supplementary information S2 (box) : Thirty years of AD genetics [nrn2494-s2]</note><relatedItem type="host"><titleInfo><title>Nature Reviews Neuroscience</title></titleInfo><identifier type="ISSN">1471-003X</identifier><identifier type="eISSN">1471-0048</identifier><part><date>2008</date><detail type="volume"><caption>vol.</caption><number>9</number></detail><detail type="issue"><caption>no.</caption><number>10</number></detail><extent unit="pages"><start>768</start><end>778</end><total>11</total></extent></part></relatedItem><identifier type="istex">9A457A2B8EE9D7085386C87B4511BADB2AA424C0</identifier><identifier type="DOI">10.1038/nrn2494</identifier><identifier type="ArticleID">nrn2494</identifier><accessCondition type="use and reproduction" contentType="copyright">©2008 Nature Publishing Group</accessCondition><recordInfo><recordContentSource>NATURE</recordContentSource></recordInfo></mods></metadata><annexes><json:item><original>true</original><mimetype>application/vnd.ms-powerpoint</mimetype><extension>ppt</extension><uri>https://api.istex.fr/document/9A457A2B8EE9D7085386C87B4511BADB2AA424C0/annexes/ppt</uri></json:item><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/9A457A2B8EE9D7085386C87B4511BADB2AA424C0/annexes/pdf</uri></json:item><json:item><original>true</original><mimetype>image/jpeg</mimetype><extension>jpeg</extension><uri>https://api.istex.fr/document/9A457A2B8EE9D7085386C87B4511BADB2AA424C0/annexes/jpeg</uri></json:item></annexes><enrichments><istex:catWosTEI uri="https://api.istex.fr/document/9A457A2B8EE9D7085386C87B4511BADB2AA424C0/enrichments/catWos"><teiHeader><profileDesc><textClass><classCode scheme="WOS">NEUROSCIENCES</classCode></textClass></profileDesc></teiHeader></istex:catWosTEI></enrichments><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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