array:24 [ "pii" => "S2387020615003605" "issn" => "23870206" "doi" => "10.1016/j.medcle.2014.05.012" "estado" => "S300" "fechaPublicacion" => "2015-07-20" "aid" => "3023" "copyright" => "Elsevier España, S.L.U.. All rights reserved" "copyrightAnyo" => "2014" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Med Clin. 2015;145:76-83" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 28 "formatos" => array:2 [ "HTML" => 18 "PDF" => 10 ] ] "Traduccion" => array:1 [ "es" => array:19 [ "pii" => "S0025775314004060" "issn" => "00257753" "doi" => "10.1016/j.medcli.2014.05.023" "estado" => "S300" "fechaPublicacion" => "2015-07-20" "aid" => "3023" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Med Clin. 2015;145:76-83" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 195 "formatos" => array:2 [ "HTML" => 154 "PDF" => 41 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Revisión</span>" "titulo" => "Enfermedad de Alzheimer: nuevas estrategias terapéuticas" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "76" "paginaFinal" => "83" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Alzheimer's disease: New therapeutic strategies" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figura 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2788 "Ancho" => 2960 "Tamanyo" => 734754 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Estructuras tridimensionales del péptido Aβ y de fragmentos de anticuerpos. (A) Unidad trimérica que conforma los oligómeros Aβ humanos (pdb 2M4J)<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>. Se puede observar cómo la secuencia N-terminal (DAEFR, residuos 1-5) queda expuesta al solvente, mientras que el extremo C-terminal, de naturaleza hidrofóbica, se entierra en el núcleo del trímero. A su vez, el empaquetamiento hidrofóbico entre trímeros genera las fibras amiloideas (no mostrado)<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>. (B) scFv-h3D6 reconoce la región N-terminal 1-5 del péptido Aβ mediante sus CDR<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a>. Los CDR se sitúan en la parte frontal de la imagen (coloreados diferencialmente). Magenta: CDR V<span class="elsevierStyleInf">H</span>; naranja: CDR V<span class="elsevierStyleInf">L</span>; cian: conector. (C) Estructura de un Fab de bapineuzumab en complejo con el péptido Aβ sintético 1-6 (pdb 4HIX)<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a>. Magenta: V<span class="elsevierStyleInf">H</span>; naranja: V<span class="elsevierStyleInf">L</span>; verde: fragmento Aβ. (D) Estructura de un Fab de ponezumab en complejo con el péptido Aβ sintético 30-40 (pdb 3UOT)<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a>. Magenta: V<span class="elsevierStyleInf">H</span>; naranja: V<span class="elsevierStyleInf">L</span>; verde: fragmento Aβ. Disponible en color en la versión online del artículo.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Sandra Villegas" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Sandra" "apellidos" => "Villegas" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020615003605" "doi" => "10.1016/j.medcle.2014.05.012" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020615003605?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775314004060?idApp=UINPBA00004N" "url" => "/00257753/0000014500000002/v1_201506280049/S0025775314004060/v1_201506280049/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S238702061500371X" "issn" => "23870206" "doi" => "10.1016/j.medcle.2015.12.054" "estado" => "S300" "fechaPublicacion" => "2015-07-20" "aid" => "3205" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "sco" "cita" => "Med Clin. 2015;145:84-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 24 "formatos" => array:2 [ "HTML" => 20 "PDF" => 4 ] ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Special article</span>" "titulo" => "Is the recruitment of researchers economically profitable for institutions of the National Health System? The case of the Miguel Servet Programme" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "84" "paginaFinal" => "87" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "¿Es la contratación de investigadores rentable económicamente para los centros del Sistema Nacional de Salud? El caso del Programa Miguel Servet" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Jesús Rey-Rocha, Irene López-Navarro, María Teresa Antonio-García" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Jesús" "apellidos" => "Rey-Rocha" ] 1 => array:2 [ "nombre" => "Irene" "apellidos" => "López-Navarro" ] 2 => array:2 [ "nombre" => "María Teresa" "apellidos" => "Antonio-García" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775315000251" "doi" => "10.1016/j.medcli.2014.12.013" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775315000251?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S238702061500371X?idApp=UINPBA00004N" "url" => "/23870206/0000014500000002/v1_201602250041/S238702061500371X/v1_201602250041/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2387020615003617" "issn" => "23870206" "doi" => "10.1016/j.medcle.2014.04.005" "estado" => "S300" "fechaPublicacion" => "2015-07-20" "aid" => "3025" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Med Clin. 2015;145:70-5" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 35 "formatos" => array:2 [ "HTML" => 31 "PDF" => 4 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "New insulin types in type 1 diabetes mellitus" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "70" "paginaFinal" => "75" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Nuevas insulinas en la diabetes tipo 1" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Jordi Mesa" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Jordi" "apellidos" => "Mesa" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775314004084" "doi" => "10.1016/j.medcli.2014.04.024" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775314004084?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020615003617?idApp=UINPBA00004N" "url" => "/23870206/0000014500000002/v1_201602250041/S2387020615003617/v1_201602250041/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Alzheimer's disease: New therapeutic strategies" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "76" "paginaFinal" => "83" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Sandra Villegas" "autores" => array:1 [ 0 => array:3 [ "nombre" => "Sandra" "apellidos" => "Villegas" "email" => array:1 [ 0 => "sandra.villegas@uab.cat" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Protein Folding and Stability Group, Unitat de Biociències, Departament de Bioquímica i Biología Molecular, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Enfermedad de Alzheimer: nuevas estrategias terapéuticas" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2785 "Ancho" => 2960 "Tamanyo" => 690648 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Threedimensional structures of the Aβ peptide and antibody fragments. (A) Trimeric unit that forms the human Aβ oligomers (pdb <a class="elsevierStyleInterRef" id="intr0005" href="pdb:2M4J">2M4J</a>)<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a>. It can be observed how the N-terminal sequence (DAEFR, residues 1–5) is exposed to the solvent, whereas the C-terminal end, of a hydrophobic nature, buries into the nucleus of the trimer. In turn, the hydrophobic packing between trimers generates amyloid fibres (not shown).<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> (B) scFv-h3D6 recognises the N-terminal region 1–5 of the Aβ peptide by its CDR.<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">46</span></a> The CDR are in the front part of the image (differently coloured). Magenta: CDR V<span class="elsevierStyleInf">H</span>; orange: CDR V<span class="elsevierStyleInf">L</span>; cyan: connector. (C) Structure of a bapineuzumab Fab in complex with the synthetic Aβ peptide 1–6 (pdb <a class="elsevierStyleInterRef" id="intr0010" href="pdb:4HIX">4HIX</a>).<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">40</span></a> Magenta: V<span class="elsevierStyleInf">H</span>; orange: V<span class="elsevierStyleInf">L</span>; green: Aβ fragment. (D) Structure of a ponezumab Fab in complex with the synthetic Aβ peptide 30–40 (pdb <a class="elsevierStyleInterRef" id="intr0015" href="pdb:3UOT">3UOT</a>).<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">54</span></a> Magenta: V<span class="elsevierStyleInf">H</span>; orange: V<span class="elsevierStyleInf">L</span>; green: Aβ fragment. Available in colour in the online version of the article.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In their 2013 report, the Alzheimer's Disease International Organisation, estimated that there were 44.4 million people with dementia worldwide at that time and most cases were attributable to AD.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a> Future projections on the prevalence of the disease are startling, with an estimated 75.6 million cases by the year 2030 and 134.5 million by 2050; therefore, AD is considered a 21st century pandemic. Because the neurodegenerative process can extend over more than a decade, the associated dementia causes suffering to both the patient and their carers, with the consequent social impact. Accordingly, the global economic impact is enormous, the estimated expenditure being 600,000 million dollars for 2010 alone.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In Spain, the prevalence of dementia in 2013 was around 600,000 cases, 67% with AD and 33% with other types of dementia, particularly dementia of vascular origen.<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">3</span></a> Bearing in mind that Spain is one of the European countries with the most ageing population, the future projections are extremely worrying.</p><p id="par0015" class="elsevierStylePara elsevierViewall">At present, there are two types of drugs which have been approved by agencies such as the Food and Drug Administration (U.S.A.) or the European Medicines Agency for treating the symptoms of AD. The first acts on the cholinergic system and the second on the glutamatergic system. Because the disease's main outcome is the death of cholinergic neurones, increased acetylcholine levels partially compensate for the loss of this neurotransmitter.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">4</span></a> Cholinesterase, donepezil, galantamine and rivastigmine inhibitors are used for this purpose. Furthermore, it is known that glutamate increases in patients with AD, as in other neurodegenerative diseases, and that this imbalance results in cell death. Memantine, an N-methyl-<span class="elsevierStyleSmallCaps">d</span>-aspartate receptor antagonist, a subtype of glutamate ionotropic receptors is used for its neuroprotective effect.<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">5</span></a> However, these treatments do not halt the progression of the disease, they have a beneficial effect only in some stages, and are very variable depending on the patient.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Aetiopathology of Alzheimer's disease</span><p id="par0020" class="elsevierStylePara elsevierViewall">The principal histological features of AD are a considerable reduction in the number of cortical cells, and the presence of two types of protein structures, extracellular amyloid plaques and intracellular neurofibrillary tangles. The main component of amyloid deposits is a 4<span class="elsevierStyleHsp" style=""></span>kDa peptide, named the Aβ peptide, which is generated by limited proteolysis of the amyloid precursor protein (APP protein), a transmembrane protein.<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> Neurofibrillary tangles are composed of aberrant microtubule-associated tau, generally hyperphosphorylated and fragmented. Unlike that which occurs with the Aβ peptide, abnormal tau metabolism is linked to other neurodegenerative diseases, known collectively as tauopathies.<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">7</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Depending on the age at which it starts, AD is classified as early-onset, EOAD or late-onset, LOAD, the age between early and late onset being approximately 65. Although 1% to 2% of cases of AD are classified as early onset, fewer than half correspond to the familiar form, which is inherited as an autosomal trait of high penetrance. Non-familial early onset AD is classified along with late onset AD in that it is known as the sporadic form of the disease.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Three genes which cause familial AD are known: the amyloid precursor protein gene (<span class="elsevierStyleItalic">APP</span>, chromosome 21), the presenilin 1 gene (<span class="elsevierStyleItalic">PSEN1</span>, chromosome 14) and the presenilin 2 gene (<span class="elsevierStyleItalic">PSEN2</span>, chromosome 1). The fact that the APP gene is located in chromosome 21 results in a gene dosis effect in Down's syndrome, causing early onset. The presenilins are the constituent enzymes of the secretase complexes which are in charge of processing APP. Missense mutations of the <span class="elsevierStyleItalic">PSEN1</span> gene are the most common cause of familial AD.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The amyloid cascade hypothesis was proposed, based on this information, in which the accumulation of the Aβ peptide in the form of amyloid plaques will trigger the disease. In the last decade it has been demonstrated that the so-called Aβ oligomers are the precursors of these plaques, the cause of the toxicity that leads to neuronal death.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">APP is a glycoprotein of 695–770 residues located in all neurone types, and other tissue, which can be processed through two pathways (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). In the non-amyloidogenic pathway, the sequential proteolytic action of α-secretase and γ-secretase generates soluble APPα (sAPPα), involved in neuronal plasticity, P3 peptide and AICD domain, the latter being associated with the metabolism of cholesterol in the neurones. In the amyloidogenic pathway β-secretase, also known as β-site APP-cleaving enzyme (BACE-1) acts in place of α-secretase, generating the Aβ peptide, of greater length than P3. The difference in size between P3 and Aβ peptide lies in the N-terminal, the end which participates from residue 6 in the β hairpin on which is based the three-dimensional structure of the Aβ trimers, resolved recently from samples from AD patients<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Genetic factors of sporadic Alzheimer's disease</span><p id="par0045" class="elsevierStylePara elsevierViewall">With regard to genetic influence in sporadic AD, the genome-wide association studies (GWAS) point to polymorphisms in the genes of the principal apolipoproteins which transport cholesterol in the central nervous system, apoE and clusterin (apoJ), as risk factors.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a> Clinical and pathological studies indicate that there is a significant association between the deterioration of cerebral lipid homeostasis, vascular changes and the pathophysiology of sporadic AD.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The non-neuronal cells of the central nervous system, especially the astroglia, are the primary producers of apoE, while neurons preferentially express the apoE receptors. It is known that apoE collocalizes with Aβ deposits and plays a role in their clearance and degradation.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">12</span></a> In fact, the human APOE4 allele increases the risk of developing sporadic AD, this may well be because it binds to the Aβ peptide approximately 20 times less avidly than the most common allele in humans, APOE3.<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">13</span></a> A second mechanism has been proposed recently, in which the APOE phenotype would be associated with innate immune response regulation.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">14</span></a> It is known that the lipoproteins which contain ApoE protect the neurons from apoptosis by signalling via the LRP-1 receptor,<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">15</span></a>which is a member of the LDLR family. Furthermore, microglial activation by ApoE, in early stages, appears to delay the progression of AD. However, as the disease advances it appears that the microglia become dysfunctional again and stop phagocytizing and/or degrading the Aβ deposits, which contributes to the progression of the disease. The microglial activation role of ApoE concurs with the role described recently for one of its modulators, apoC-1, as an immunosupressant.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">14</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Apart from being a lipid transporter, apoJ (encoded by the <span class="elsevierStyleItalic">CLU</span> gene) is an extracellular chaperone which is principally secreted by the astroglia which has been found in association with all the extracellular deposits of protein aggregates which cause conformational diseases, including those produced in AD.<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">16</span></a> It is known that apoJ inhibits the formation of aggregates by binding hydrophobic residues exposed to the solvent, and that it forms stable complexes with Aβ oligomers of different sizes. These complexes are eliminated through interaction with megalin (LRP-2), and other receptors of the LDLR family.<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">New non-immunological therapeutic strategies</span><p id="par0060" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the different phase 2–4 clinical trials focussed towards finding treatment for Ad. These trials are set out below according to the type of therapeutic strategy.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Improvement of symptoms using receptor agonists</span><p id="par0065" class="elsevierStylePara elsevierViewall">Various acetylcholine receptor agonists (AChR) are under clinical phase 2.<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">18–20</span></a> These drugs, which are also in clinical trials for attention deficit hyperactivity disorder and schizophrenia, have to date provided negative results for patients with AD. In recent years it has been demonstrated that the cannabinoid receptor CB<span class="elsevierStyleInf">2</span> is augmented in the microglia which surround the amyloid plaques.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> Studies in animal models treated with cannabinoid agonists show that the Aβ peptide is eliminated through the blood–brain barrier. In parallel, in the few clinical trials that have been undertaken to date, the behaviour pattern of patients with AD has been improved, although wider studies are necessary to confirm its beneficial effect.</p><p id="par0070" class="elsevierStylePara elsevierViewall">In any case, these palliative medicines appear to be more effective when they are used as combined treatments in patients with a moderate to severe degree of the disease; this has not been possible to demonstrate in patients with mild to moderate AD.<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">22</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Interference in Aβ peptide aggregation</span><p id="par0075" class="elsevierStylePara elsevierViewall">Alzhemed<span class="elsevierStyleSup">®</span> (tramiprosate, 3APS, homotaurine) is a glycosaminoglycan mimetic designed to bind to the Aβ peptide, which has completed clinical phase 3, although with contradicting results<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">23</span></a> (reviewed in Caltagirone et al.<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">24</span></a>). A similar situation occurs with ELND005 (scyllo-inositol), under phase 2 clinical trial, which interferes directly in the formation of β structures by the Aβ peptide,<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a> although in this case the lack of evidence on the effect of the drug is attributed to the small size of the group studied. In this regard, 2 new phase 2 studies are recruiting a greater number of patients.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a> More positive results have been found with PBT2 in phase 2a, a copper and zinc ionophore which uses these metals to interfere with aggregation.<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">26</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Therefore, at the moment, Alzhemed<span class="elsevierStyleSup">®</span> (3APS) is the only aggregation inhibitor which has reached phase III, and studies came to a halt in 2007. It is currently being marketed as a nutritional supplement, although some studies demonstrate that it promotes inadequate tau aggregation.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Secretases</span><p id="par0085" class="elsevierStylePara elsevierViewall">Inhibition of β-secretase would enable the amyloidogenic pathway to be redirected towards the non-amyloidogenic pathway, as would activation of α-secretase. Various β-secretase inhibitors are undergoing the first efficacy and safety studies in humans, paying particular attention to possible side effects.<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">27</span></a> The activation of α-secretase has been demonstrated in mice as one of the effects of the administration of an mGlu3 ionotropic glutamate receptor agonist (LY379268) expressed by astroglia.<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">28</span></a> In addition, etazolate (EHT0202)–α-secretase activator–has completed clinical phase II with positive results.<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The compounds for inhibiting or modulating γ-secretase activity are in more advanced phases. Flurizan<span class="elsevierStyleSup">®</span> (tarenflurbil/MPC-7869, Myriad Genetics)–an inhibitor–and semagacestat (LY-450139, Eli Lilly)–a modulator–have achieved contradictory results in phase III clinical trials.<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">30</span></a> However, it is clear that both drugs reduce the concentration of Aβ<span class="elsevierStyleInf">1–42</span> peptide, the most amyloidogenic, increasing the concentration of Aβ<span class="elsevierStyleInf">1–38</span> peptide.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Therefore, to date, the only protease inhibitors which have reached phase 3 target γ-secretase, but with contradicting results.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Lipid lowering agents and apolipoproteins</span><p id="par0100" class="elsevierStylePara elsevierViewall">Various statins–HMG-CoA reductase inhibitors–have already completed phase IV,<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a> the results for the most-studied molecule (simvastatin) are negative.<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">31</span></a> Although over the past decade a great number of experimental observations have shown a relationship between alterations in cholesterol homeostasis and AD, a recent meta-analysis yielded inconclusive data.<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">32</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Another therapeutic alternative is the use of mimetic peptides derived from apolipoproteins, which can reproduce their function in part. Peptides derived from apoE span the area of receptor recognition of the very low density lipoproteins (VLDL) and of the low density lipoproteins (LDL); therefore, they reduce plasma cholesterol levels enabling clearance of these lipoproteins. One of these peptides, Ac-hE18A-NH2, also attenuates the development of amyloid plaques in a murine model of Alzheimer's disease, showing an anti-inflammatory effect.<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">33</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">A similar therapeutic strategy is to modulate the expression levels of apoJ with valproic acid, used for its anticonvulsant properties in epilepsy and bipolar disorders. Its effect on healthy individuals is being assessed in phase 0.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Therefore, only the statins have reached phase 4, but without demonstrating a clear beneficial effect. Other therapeutic strategies associated with the function of different apolipoproteins are currently in preclinical phases.</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Immunotherapy</span><p id="par0120" class="elsevierStylePara elsevierViewall">Immunotherapy is a promising tool in the treatment of AD, as is reflected by the great number of clinical trials using this therapeutic strategy<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a> and its recent review.<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">34,35</span></a> This section presents clinical studies which have been completed or which are active, as well as current studies in the preclinical phase.</p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Active immunisation</span><p id="par0125" class="elsevierStylePara elsevierViewall">Active immunisation is based on the administration of antigens, or other molecules, which activate the body's immunological response. The efficacy of active immunisation against the Aβ peptide in the elimination of amyloid plaques was demonstrated in the clinical trial AN-1792,<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">36</span></a> in which a synthetic Aβ<span class="elsevierStyleInf">1–42</span> peptide in aggregate form was used, and the adjuvant QS-21. Although the onset of neuroinflammatory complications made it necessary to stop this trial, follow-up of immunised patients showed clear deceleration of cognitive impairment, even one year after the final dose had been administered.</p><p id="par0130" class="elsevierStylePara elsevierViewall">There is currently a second generation of anti- Aβ vaccinations in phase 2 which, amongst other improvements, use adjuvants which do not activate the immune response acquired via the Th1 cells (which secrete interferon γ), and as occurred with QS-21, but which activate the immune response mediated by the Th2 cells (which secrete interleukin-4). Thus, a humoral response is generated rather than the undesired cellular response. Curiously, ACC-001, an N-terminal fragment of the Aβ peptide conjugated with diphtheria toxin (Janssen and Pfizer),<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">37</span></a> has been tested in the presence of QS-21 in 8 recently-completed studies.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a> Another second generation molecule, CAD106, N-terminal fragment 1–6 encapsulated in virus-derived particles (Novartis),<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">38</span></a> has also recently completed several phase 2 studies.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a> Finally, the use of mimotopes (peptide fragments that mimic antigens), specifically Affitope AD02, which mimics the N-terminal of the Aβ peptide (Affiris AG),<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">39</span></a> has just completed the first phase 2 trial.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Passive immunisation</span><p id="par0135" class="elsevierStylePara elsevierViewall">The main disadvantage of active immunotherapy is the incapacity to intervene once the immune system activates, which makes passive immunotherapy an attractive alternative. Passive immunotherapy is based on recombinant monoclonal antibodies (mAb), in this case targeting the different forms of the Aβ peptide. These antibodies can be obtained in murine models and subsequently humanised (-zumab), or, as with the latest generation, can be directly obtained from human cell lines (-umab). Humanisation consists of substituting the framework region sequences (FR) of mice by the corresponding sequences in humans, maintaining the hypervariable region sequences (or complementary determining regions [CDR]). This means that an immunological reaction against the mAb administered is not provoked, keeping the bond with the antigen intact.</p><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Bapineuzumab (Elan/Wyeth)</span><p id="par0140" class="elsevierStylePara elsevierViewall">In 2000 Bard et al. demonstrated for the first time that the systemic injection in a mouse model of AD (PDAPP) of a specific humanised monoclonal IgG2b antibody for residues 1–5 of the N-terminal of the Aβ peptide (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>C),<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">40</span></a> 3D6-mAb, generated transfer of the antibody to the brain, binding of the antibody to the amyloid plaques, and the induction of microglial phagocytosis (mediated by the Fc fraction of the antibody) of Aβ deposits.<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">41</span></a> This antibody is the precursor of AAB-001 or bapineuzumab, which has been tested in several clinical trials.<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">19,35</span></a> In phase 2 trials, in addition to vasogenic oedema, the side effects of bapineuzumab were in the majority mild and transitory.<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">42</span></a> The oedema observed was associated with the use of high doses, and was found to be more frequent in APOE4 allele carriers. However in subsequent phase 3 studies,<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">43</span></a> which only included patients who were not carriers of this allele, the results were contradictory, and the trial was halted in August.<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">44</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Pfizer and Janssen are currently undertaking phase 1 trials with an improved version of bapineuzumab, AAB-003, designed to reduce the risk of vasogenic oedema and microhaemorrhages.<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">19,35</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Another therapeutic strategy to reduce vasogenic oedema and microhaemorrhages might be the use of single chain variable fragments (scFv), in other words, fragments of the antibody lacking in the Fc portion and therefore, incapable of directly activating the microglia. Single chain variable fragments are obtained by recombinant DNA techniques, and consist of the variable domain of the heavy chain bound by a protein connector to the variable domain of the light chain (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B).<a class="elsevierStyleCrossRefs" href="#bib0525"><span class="elsevierStyleSup">45,46</span></a> The single chain variable fragment scFv-h3D6 is a derivative of bapineuzumab which has recently been shown to be effective in a murine model of AD, 3xTg-AD.<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">47,48</span></a> Five-month old 3xTg-AD females show the first behavioural and psychological symptoms of dementia (similar to BPSD), and a large amount of Aβ oligomers, high apoE and apoJ levels, and neuronal death. Cognitive deficits include memory and learning deficits, and a high swimming speed. After a single 85<span class="elsevierStyleHsp" style=""></span>μg intraperitoneal dose of scFv-h3D6, the swimming speed returned to normal levels, and the memory and learning deficits improved.<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">47</span></a> At a molecular level, the protein extracts revealed a great reduction in Aβ oligomers in the cortex, and the olfactory bulb after treatment.<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">47</span></a> These oligomers are multiples of three units (trimers, hexamers, nonamers and dodecamers), therefore the effectiveness of an antibody fragment targeting the N-terminal end 1–5 removing these species makes sense when observing the threedimensional structure, recently resolved for human oligomers of the Aβ peptide (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A).<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> This structure is based on stacking various trimer units, in which each momomer directs the 5 N-terminal residues towards the solvent.</p><p id="par0155" class="elsevierStylePara elsevierViewall">Another interesting observation with regard to treatment with scFv-h3D6 was its capacity to completely revert the levels of apoE and apoJ apolipoproteins, which are raised in the cortex of the 3xTg-AD.<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">47</span></a> The effect on these apolipoproteins indicates a possible involvement in the clearance of the scFv-Aβ complex which, accordingly, shows a highly hydrophobic surface.<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">45</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Finally, treatment with scFv-h3D6 protected the neurons of the cortex (in preparation), and also protected the deep cerebellar nuclei neurons in 3xTg-AD mice, as 5 days after injection of a single intraperitoneal dose, the number of neurons was the same as in the control used.<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">48</span></a> Thus, scFv-h3D6 shows great therapeutic potential, although more research is required to progress to the desired clinical trial phases.</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Solanezumab (LY2062430, Eli Lilly)</span><p id="par0165" class="elsevierStylePara elsevierViewall">In 2001, DeMattos et al. reported that administration of a humanised IgG1 monoclonal antibody which recognises the central region (16–24) of the Aβ peptide reduced the amyloid burden and increased plasma levels of Aβ, which shows that the antibodies improved clearance from the brain to blood circulation.<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">49</span></a> The monoclonal antibody m266 is the precursor of Eli Lilly's solanezumab, which is currently under phase 3.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a> Solanezumab has not been associated with vasogenic oedema or microhaemorrhage, but it has been associated with high plasma levels of Aβ. In 2012, Lilly announced that 18 months’ treatment with solanezumab significantly improved cognitive impairment in patients with mild AD (combining 2 phase 3 studies). However, it has just been published that a subsequent study indicates that phase 3 of this compound has failed.<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">50</span></a> New phase 3 studies are underway, which are recruiting positron- emission tomography (PET)-positive, asymptomatic patients. PET enables the disease to be diagnosed in the prodromal stage.</p><p id="par0170" class="elsevierStylePara elsevierViewall">In the preclinical phase, we found the solanezumab derivative scFv59. It has been demonstrated that administration using adeno-associated recombinant viruses, injected intramuscularly, increases efflux of Aβ from the brain owing to clearance of peripheral Aβ.<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">51</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Gantenerumab (Hoffmann-La Roche)</span><p id="par0175" class="elsevierStylePara elsevierViewall">This is a completely human IgG1 which simultaneously recognises the N-terminal and the central region of the Aβ peptide. It has just entered phase 3, recruiting, like the solanezumab trial which is in progress, asymptomatic, PET-positive patients.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">34</span></a> In phase 2 trials,<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a> unlike solanezumab, gantenerumab did not increase plasma levels of Aβ, but directly activated the microglia, and phagocytic activity. Microhaemorrhage was one of the side effects observed, and therefore the mechanism of action appears to be more similar to that of bapineuzumab than to that of solanezumab. However, a major difference is that gantenerumab recognises both oligomers and amyloid fibres, whereas bapineuzumab and solanezumab only recognise oligomers.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Crenezumab (MABT5102A, Genentech)</span><p id="par0180" class="elsevierStylePara elsevierViewall">In order to prevent the microglia-mediated proinflammatory effects, oedema and haemorrhages, Genentech have proposed an lgG4 subclass antibody instead of lgG2b (bapineuzumab) or IgG1 (solanezumab, gantenerumab), which was obtained through immunisation with region 1–15 of the Aβ peptide. This antibody recognises protofibrillar species, including Aβ oligomers, while preventing aggregation and promoting disaggregation. The lgG4 subclass does not activate the complement pathway or, therefore, the innate immune response. In previous studies the administration of anti-Aβ lgG4 did not generate oedema, even in APOE4 allele carriers.<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">53</span></a> Young patients (aged 30) are currently being recruited for phase 2, from a Columbian family of 300 individuals who are carriers of the PS1 E280A variant, a dominant mutation which causes early onset AD.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Ponezumab (PF-04360365RN1219, Pfizer)</span><p id="par0185" class="elsevierStylePara elsevierViewall">This is a humanised monoclonal antibody subclass lgG2a which contains 2 mutations (A33S, P331S) designed to eliminate a potential immune effect. Unlike the other Anti-Aβ monoclonal antibodies, ponezumab recognises the C-terminal end (30–40) of the Aβ peptide (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>D).<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">54</span></a> This makes it efficient binding plasma Aβ, which in murine models caused increased serum peptide levels, especially of the 1–40 form, and a reduced amyloid burden in the hippocampus. There is a phase 2 study which is currently recruiting patients, and 2 further phase 2 studies have recently been completed.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">In summary, phase 3 trials have failed for bapineuzumab and solanezumab, gantenerumab has just entered phase 3, and crenezumab and ponezumab are in phase 2. This does not mean that bapineuzumab and solanezumab should be discounted, since in recent years it has been demonstrated that studies with these drugs can fail because they have been performed in stages of the disease which are too advanced. These molecules are currently being redesigned and new clinical studies are being prepared.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a> Another aspect to consider is that for these studies to recruit patients appropriately, in addition to diagnosing the disease in the prodromal stage using PET, there need to be advances in the development of biomarkers predicting progression of the disease before the first symptoms of dementia appear.</p></span></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Other therapeutic strategies in the preclinical phase</span><p id="par0195" class="elsevierStylePara elsevierViewall">In addition to other anti-Aβ antibodies in the preclinical phase or phase 1,<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">34,35</span></a> various antibodies are being tested against different forms of phosphorylated tau, especially those which form part of the neurofibrillary tangles, and also agents that modulate their phosphorylation and aggregation.<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">55</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">More novel strategies include the proposal to reduce the translation of the RNA messenger of APP by control of the secondary structure of its 5′UTR end,<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">56</span></a> and modulating the expression of histones to interfere in its transcript.<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">57</span></a> The recent description of 12 miRNA as biomarkers of AD<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">58</span></a> opens up the possibility of future treatments aimed at control of the disease by gene silencing. In fact, preclinical studies have been registered already, and even one study in phase 0, which evaluate the effect of a lipid-lowering fibrate (gemfibrozil) as a modulator of miRNA-107 levels, the reduction of which in the early stage of the disease affects its progression by the activation of BACE1.<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">59</span></a> Finally, treatment with stem cells is being tested in animal models of AD with positive preliminary results,<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">60</span></a> although its translation to humans will not be immediate.</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conclusions</span><p id="par0205" class="elsevierStylePara elsevierViewall">The rapid increase in the prevalence rates of AD makes treatment directed at preventing, halting and reversing this devastating disease urgently necessary. Despite the advances made in understanding its molecular pathology, there are currently no drugs which can halt its progression.</p><p id="par0210" class="elsevierStylePara elsevierViewall">In clinical phase 2, there are nicotinic acetylcholine receptor agonists, aggregation inhibitors, an α-secretase activator, and various molecules for active immunotherapy. Unfortunately, Alzhemed<span class="elsevierStyleSup">®</span> (glycosaminoglycan) and the inhibitors/modulators of γ-secretase activity produced contradictory results in phase 3.</p><p id="par0215" class="elsevierStylePara elsevierViewall">Passive immunotherapy studies with monoclonal antibodies, either humanised or directly human, are much more advanced. The fact that the phase 3 studies for bapineuzumab and solaneuzumab have recently failed, does not invalidate the potential of immunotherapy, as we are increasingly gaining more information, and new clinical trials are starting in this area. If we take into account that a fragment of bapineuzumab is efficient in removing the trimeric Aβ oligomers from the cortex in a murine model,<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">47</span></a> and that the threedimensional structure of these oligomers extracted from humans is based on stacks of a trimer which leave the N-terminal end 1–5 (which is precisely the epitope recognised by bapineuzumab) exposed to the solvent (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A),<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> it is worth continuing to improve this antibody or the fragments that can be derived from it.</p><p id="par0220" class="elsevierStylePara elsevierViewall">In conclusion, a great deal of research is being devoted to the search for an effective treatment against Alzheimer's disease, and although none has yet been found, it appears that we are on the right track.</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflict of interests</span><p id="par0225" class="elsevierStylePara elsevierViewall">The author has no conflict of interest to declare.</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Financing</span><p id="par0230" class="elsevierStylePara elsevierViewall">FIS-PI13-01330, <span class="elsevierStyleItalic">Instituto de salud Carlos III</span>; SGR2014-0885, Government of Catalonia.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres608699" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec622259" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres608698" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec622260" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Aetiopathology of Alzheimer's disease" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Genetic factors of sporadic Alzheimer's disease" ] 7 => array:3 [ "identificador" => "sec0020" "titulo" => "New non-immunological therapeutic strategies" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Improvement of symptoms using receptor agonists" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Interference in Aβ peptide aggregation" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Secretases" ] 3 => array:2 [ "identificador" => "sec0040" "titulo" => "Lipid lowering agents and apolipoproteins" ] ] ] 8 => array:3 [ "identificador" => "sec0045" "titulo" => "Immunotherapy" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Active immunisation" ] 1 => array:3 [ "identificador" => "sec0055" "titulo" => "Passive immunisation" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "Bapineuzumab (Elan/Wyeth)" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Solanezumab (LY2062430, Eli Lilly)" ] 2 => array:2 [ "identificador" => "sec0070" "titulo" => "Gantenerumab (Hoffmann-La Roche)" ] 3 => array:2 [ "identificador" => "sec0075" "titulo" => "Crenezumab (MABT5102A, Genentech)" ] 4 => array:2 [ "identificador" => "sec0080" "titulo" => "Ponezumab (PF-04360365RN1219, Pfizer)" ] ] ] ] ] 9 => array:2 [ "identificador" => "sec0085" "titulo" => "Other therapeutic strategies in the preclinical phase" ] 10 => array:2 [ "identificador" => "sec0090" "titulo" => "Conclusions" ] 11 => array:2 [ "identificador" => "sec0095" "titulo" => "Conflict of interests" ] 12 => array:2 [ "identificador" => "sec0100" "titulo" => "Financing" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-04-09" "fechaAceptado" => "2014-05-15" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec622259" "palabras" => array:5 [ 0 => "Alzheimer's disease" 1 => "New therapies" 2 => "Immunotherapy" 3 => "Vaccine" 4 => "Amyloid-β" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec622260" "palabras" => array:5 [ 0 => "Enfermedad de Alzheimer" 1 => "Nuevos tratamientos" 2 => "Inmunoterapia" 3 => "Vacuna" 4 => "β-Amiloide" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The rapid increase in prevalence rates of Alzheimer's disease means that treatments to prevent, stop or reverse this devastating disease are urgently needed. Despite advances in understanding its molecular pathology, there are no drugs that can halt its progression. This review takes a tour through phase 2, or higher studies, probing receptor agonist agents interfering with aggregation, inhibitors/modulators of secretases, lipid-lowering agents, and, finally and most extensively, immunotherapy. The fact that phase 3 studies with bapineuzumab and solaneuzumab have recently failed does not invalidate the potential of immunotherapy, as more information is available and new clinical trials are being initiated.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El rápido aumento de las tasas de prevalencia de la enfermedad de Alzheimer hace que se necesiten con urgencia tratamientos dirigidos a prevenir, detener o revertir esta devastadora enfermedad. A pesar de los avances en la comprensión de su patología molecular, todavía no existen fármacos que puedan detener su progresión. Esta revisión hace un recorrido por aquellos estudios en fase 2, o superior, que ensayan agonistas de receptores, sustancias que interfieren en la agregación, inhibidores/moduladores de las secretasas, hipolipidemiantes, y, finalmente y con mayor extensión, las inmunoterapias. El hecho de que recientemente hayan fallado las fases 3 para bapineuzumab y solaneuzumab no invalida el potencial de la inmunoterapia, ya que cada vez disponemos de más información y se están iniciando nuevos ensayos clínicos.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Villegas S. Enfermedad de Alzheimer: nuevas estrategias terapéuticas. Med Clin (Barc). 2015;145:76–83.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2765 "Ancho" => 2503 "Tamanyo" => 361913 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">APP can follow 2 proteolytic processing pathways: the non- amyloidogenic pathway and the amyloidogenic pathway. (A) Upper panel, the action of γ-secretase on fragments C83 and C99 generates the P3 peptide and Aβ peptide, respectively. (B) Lower panel, the Aβ peptide changes in size from 38 to 43 residues; forms 40 and 42 are predominant. Form 42 is the most amyloidogenic because the 2 extra residues that the C-terminal end contains are hydrophobic.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2785 "Ancho" => 2960 "Tamanyo" => 690648 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Threedimensional structures of the Aβ peptide and antibody fragments. (A) Trimeric unit that forms the human Aβ oligomers (pdb <a class="elsevierStyleInterRef" id="intr0005" href="pdb:2M4J">2M4J</a>)<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a>. It can be observed how the N-terminal sequence (DAEFR, residues 1–5) is exposed to the solvent, whereas the C-terminal end, of a hydrophobic nature, buries into the nucleus of the trimer. In turn, the hydrophobic packing between trimers generates amyloid fibres (not shown).<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> (B) scFv-h3D6 recognises the N-terminal region 1–5 of the Aβ peptide by its CDR.<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">46</span></a> The CDR are in the front part of the image (differently coloured). Magenta: CDR V<span class="elsevierStyleInf">H</span>; orange: CDR V<span class="elsevierStyleInf">L</span>; cyan: connector. (C) Structure of a bapineuzumab Fab in complex with the synthetic Aβ peptide 1–6 (pdb <a class="elsevierStyleInterRef" id="intr0010" href="pdb:4HIX">4HIX</a>).<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">40</span></a> Magenta: V<span class="elsevierStyleInf">H</span>; orange: V<span class="elsevierStyleInf">L</span>; green: Aβ fragment. (D) Structure of a ponezumab Fab in complex with the synthetic Aβ peptide 30–40 (pdb <a class="elsevierStyleInterRef" id="intr0015" href="pdb:3UOT">3UOT</a>).<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">54</span></a> Magenta: V<span class="elsevierStyleInf">H</span>; orange: V<span class="elsevierStyleInf">L</span>; green: Aβ fragment. Available in colour in the online version of the article.</p>" ] ] 2 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">HMG-CoA reductase: hydroxymethylglutaryl-coenzyme a reductase.</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>: information obtained on 04-04-2014 from <a class="elsevierStyleInterRef" id="intr0135" href="http://www.clinicaltrials.gov/">http://www.clinicaltrials.gov</a>.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a></p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Therapeutic strategy \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Name (Pharmaceutical Company) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mechanism \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Identifier (Phase) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Ref. \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="6" align="left" valign="top">Receptor agonist</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">AZD3480 (AstraZeneca & Targacept Inc.)</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Nicotinic acetylcholine R. (α4β2)</td><td class="td" title="table-entry " align="left" valign="top">Phase 2b published with negative results \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0390">[18]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><a class="elsevierStyleInterRef" id="intr0020" href="ctgov:NCT01466088">NCT01466088</a> (2) active \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0395">[19]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">MEM3454 (Hoffmann-La Roche)</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Nicotinic acetylcholine R (α7)</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleInterRef" id="intr0025" href="ctgov:NCT00454870">NCT00454870</a> (2), not published (updated 05/2008) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0395">[19]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><a class="elsevierStyleInterRef" id="intr0030" href="ctgov:NCT00884507">NCT00884507</a> (2) recently completed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0395">[19]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">GTS-21/DMXBA/anabaseine(CoMentis)</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Nicotinic acetylcholine R (α7)</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleInterRef" id="intr0035" href="ctgov:NCT00414622">NCT00414622</a> (2), not published (updated 04/2007) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0395">[19]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Reviewed in \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0400">[20]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="5" align="left" valign="top">Interference in aggregation</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Alzhemed/3APS/Tramiprosate/homotaurine (Bellus Health Inc.)</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Glycosaminoglycan that binds Aβ peptide</td><td class="td" title="table-entry " align="left" valign="top">Phase 3 published with contradictory results \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0415">[23]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Reviewed in \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0420">[24]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">ELND005/Scyllo-inositol (Ellan)</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Breaks β structures</td><td class="td" title="table-entry " align="left" valign="top">Phase 2 published with insufficient results \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0425">[25]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><a class="elsevierStyleInterRef" id="intr0040" href="ctgov:NCT01766336">NCT01766336</a> (2) and <a class="elsevierStyleInterRef" id="intr0045" href="ctgov:NCT01735630">NCT01735630</a> (2), recruiting \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0395">[19]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PBT2 (Prana Biotech.) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Copper and zinc ionophore \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase 2 published with positive results \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0430">[26]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="5" align="left" valign="top">Protease inhibitor/activator</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">MK-8931 (Merck Sharp & Dohme Corp.)</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">β-Secretase1 inhibitor (BACE1)</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleInterRef" id="intr0050" href="ctgov:NCT01739348">NCT01739348</a> (2/3) and <a class="elsevierStyleInterRef" id="intr0055" href="ctgov:NCT01953601">NCT01953601</a> (3), recruiting \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0395">[19]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Reviewed in \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0435">[27]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Etazolate/ETH0202(Exonhit) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">α-Secretase activator \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase 2a published with positive results \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0445">[29]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Flurizan/Tarenflurbil/MPC-7869(Myriad Genetics’) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">γ-Secretase modulator \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Phase 3 published with contradictory results</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0450">[30]</a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Semagacestat/LY-450139(Eli Lilly) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">γ-Secretase inhibitor \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Lipid-lowering agents (statins)</td><td class="td" title="table-entry " align="left" valign="top">Simvastatin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HMGCoA reductase inhibitor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase 4 published with negative results \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0455">[31]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Lovastatin</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">HMGCoA reductase inhibitor</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleInterRef" id="intr0060" href="ctgov:NCT00046358">NCT00046358</a> (4), not published (updated 03/2008) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0395">[19]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Inconclusive meta-analysis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0460">[32]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Active immunotherapy</td><td class="td" title="table-entry " align="left" valign="top">ACC-001(Janssen and Pfizer) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N-t Aβ<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>diphtheria toxin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleInterRef" id="intr0065" href="ctgov:NCT01227564">NCT01227564</a> (2), recruiting8 studies (2) recently completed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0485">[37]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CAD106(Novartis) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N-t Aβ (1–6) encapsulated in viral particles \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 studies (2) recently completed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0490">[38]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Affitope AD02 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N-t Aβ mimotype \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleInterRef" id="intr0070" href="ctgov:NCT02008513">NCT02008513</a> (2), recruiting<a class="elsevierStyleInterRef" id="intr0075" href="ctgov:NCT01117818">NCT01117818</a> (2), recently completed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0495">[39]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="8" align="left" valign="top">Passive immunotherapy</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Bapineuzumab/AAB-001 (Elan/Wyeth)</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">mAb anti-N-t Aβ (1–5), IgG2b subclass</td><td class="td" title="table-entry " align="left" valign="top">Phase 3 published with contradictory results \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0515">[43]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Reviewed in \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0475">[35]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Solanezumab/LY2062430 (Eli Lilly)</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">mAb anti-central region Aβ (16–24), IgG1 subclass</td><td class="td" title="table-entry " align="left" valign="top">Phase 3 published with negative results \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0550">[50]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><a class="elsevierStyleInterRef" id="intr0080" href="ctgov:NCT01127633">NCT01127633</a> (3), active <a class="elsevierStyleInterRef" id="intr0085" href="ctgov:NCT02008357">NCT02008357</a> (3), <a class="elsevierStyleInterRef" id="intr0090" href="ctgov:NCT01760005">NCT01760005</a> (3) & <a class="elsevierStyleInterRef" id="intr0095" href="ctgov:NCT01900665">NCT01900665</a> (3), recruiting \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0395">[19]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Gantenerumab (Hoffmann-La Roche)</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">mAb anti-N-t Aβ (1–10) and -central region Aβ (23–25), IgG1 subclass</td><td class="td" title="table-entry " align="left" valign="top">Phase 2 published with positive results, transitory inflammation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0560">[52]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><a class="elsevierStyleInterRef" id="intr0100" href="ctgov:NCT01224106">NCT01224106</a> (3) & <a class="elsevierStyleInterRef" id="intr0105" href="ctgov:NCT02051608">NCT02051608</a> (3), recruiting \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0395">[19]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Crenezumab/MABT5102A (Genentech) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">mAb anti-N-t Aβ (1–15) conformational, IgG4 subclass \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleInterRef" id="intr0110" href="ctgov:NCT01723826">NCT01723826</a> (2) <a class="elsevierStyleInterRef" id="intr0115" href="ctgov:NCT01998841">NCT01998841</a> (2), recruiting \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0395">[19]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ponezumab/PF-04360365RN1219 (Pfizer) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">mAb anti-C-t Aβ (30–40), IgG2a subclass \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleInterRef" id="intr0120" href="ctgov:NCT01821118">NCT01821118</a> (2) recruiting <a class="elsevierStyleInterRef" id="intr0125" href="ctgov:NCT00945672">NCT00945672</a> (2) & <a class="elsevierStyleInterRef" id="intr0130" href="ctgov:NCT00722046">NCT00722046</a> (2) recently completed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0395">[19]</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab996550.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Clinical trials in phases 2–4 with different approaches aimed at palliating and curing Alzheimer's disease.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:60 [ 0 => array:3 [ "identificador" => "bib0305" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Alzheimer's Disease International. 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Alzheimer's disease: New therapeutic strategies
Enfermedad de Alzheimer: nuevas estrategias terapéuticas
Sandra Villegas
Protein Folding and Stability Group, Unitat de Biociències, Departament de Bioquímica i Biología Molecular, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, Spain