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1. Clinical value of plasma pTau181 to predict Alzheimer's disease pathology in a large real-world cohort of a memory clinicResearch in context

Author: Amanda Cano, María Capdevila, Raquel Puerta, Javier Arranz, Laura Montrreal, Itziar de Rojas, Pablo García-González, Claudia Olivé, Fernando García-Gutiérrez, Oscar Sotolongo-Grau, Adelina Orellana, Nuria Aguilera, Maribel Ramis, Maitee Rosende-Roca, Alberto Lleó, Juan Fortea, Juan Pablo Tartari, Asunción Lafuente, Liliana Vargas, Alba Pérez-Cordón, Nathalia Muñoz, Ángela Sanabria, Montserrat Alegret, Xavier Morató, Lluís Tárraga, Victoria Fernández, Marta Marquié, Sergi Valero, Daniel Alcolea, Mercè Boada, and Agustín Ruiz
Subjects: Plasma biomarkers, pTau181, Alzheimer's disease, Prodromal AD, Mild cognitive impairment, Real-world cohort, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: The identification of patients with an elevated risk of developing Alzheimer's disease (AD) dementia and eligible for the disease-modifying treatments (DMTs) in the earliest stages is one of the greatest challenges in the clinical practice. Plasma biomarkers has the potential to predict these issues, but further research is still needed to translate them to clinical practice. Here we evaluated the clinical applicability of plasma pTau181 as a predictive marker of AD pathology in a large real-world cohort of a memory clinic. Methods: Three independent cohorts (modelling [n = 991, 59.7% female], testing [n = 642, 56.2% female] and validation [n = 441, 55.1% female]) of real-world patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD dementia, and other dementias were included. Paired cerebrospinal fluid (CSF) and plasma samples were used to measure AT(N) CSF biomarkers and plasma pTau181. Findings: CSF and plasma pTau181 showed correlation in all phenotypes except in SCD and other dementias. Age significantly influenced the biomarker's performance. The general Aβ(+) vs Aβ(−) ROC curve showed an AUC = 0.77 [0.74–0.80], whereas the specific ROC curve of MCI due to AD vs non-AD MCI showed an AUC = 0.89 [0.85–0.93]. A cut-off value of 1.30 pg/ml of plasma pTau181 exhibited a sensitivity of 93.57% [88.72–96.52], specificity of 72.38% [62.51–79.01], VPP of 77.85% [70.61–83.54], and 8.30% false negatives in the subjects with MCI of the testing cohort. The HR of cox regression showed that patients with MCI up to this cut-off value exhibited a HR = 1.84 [1.05–3.22] higher risk to convert to AD dementia than patients with MCI below the cut-off value. Interpretation: Plasma pTau181 has the potential to be used in the memory clinics as a screening biomarker of AD pathology in subjects with MCI, presenting a valuable prognostic utility in predicting the MCI conversion to AD dementia. In the context of a real-world population, a confirmatory test employing gold-standard procedures is still advisable. Funding: This study has been mainly funded by Ace Alzheimer Center Barcelona, Instituto de Salud Carlos III (ISCIII), Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Spanish Ministry of Science and Innovation, Fundación ADEY, Fundación Echevarne and Grífols S.A.
Published: 2024
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2. Macular vessel density in the superficial plexus is not a proxy of cerebrovascular damage in non-demented individuals: data from the NORFACE cohort

Author: Ainhoa García-Sánchez, Oscar Sotolongo-Grau, Juan Pablo Tartari, Ángela Sanabria, Ester Esteban - De Antonio, Alba Pérez-Cordón, Montserrat Alegret, Vanesa Pytel, Joan Martínez, Núria Aguilera, Itziar de Rojas, Amanda Cano, Pablo García-González, Raquel Puerta, Clàudia Olivé, Maria Capdevila, Fernando García-Gutiérrez, Assumpta Vivas, Marta Gómez-Chiari, Juan Giménez, Miguel Ángel Tejero, Miguel Castilla-Martí, Luis Castilla-Martí, Lluís Tárraga, Sergi Valero, Agustín Ruiz, Mercè Boada, Marta Marquié, on behalf of the FACEHBI study group, and on behalf of the BIOFACE study group
Subjects: Vessel density, Optical coherence tomography-angiography, Cerebrovascular damage, Brain atrophy, NORFACE, FACEHBI, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Introduction Optical coherence tomography angiography (OCT-A) is a novel tool that allows the detection of retinal vascular changes. We investigated the association of macular vessel density (VD) in the superficial plexus assessed by OCT-A with measures of cerebrovascular pathology and atrophy quantified by brain magnetic resonance imaging (MRI) in non-demented individuals. Methods Clinical, demographical, OCT-A, and brain MRI data from non-demented research participants were included. We analyzed the association of regional macular VD with brain vascular burden using the Fazekas scale assessed in a logistic regression analysis, and the volume of white matter hyperintensities (WMH) assessed in a multiple linear regression analysis. We also explored the associations of macular VD with hippocampal volume, ventricle volume and Alzheimer disease cortical signature (ADCS) thickness assessed in multiple linear regression analyses. All analyses were adjusted for age, sex, syndromic diagnosis and cardiovascular variables. Results The study cohort comprised 188 participants: 89 with subjective cognitive decline and 99 with mild cognitive impairment. No significant association of regional macular VD with the Fazekas categories (all, p > 0.111) and WMH volume (all, p > 0.051) were detected. VD in the nasal quadrant was associated to hippocampal volume (p = 0.007), but no other associations of macular VD with brain atrophy measures were detected (all, p > 0.05). Discussion Retinal vascular measures were not a proxy of cerebrovascular damage in non-demented individuals, while VD in the nasal quadrant was associated with hippocampal atrophy independently of the amyloid status.
Published: 2024
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3. Automatized FACEmemory® scoring is related to Alzheimer’s disease phenotype and biomarkers in early-onset mild cognitive impairment: the BIOFACE cohort

Author: Montserrat Alegret, Oscar Sotolongo-Grau, Ester Esteban de Antonio, Alba Pérez-Cordón, Adelina Orellana, Ana Espinosa, Silvia Gil, Daniel Jiménez, Gemma Ortega, Angela Sanabria, Natalia Roberto, Isabel Hernández, Maitee Rosende-Roca, Juan Pablo Tartari, Emilio Alarcon-Martin, Itziar de Rojas, Laura Montrreal, Xavier Morató, Amanda Cano, Dorene M. Rentz, Lluís Tárraga, Agustín Ruiz, Sergi Valero, Marta Marquié, and Mercè Boada
Subjects: Endophenotype, Early detection, Alzheimer’s disease, New technologies, Episodic memory, Computerized assessment, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Background FACEmemory® is the first computerized, self-administered verbal episodic memory test with voice recognition. It can be conducted under minimal supervision and contains an automatic scoring system to avoid administrator errors. Moreover, it is suitable for discriminating between cognitively healthy and amnestic mild cognitive impairment (MCI) individuals, and it is associated with Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers. This study aimed to determine whether FACEmemory scoring is related to performance on classical memory tests and to AD biomarkers of brain magnetic resonance imaging (MRI) and CSF in patients with early-onset MCI (EOMCI). Methods Ninety-four patients with EOMCI from the BIOFACE study completed FACEmemory, classical memory tests (the Spanish version of the Word Free and Cued Selective Reminding Test -FCSRT-, the Word List from the Wechsler Memory Scale, third edition, and the Spanish version of the Rey–Osterrieth Complex Figure Test), and a brain MRI. Eighty-two individuals also underwent a lumbar puncture. Results FACEmemory scoring was moderately correlated with FCSRT scoring. With regard to neuroimaging MRI results, worse execution on FACEmemory was associated with lower cortical volume in the right prefrontal and inferior parietal areas, along with the left temporal and associative occipital areas. Moreover, the total FACEmemory score correlated with CSF AD biomarkers (Aβ1-42/Aβ1-40 ratio, p181-tau, and Aβ1-42/p181-tau ratio). When performance on FACEmemory was compared among the ATN classification groups, significant differences between the AD group and normal and SNAP groups were found. Conclusions FACEmemory is a promising tool for detecting memory deficits sensitive to early-onset AD, but it also allows the detection of memory-impaired cases due to other etiologies. Our findings suggest that FACEmemory scoring can detect the AD endophenotype and that it is also associated with AD-related changes in MRI and CSF in patients with EOMCI. The computerized FACEmemory tool might be an opportunity to facilitate early detection of MCI in younger people than 65, who have a growing interest in new technologies.
Published: 2022
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4. Author Correction: Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Author: Itziar de Rojas, Sonia Moreno-Grau, Niccolo Tesi, Benjamin Grenier-Boley, Victor Andrade, Iris E. Jansen, Nancy L. Pedersen, Najada Stringa, Anna Zettergren, Isabel Hernández, Laura Montrreal, Carmen Antúnez, Anna Antonell, Rick M. Tankard, Joshua C. Bis, Rebecca Sims, Céline Bellenguez, Inés Quintela, Antonio González-Perez, Miguel Calero, Emilio Franco-Macías, Juan Macías, Rafael Blesa, Laura Cervera-Carles, Manuel Menéndez-González, Ana Frank-García, Jose Luís Royo, Fermin Moreno, Raquel Huerto Vilas, Miquel Baquero, Mónica Diez-Fairen, Carmen Lage, Sebastián García-Madrona, Pablo García-González, Emilio Alarcón-Martín, Sergi Valero, Oscar Sotolongo-Grau, Abbe Ullgren, Adam C. Naj, Afina W. Lemstra, Alba Benaque, Alba Pérez-Cordón, Alberto Benussi, Alberto Rábano, Alessandro Padovani, Alessio Squassina, Alexandre de Mendonça, Alfonso Arias Pastor, Almar A. L. Kok, Alun Meggy, Ana Belén Pastor, Ana Espinosa, Anaïs Corma-Gómez, Angel Martín Montes, Ángela Sanabria, Anita L. DeStefano, Anja Schneider, Annakaisa Haapasalo, Anne Kinhult Ståhlbom, Anne Tybjærg-Hansen, Annette M. Hartmann, Annika Spottke, Arturo Corbatón-Anchuelo, Arvid Rongve, Barbara Borroni, Beatrice Arosio, Benedetta Nacmias, Børge G. Nordestgaard, Brian W. Kunkle, Camille Charbonnier, Carla Abdelnour, Carlo Masullo, Carmen Martínez Rodríguez, Carmen Muñoz-Fernandez, Carole Dufouil, Caroline Graff, Catarina B. Ferreira, Caterina Chillotti, Chandra A. Reynolds, Chiara Fenoglio, Christine Van Broeckhoven, Christopher Clark, Claudia Pisanu, Claudia L. Satizabal, Clive Holmes, Dolores Buiza-Rueda, Dag Aarsland, Dan Rujescu, Daniel Alcolea, Daniela Galimberti, David Wallon, Davide Seripa, Edna Grünblatt, Efthimios Dardiotis, Emrah Düzel, Elio Scarpini, Elisa Conti, Elisa Rubino, Ellen Gelpi, Eloy Rodriguez-Rodriguez, Emmanuelle Duron, Eric Boerwinkle, Evelyn Ferri, Fabrizio Tagliavini, Fahri Küçükali, Florence Pasquier, Florentino Sanchez-Garcia, Francesca Mangialasche, Frank Jessen, Gaël Nicolas, Geir Selbæk, Gemma Ortega, Geneviève Chêne, Georgios Hadjigeorgiou, Giacomina Rossi, Gianfranco Spalletta, Giorgio Giaccone, Giulia Grande, Giuliano Binetti, Goran Papenberg, Harald Hampel, Henri Bailly, Henrik Zetterberg, Hilkka Soininen, Ida K. Karlsson, Ignacio Alvarez, Ildebrando Appollonio, Ina Giegling, Ingmar Skoog, Ingvild Saltvedt, Innocenzo Rainero, Irene Rosas Allende, Jakub Hort, Janine Diehl-Schmid, Jasper Van Dongen, Jean-Sebastien Vidal, Jenni Lehtisalo, Jens Wiltfang, Jesper Qvist Thomassen, Johannes Kornhuber, Jonathan L. Haines, Jonathan Vogelgsang, Juan A. Pineda, Juan Fortea, Julius Popp, Jürgen Deckert, Katharina Buerger, Kevin Morgan, Klaus Fließbach, Kristel Sleegers, Laura Molina-Porcel, Lena Kilander, Leonie Weinhold, Lindsay A. Farrer, Li-San Wang, Luca Kleineidam, Lucia Farotti, Lucilla Parnetti, Lucio Tremolizzo, Lucrezia Hausner, Luisa Benussi, Lutz Froelich, M. Arfan Ikram, M. Candida Deniz-Naranjo, Magda Tsolaki, Maitée Rosende-Roca, Malin Löwenmark, Marc Hulsman, Marco Spallazzi, Margaret A. Pericak-Vance, Margaret Esiri, María Bernal Sánchez-Arjona, Maria Carolina Dalmasso, María Teresa Martínez-Larrad, Marina Arcaro, Markus M. Nöthen, Marta Fernández-Fuertes, Martin Dichgans, Martin Ingelsson, Martin J. Herrmann, Martin Scherer, Martin Vyhnalek, Mary H. Kosmidis, Mary Yannakoulia, Matthias Schmid, Michael Ewers, Michael T. Heneka, Michael Wagner, Michela Scamosci, Miia Kivipelto, Mikko Hiltunen, Miren Zulaica, Montserrat Alegret, Myriam Fornage, Natalia Roberto, Natasja M. van Schoor, Nazib M. Seidu, Nerisa Banaj, Nicola J. Armstrong, Nikolaos Scarmeas, Norbert Scherbaum, Oliver Goldhardt, Oliver Hanon, Oliver Peters, Olivia Anna Skrobot, Olivier Quenez, Ondrej Lerch, Paola Bossù, Paolo Caffarra, Paolo Dionigi Rossi, Paraskevi Sakka, Patrizia Mecocci, Per Hoffmann, Peter A. Holmans, Peter Fischer, Peter Riederer, Qiong Yang, Rachel Marshall, Rajesh N. Kalaria, Richard Mayeux, Rik Vandenberghe, Roberta Cecchetti, Roberta Ghidoni, Ruth Frikke-Schmidt, Sandro Sorbi, Sara Hägg, Sebastiaan Engelborghs, Seppo Helisalmi, Sigrid Botne Sando, Silke Kern, Silvana Archetti, Silvia Boschi, Silvia Fostinelli, Silvia Gil, Silvia Mendoza, Simon Mead, Simona Ciccone, Srdjan Djurovic, Stefanie Heilmann-Heimbach, Steffi Riedel-Heller, Teemu Kuulasmaa, Teodoro del Ser, Thibaud Lebouvier, Thomas Polak, Tiia Ngandu, Timo Grimmer, Valentina Bessi, Valentina Escott-Price, Vilmantas Giedraitis, Vincent Deramecourt, Wolfgang Maier, Xueqiu Jian, Yolande A. L. Pijnenburg, EADB contributors, DEGESCO consortium, IGAP (ADGC, CHARGE, EADI, GERAD), PGC-ALZ consortia, Patrick Gavin Kehoe, Guillermo Garcia-Ribas, Pascual Sánchez-Juan, Pau Pastor, Jordi Pérez-Tur, Gerard Piñol-Ripoll, Adolfo Lopez de Munain, Jose María García-Alberca, María J. Bullido, Victoria Álvarez, Alberto Lleó, Luis M. Real, Pablo Mir, Miguel Medina, Philip Scheltens, Henne Holstege, Marta Marquié, María Eugenia Sáez, Ángel Carracedo, Philippe Amouyel, Gerard D. Schellenberg, Julie Williams, Sudha Seshadri, Cornelia M. van Duijn, Karen A. Mather, Raquel Sánchez-Valle, Manuel Serrano-Ríos, Adelina Orellana, Lluís Tárraga, Kaj Blennow, Martijn Huisman, Ole A. Andreassen, Danielle Posthuma, Jordi Clarimón, Mercè Boada, Wiesje M. van der Flier, Alfredo Ramirez, Jean-Charles Lambert, Sven J. van der Lee, and Agustín Ruiz
Subjects: Science
Published: 2023
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5. Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Author: Itziar de Rojas, Sonia Moreno-Grau, Niccolo Tesi, Benjamin Grenier-Boley, Victor Andrade, Iris E. Jansen, Nancy L. Pedersen, Najada Stringa, Anna Zettergren, Isabel Hernández, Laura Montrreal, Carmen Antúnez, Anna Antonell, Rick M. Tankard, Joshua C. Bis, Rebecca Sims, Céline Bellenguez, Inés Quintela, Antonio González-Perez, Miguel Calero, Emilio Franco-Macías, Juan Macías, Rafael Blesa, Laura Cervera-Carles, Manuel Menéndez-González, Ana Frank-García, Jose Luís Royo, Fermin Moreno, Raquel Huerto Vilas, Miquel Baquero, Mónica Diez-Fairen, Carmen Lage, Sebastián García-Madrona, Pablo García-González, Emilio Alarcón-Martín, Sergi Valero, Oscar Sotolongo-Grau, Abbe Ullgren, Adam C. Naj, Afina W. Lemstra, Alba Benaque, Alba Pérez-Cordón, Alberto Benussi, Alberto Rábano, Alessandro Padovani, Alessio Squassina, Alexandre de Mendonça, Alfonso Arias Pastor, Almar A. L. Kok, Alun Meggy, Ana Belén Pastor, Ana Espinosa, Anaïs Corma-Gómez, Angel Martín Montes, Ángela Sanabria, Anita L. DeStefano, Anja Schneider, Annakaisa Haapasalo, Anne Kinhult Ståhlbom, Anne Tybjærg-Hansen, Annette M. Hartmann, Annika Spottke, Arturo Corbatón-Anchuelo, Arvid Rongve, Barbara Borroni, Beatrice Arosio, Benedetta Nacmias, Børge G. Nordestgaard, Brian W. Kunkle, Camille Charbonnier, Carla Abdelnour, Carlo Masullo, Carmen Martínez Rodríguez, Carmen Muñoz-Fernandez, Carole Dufouil, Caroline Graff, Catarina B. Ferreira, Caterina Chillotti, Chandra A. Reynolds, Chiara Fenoglio, Christine Van Broeckhoven, Christopher Clark, Claudia Pisanu, Claudia L. Satizabal, Clive Holmes, Dolores Buiza-Rueda, Dag Aarsland, Dan Rujescu, Daniel Alcolea, Daniela Galimberti, David Wallon, Davide Seripa, Edna Grünblatt, Efthimios Dardiotis, Emrah Düzel, Elio Scarpini, Elisa Conti, Elisa Rubino, Ellen Gelpi, Eloy Rodriguez-Rodriguez, Emmanuelle Duron, Eric Boerwinkle, Evelyn Ferri, Fabrizio Tagliavini, Fahri Küçükali, Florence Pasquier, Florentino Sanchez-Garcia, Francesca Mangialasche, Frank Jessen, Gaël Nicolas, Geir Selbæk, Gemma Ortega, Geneviève Chêne, Georgios Hadjigeorgiou, Giacomina Rossi, Gianfranco Spalletta, Giorgio Giaccone, Giulia Grande, Giuliano Binetti, Goran Papenberg, Harald Hampel, Henri Bailly, Henrik Zetterberg, Hilkka Soininen, Ida K. Karlsson, Ignacio Alvarez, Ildebrando Appollonio, Ina Giegling, Ingmar Skoog, Ingvild Saltvedt, Innocenzo Rainero, Irene Rosas Allende, Jakub Hort, Janine Diehl-Schmid, Jasper Van Dongen, Jean-Sebastien Vidal, Jenni Lehtisalo, Jens Wiltfang, Jesper Qvist Thomassen, Johannes Kornhuber, Jonathan L. Haines, Jonathan Vogelgsang, Juan A. Pineda, Juan Fortea, Julius Popp, Jürgen Deckert, Katharina Buerger, Kevin Morgan, Klaus Fließbach, Kristel Sleegers, Laura Molina-Porcel, Lena Kilander, Leonie Weinhold, Lindsay A. Farrer, Li-San Wang, Luca Kleineidam, Lucia Farotti, Lucilla Parnetti, Lucio Tremolizzo, Lucrezia Hausner, Luisa Benussi, Lutz Froelich, M. Arfan Ikram, M. Candida Deniz-Naranjo, Magda Tsolaki, Maitée Rosende-Roca, Malin Löwenmark, Marc Hulsman, Marco Spallazzi, Margaret A. Pericak-Vance, Margaret Esiri, María Bernal Sánchez-Arjona, Maria Carolina Dalmasso, María Teresa Martínez-Larrad, Marina Arcaro, Markus M. Nöthen, Marta Fernández-Fuertes, Martin Dichgans, Martin Ingelsson, Martin J. Herrmann, Martin Scherer, Martin Vyhnalek, Mary H. Kosmidis, Mary Yannakoulia, Matthias Schmid, Michael Ewers, Michael T. Heneka, Michael Wagner, Michela Scamosci, Miia Kivipelto, Mikko Hiltunen, Miren Zulaica, Montserrat Alegret, Myriam Fornage, Natalia Roberto, Natasja M. van Schoor, Nazib M. Seidu, Nerisa Banaj, Nicola J. Armstrong, Nikolaos Scarmeas, Norbert Scherbaum, Oliver Goldhardt, Oliver Hanon, Oliver Peters, Olivia Anna Skrobot, Olivier Quenez, Ondrej Lerch, Paola Bossù, Paolo Caffarra, Paolo Dionigi Rossi, Paraskevi Sakka, Per Hoffmann, Peter A. Holmans, Peter Fischer, Peter Riederer, Qiong Yang, Rachel Marshall, Rajesh N. Kalaria, Richard Mayeux, Rik Vandenberghe, Roberta Cecchetti, Roberta Ghidoni, Ruth Frikke-Schmidt, Sandro Sorbi, Sara Hägg, Sebastiaan Engelborghs, Seppo Helisalmi, Sigrid Botne Sando, Silke Kern, Silvana Archetti, Silvia Boschi, Silvia Fostinelli, Silvia Gil, Silvia Mendoza, Simon Mead, Simona Ciccone, Srdjan Djurovic, Stefanie Heilmann-Heimbach, Steffi Riedel-Heller, Teemu Kuulasmaa, Teodoro del Ser, Thibaud Lebouvier, Thomas Polak, Tiia Ngandu, Timo Grimmer, Valentina Bessi, Valentina Escott-Price, Vilmantas Giedraitis, Vincent Deramecourt, Wolfgang Maier, Xueqiu Jian, Yolande A. L. Pijnenburg, EADB contributors, DEGESCO consortium, IGAP (ADGC, CHARGE, EADI, GERAD), PGC-ALZ consortia, Patrick Gavin Kehoe, Guillermo Garcia-Ribas, Pascual Sánchez-Juan, Pau Pastor, Jordi Pérez-Tur, Gerard Piñol-Ripoll, Adolfo Lopez de Munain, Jose María García-Alberca, María J. Bullido, Victoria Álvarez, Alberto Lleó, Luis M. Real, Pablo Mir, Miguel Medina, Philip Scheltens, Henne Holstege, Marta Marquié, María Eugenia Sáez, Ángel Carracedo, Philippe Amouyel, Gerard D. Schellenberg, Julie Williams, Sudha Seshadri, Cornelia M. van Duijn, Karen A. Mather, Raquel Sánchez-Valle, Manuel Serrano-Ríos, Adelina Orellana, Lluís Tárraga, Kaj Blennow, Martijn Huisman, Ole A. Andreassen, Danielle Posthuma, Jordi Clarimón, Mercè Boada, Wiesje M. van der Flier, Alfredo Ramirez, Jean-Charles Lambert, Sven J. van der Lee, and Agustín Ruiz
Subjects: Science
Abstract: Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.
Published: 2021
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6. Early detection of amyloid load using 18F-florbetaben PET

Author: Santiago Bullich, Núria Roé-Vellvé, Marta Marquié, Susan M. Landau, Henryk Barthel, Victor L. Villemagne, Ángela Sanabria, Juan Pablo Tartari, Oscar Sotolongo-Grau, Vincent Doré, Norman Koglin, Andre Müller, Audrey Perrotin, Aleksandar Jovalekic, Susan De Santi, Lluís Tárraga, Andrew W. Stephens, Christopher C. Rowe, Osama Sabri, John P. Seibyl, and Mercè Boada
Subjects: Florbetaben, PET, Amyloid-beta, Subjective memory complainers, Mild cognitive impairment, Alzheimer’s disease, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Background A low amount and extent of Aβ deposition at early stages of Alzheimer’s disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using 18F-florbetaben PET. Quantitative thresholds for the early (SUVRearly) and established (SUVRestab) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition. Methods The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition (“gray zone”), and subjects with established Aβ pathology. Results SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the “gray zone” or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology. Conclusions This study supports the utility of using two cutoffs for amyloid PET abnormality defining a “gray zone”: a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention. Trial registration Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov ( NCT00928304 , NCT00750282 , NCT01138111 , NCT02854033 ) and EudraCT (2014-000798-38).
Published: 2021
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7. Association between retinal thickness and β-amyloid brain accumulation in individuals with subjective cognitive decline: Fundació ACE Healthy Brain Initiative

Author: Marta Marquié, Sergi Valero, Miguel Castilla-Marti, Joan Martínez, Octavio Rodríguez-Gómez, Ángela Sanabria, Juan Pablo Tartari, Gemma C. Monté-Rubio, Oscar Sotolongo-Grau, Montserrat Alegret, Alba Pérez-Cordón, Natalia Roberto, Itziar de Rojas, Sonia Moreno-Grau, Laura Montrreal, Isabel Hernández, Maitee Rosende-Roca, Ana Mauleón, Liliana Vargas, Carla Abdelnour, Silvia Gil, Ester Esteban-De Antonio, Ana Espinosa, Gemma Ortega, Francisco Lomeña, Javier Pavia, Assumpta Vivas, Miguel Ángel Tejero, Marta Gómez-Chiari, Rafael Simó, Andreea Ciudin, Cristina Hernández, Adelina Orellana, Alba Benaque, Agustín Ruiz, Lluís Tárraga, Mercè Boada, and on behalf of the FACEHBI study group
Subjects: Optical coherence tomography, Retinal thickness, Subjective cognitive decline, β-Amyloid, Florbetaben, Positron emission tomography, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Background Optical coherence tomography (OCT) of the retina is a fast and easily accessible tool for the quantification of retinal structural measurements. Multiple studies show that patients with Alzheimer’s disease (AD) exhibit thinning in several retinal layers compared to age-matched controls. Subjective cognitive decline (SCD) has been proposed as a risk factor for progression to AD. There is little data about retinal changes in preclinical AD and their correlation with amyloid-β (Aβ) uptake. Aims We investigated the association of retinal thickness quantified by OCT with Aβ accumulation and conversion to mild cognitive impairment (MCI) over 24 months in individuals with SCD. Methods One hundred twenty-nine individuals with SCD enrolled in Fundació ACE Healthy Brain Initiative underwent comprehensive neuropsychological testing, OCT scan of the retina and florbetaben (FBB) positron emission tomography (PET) at baseline (v0) and after 24 months (v2). We assessed the association of sixteen retinal thickness measurements at baseline with FBB-PET status (+/−) and global standardize uptake value ratio (SUVR) as a continuous measure at v0 and v2 and their predictive value on clinical status change (conversion to mild cognitive impairment (MCI)) at v2. Results Mean age of the sample was 64.72 ± 7.27 years; 62.8% were females. Fifteen participants were classified as FBB-PET+ at baseline and 22 at v2. Every 1 μm of increased thickness in the inner nasal macular region conferred 8% and 6% higher probability of presenting a FBB-PET+ status at v0 (OR = 1.08, 95% CI = 1.02–1.14, p = 0.007) and v2 (OR = 1.06, 95% CI = 1.02–1.11, p = 0.004), respectively. Inner nasal macular thickness also positively correlated with global SUVR (at v0: β = 0.23, p = 0.004; at v2: β = 0.26, p = 0.001). No retinal measurements were associated to conversion to MCI over 24 months. Conclusions Subtle retinal thickness changes in the macular region are already present in SCD and correlate with Aβ uptake.
Published: 2020
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8. Plasma Aβ42/40 ratio alone or combined with FDG-PET can accurately predict amyloid-PET positivity: a cross-sectional analysis from the AB255 Study

Author: Virginia Pérez-Grijalba, Javier Arbizu, Judith Romero, Elena Prieto, Pedro Pesini, Leticia Sarasa, Fernando Guillen, Inmaculada Monleón, Itziar San-José, Pablo Martínez-Lage, Josep Munuera, Isabel Hernández, Mar Buendía, Oscar Sotolongo-Grau, Montserrat Alegret, Agustín Ruiz, Lluis Tárraga, Mercè Boada, Manuel Sarasa, and The AB255 Study Group
Subjects: Plasma, Amyloid-beta, FDG-PET, Biomarker, Preclinical Alzheimer’s disease, Amyloid-PET, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Background To facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer’s disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (Aβ) levels with the presence of pathological accumulation of Aβ in the brain measured by amyloid-PET. Both plasma Aβ42/40 ratio alone or combined with an FDG-PET-based biomarker of neurodegeneration were assessed as potential AD biomarkers. Methods We included 39 cognitively normal subjects and 20 patients with mild cognitive impairment from the AB255 Study who had undergone PiB-PET scans. Total Aβ40 and Aβ42 levels in plasma (TP42/40) were quantified using ABtest kits. Subjects were dichotomized as Aβ-PET positive or negative, and the ability of TP42/40 to detect Aβ-PET positivity was assessed by logistic regression and receiver operating characteristic analyses. Combination of plasma Aβ biomarkers and FDG-PET was further assessed as an improvement for brain amyloidosis detection and diagnosis classification. Results Eighteen (30.5%) subjects were Aβ-PET positive. TP42/40 ratio alone identified Aβ-PET status with an area under the curve (AUC) of 0.881 (95% confidence interval [CI] = 0.779–0.982). Discriminating performance of TP42/40 to detect Aβ-PET-positive subjects yielded sensitivity and specificity values at Youden’s cutoff of 77.8% and 87.5%, respectively, with a positive predictive value of 0.732 and negative predictive value of 0.900. All these parameters improved after adjusting the model for significant covariates. Applying TP42/40 as the first screening tool in a sequential diagnostic work-up would reduce the number of Aβ-PET scans by 64%. Combination of both FDG-PET scores and plasma Aβ biomarkers was found to be the most accurate Aβ-PET predictor, with an AUC of 0.965 (95% CI = 0.913–0.100). Conclusions Plasma TP42/40 ratio showed a relevant and significant potential as a screening tool to identify brain Aβ positivity in preclinical and prodromal stages of Alzheimer’s disease.
Published: 2019
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9. Correction: Blood Amyloid Beta Levels in Healthy, Mild Cognitive Impairment and Alzheimer’s Disease Individuals: Replication of Diastolic Blood Pressure Correlations and Analysis of Critical Covariates.

Author: Agustín Ruiz, Pedro Pesini, Ana Espinosa, Virginia Pérez-Grijalba, Sergi Valero, Oscar Sotolongo-Grau, Montserrat Alegret, Inmaculada Monleón, Asunción Lafuente, Mar Buendía, Marta Ibarria, Susana Ruiz, Isabel Hernández, Itziar San José, Lluís Tárraga, Mercè Boada, and Manuel Sarasa
Subjects: Medicine, Science
Published: 2014
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10. Blood amyloid beta levels in healthy, mild cognitive impairment and Alzheimer's disease individuals: replication of diastolic blood pressure correlations and analysis of critical covariates.

Author: Agustín Ruiz, Pedro Pesini, Ana Espinosa, Virginia Pérez-Grijalba, Sergi Valero, Oscar Sotolongo-Grau, Montserrat Alegret, Inmaculada Monleón, Asunción Lafuente, Mar Buendía, Marta Ibarria, Susana Ruiz, Isabel Hernández, Itziar San José, Lluís Tárraga, Mercè Boada, and Manuel Sarasa
Subjects: Medicine, Science
Abstract: Plasma amyloid beta (Aβ) levels are being investigated as potential biomarkers for Alzheimer's disease. In AB128 cross-sectional study, a number of medical relevant correlates of blood Aβ40 or Aβ42 were analyzed in 140 subjects (51 Alzheimer's disease patients, 53 healthy controls and 36 individuals diagnosed with mild cognitive impairment). We determined the association between multiple variables with Aβ40 and Aβ42 levels measured in three different blood compartments called i) Aβ directly accessible (DA) in the plasma, ii) Aβ recovered from the plasma matrix (RP) after diluting the plasma sample in a formulated buffer, and iii) associated with the remaining cellular pellet (CP). We confirmed that diastolic blood pressure (DBP) is consistently correlated with blood DA Aβ40 levels (r=-0.19, P=0.032). These results were consistent in the three phenotypic groups studied. Importantly, the observation resisted covariation with age, gender or creatinine levels. Observed effect size and direction of Aβ40 levels/DBP correlation are in accordance with previous reports. Of note, DA Aβ40 and the RP Aβ40 were also strongly associated with creatinine levels (r=0.599, P<
Published: 2013
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11. Identification of a sex-specific genetic signature in dementia with Lewy bodies: a meta-analysis of genome-wide association studies

Author: Elizabeth Gibbons, Arvid Rongve, Itziar de Rojas, Alexey Shadrin, Kaitlyn Westra, Allison Baumgartner, Levi Rosendall, Zachary Madaj, Dena G. Hernandez, Owen A. Ross, Valentina Escott-Price, Claire Shepherd, Laura Parkkinen, Sonja W. Scholz, Juan C. Troncoso, Olga Pletnikova, Ted Dawson, Liana Rosenthal, Olaf Ansorge, Jordi Clarimon, Alberto Lleo, Estrella Morenas-Rodriguez, Lorraine Clark, Lawrence S Honig, Karen Marder, Afina Lemstra, Ekaterina Rogaeva, Peter St. George-Hyslop, Elisabet Londos, Henrik Zetterberg, Kevin Morgan, Claire Troakes, Safa Al-Sarraj, Tammaryn Lashley, Janice Holton, Yaroslau Compta, Vivianna Van Deerlin, Geidy E Serrano, Thomas G Beach, Suzanne Lesage, Douglas Galasko, Eliezer Masliah, Isabel Santana, Pau Pastor, Monica Diez-Fairen, Miquel Aguilar, Marta Marquie, Pablo Garcia-Gonzalez, Claudia Olive, Raquel Puerta, Amanda Cano, Oscar Sotolongo-Grau, Sergi Valero, Vanesa Veronica Pytel, Maitee Rosende-Roca, Montserrat Alegret, Lluis Tarraga, Merce Boada, Angel Carracedo, Emilio Franco-Macias, Jordi Perez-Tur, Jose Luis Royo, Jose Maria Garcia-Alberca, Luis Miguel Real, Maria Eugenia Saez, Maria Jesus Bullido, Miguel Calero, Miguel Medina, Pablo Mir, Pascual Sanchez-Juan, Victoria Alvarez, Kayenat Parveen, Kumar Parijat Tripathi, Stefanie Heilmann-Heimbach, Alfredo Ramirez, Pentti J. Tienari, Olivier Bousiges, Frederic Blanc, Chiara Fenoglio, Alessandro Padovani, Barbara Borroni, Andrea Pilotto, Flavio Nobili, Ingvild Saltvedt, Tormod Fladby, Geir Selbaek, Ingunn Bosnes, Geir Brathen, Annette Hartmann, Afina W. Lemstra, Dan Rujescu, Brit Mollenhauer, Byron Creese, Marie-Christine Chartier-Harlin, Lavinia Athanasiu, Srdjan Djurovic, Leonidas Chouliaras, John T. OBrien, Liisa Myllykangas, Minna Oinas, Tamas Revesz, Andrew Lees, Brad F Boeve, Ronald C. Petersen, Tanis J Ferman, Neill Graff-Radford, Nigel J. Cairns, John C. Morris, Glenda M. Halliday, John Hardy, Dennis W. Dickson, Andrew Singleton, David J. Stone, Ole A. Andreassen, Agustin Ruiz, Dag Aarsland, Rita Guerreiro, and Jose Bras
Abstract: BackgroundGenome-wide Association Studies (GWAS) have reshaped our understanding of the genetic bases of complex diseases in general and neurodegenerative diseases in particular. Despite being a common disorder, dementia with Lewy bodies (DLB), which, together with Parkinson’s disease dementia (PDD), comprise the umbrella term Lewy body dementias (LBD), is far from being well-characterized genetically. This is primarily due to a lack of familial cases and difficulty recruiting large, deeply characterized cohorts, given the high rate of misdiagnosis. By performing the largest GWAS in DLB, we aimed to identify novel risk loci to gain a better understanding of this disease’s pathobiology.MethodsHere, we conducted the largest meta-analysis of genome-wide association studies performed in LBD, using a total of 5,119 cases and 20,988 controls, from five independent datasets, aggregating all previously published DLB genome-wide association results to date, as well as two previously undescribed cohorts. Additionally, we performed a sex stratified GWAS using the discovery datasets. We updated the heritability estimates for DLB and, to fine map these estimates, we used local heritability analysis. We calculated genetic correlation estimates between DLB and a range of other diseases and traits to identify potential pleiotropy. We also performed gene-set analysis to identify genes with excess burden of rare variability and pathway analysis. Lastly, we used the UK Biobank data to perform a PheWas using individuals at the extremes of genetic risk for DLB.FindingsBetween November 2018 and September 2022 we analyzed 8.6 million single nucleotide polymorphisms in 3293 DLB cases, 1826 LBD cases and 20,988 controls, as well as phenotypes from the UK Biobank dataset. Despite more than doubling the sample size from the previous GWAS in DLB, we did not identify significant loci in addition to those previously reported atGBA, SNCA, STX1B, andAPOE. However, the sex-stratified analysis revealed that theGBAandSNCAsignals are mainly driven by males, suggesting a sex-specific genetic architecture of disease. Using only clinical and neuropathologically diagnosed cases, we highlight four loci surpassing the significance threshold. Using the largest cohort of DLB we update our heritability estimates to 13% and fine map these results highlighting regions of the genome with high heritability but no genome-wide significant result so far.InterpretationThese data provide the most comprehensive analysis of genetic variability in DLB to date. The fact that no novel risk loci have been identified after doubling the cohort size indicates the potentially significant role of rare variants in the genetic architecture of DLB and stresses the urgent need for larger, well-characterized cohorts of this disease for genetic studies. The sex-stratified analysis shows that males and females have different signatures of genetic risk for DLB. These results have widespread implications for clinical practice and clinical trials’ design in DLB.
Published: 2022

12. BIOFACE: A Prospective Study of Risk Factors, Cognition, and Biomarkers in a Cohort of Individuals with Early-Onset Mild Cognitive Impairment. Study Rationale and Research Protocols

Author: Montserrat Alegret, Silvia Gil, Sergi Valero, Alba Pérez-Cordón, E. L. Martin, Emilio Alarcón-Martín, Mireia Bernuz, Marta Marquié, Oscar Sotolongo-Grau, Adelina Orellana, Lluís Tárraga, Joan Martínez, Agustín Ruiz, Assumpta Vivas, Marta Gomez-Chiari, Miguel Angel Tejero, Mercè Boada, Amanda Cano, Ana Espinosa, Ester Esteban de Antonio, and Itziar de Rojas
Subjects: Male, medicine.medical_specialty, exosomes, Disease, Neuropsychological Tests, Cognition, mild cognitive impairment, proteomics, Risk Factors, Internal medicine, Humans, Medicine, Dementia, Cognitive Dysfunction, Early-onset Alzheimer's disease, Prospective Studies, Family history, Prospective cohort study, business.industry, General Neuroscience, Neuropsychology, biomarkers, General Medicine, Middle Aged, early onset Alzheimer’s disease, medicine.disease, Magnetic Resonance Imaging, Psychiatry and Mental health, Clinical Psychology, Cohort, Biomarker (medicine), Female, Geriatrics and Gerontology, business, Alzheimer’s disease, Research Article, dementia, presenile
Abstract: Background: Mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) diagnosis is based on cerebrospinal fluid (CSF) or neuroimaging biomarkers. Currently, non-invasive and inexpensive blood-based biomarkers are being investigated, such as neuronal-derived plasma exosomes (NPEs). Neuroinflammation and early vascular changes have been described in AD pathogenesis and can be traced in plasma and NPEs. However, they have not been studied in early onset MCI (EOMCI). Objective: To describe the rationale, design, and baseline characteristics of the participants from the BIOFACE cohort, a two-year observational study on EOMCI conducted at Fundació ACE. The study goal is to characterize the different phenotypes from a clinical, neuropsychological, and biomarker point of view and to investigate the CSF and plasma proteomics as well as the role of NPEs as early biomarkers of AD. Methods: Participants underwent extended neurological and neuropsychological batteries, multimodal biomarkers including brain MRI, blood, saliva, CSF, anthropometric, and neuro-ophthalmological examinations. Results: Ninety-seven patients with EOMCI were recruited. 59.8%were women. Mean age at symptom onset was 57 years; mean MMSE was 28. First degree and presenile family history of dementia was present in 60.8%and 15.5%, respectively. Depressive and anxiety disorders along with vascular risk factors were the most frequent comorbidities. 29%of participants were APOE ɛ4 carriers, and 67%showed a CSF normal ATN profile. Conclusion: BIOFACE is a two-year study of clinical, cognition, and biomarkers that will shed light on the physiopathology and the potential utility of plasma and NPEs as non-invasive early diagnostic and prognostic biomarkers in people younger than 65 years.
Published: 2021

13. Combination of white matter hyperintensities and Aβ burden is related to cognitive composites domain scores in subjective cognitive decline: the FACEHBI cohort

Author: Laura Montrreal, Angela Sanabria, Assumpta Vivas, Marta Marquié, Emilio Alarcón-Martín, Silvia Alonso-Lana, Montse Alegret, Gemma C Monté-Rubio, R López-Cuevas, Octavio Rodriguez-Gomez, E Esteban De Antonio, Mercè Boada, Natalia Roberto, Sergi Valero, Ana Espinosa, Ana Mauleón, Sonia Moreno-Grau, Oscar Sotolongo-Grau, I de Rojas, Carla Abdelnour, Adelina Orellana, Juan Pablo Tartari, Alba Pérez-Cordón, Gemma Ortega, Maitée Rosende-Roca, Marta Gomez-Chiari, L. Tárraga, Liliana Vargas, Isabel Hernández, and Agustín Ruiz
Subjects: Cognitive Neuroscience, Neurosciences. Biological psychiatry. Neuropsychiatry, Neuropsychological Tests, Cognition, FBB-PET, Magnetic resonance imaging, Linear regression, White matter hyperintensities, medicine, Humans, Cognitive composites domain scores, Cognitive Dysfunction, Neuropsychological assessment, Effects of sleep deprivation on cognitive performance, Cognitive decline, Composite material, RC346-429, Episodic memory, Amyloid-beta (Aß), Amyloid beta-Peptides, medicine.diagnostic_test, business.industry, Research, White Matter, Hyperintensity, Neurology, Cohort, Subjective cognitive decline, Neurology (clinical), Apolipoprotein E, Neurology. Diseases of the nervous system, business, RC321-571
Abstract: BackgroundTo explore whether the combination of white matter hyperintensities (WMHs) and amyloid-beta (Aβ) deposition is associated with worse cognitive performance on cognitive composites (CCs) domain scores in individuals with subjective cognitive decline (SCD).MethodsTwo hundred participants from the FACEHBI cohort underwent structural magnetic resonance imaging (MRI),18F-florbetaben positron emission tomography (FBB-PET), and neuropsychological assessment. WMHs were addressed through the Fazekas scale, the Age-Related White Matter Changes (ARWMC) scale, and the FreeSurfer pipeline. Eight CCs domain scores were created using the principal component analysis (PCA). Age, sex, education, and apolipoprotein E (APOE) were used as adjusting variables.ResultsAdjusted multiple linear regression models showed that FreeSurfer (B − .245; 95% CI − .1.676, − .393,p = .016) and β burden (SUVR) (B − .180; 95% CI − 2.140, − .292;p = .070) were associated with face–name associative memory CCs domain score, although the latest one was not statistically significant after correction for multiple testing (p = .070). There was non-significant interaction of these two factors on this same CCs domain score (p = .54). However, its cumulative effects on face–name associative performance indicated that those individuals with either higher WMH load or higher Aβ burden showed the worst performance on the face–name associative memory CCs domain score.ConclusionsOur results suggest that increased WMH load and increased Aβ are independently associated with poorer episodic memory performance in SCD individuals, indicating a cumulative effect of the combination of these two pathological conditions in promoting lower cognitive performance, an aspect that could help in terms of treatment and prevention.
Published: 2021

14. Association between retinal thickness and β-amyloid brain accumulation in individuals with subjective cognitive decline: Fundació ACE Healthy Brain Initiative

Author: Angela Sanabria, Francisco Lomeña, Assumpta Vivas, Carla Abdelnour, Gemma Ortega, Miguel Castilla-Marti, Adelina Orellana, Joan Martínez, Ana Mauleón, Liliana Vargas, Miguel Angel Tejero, Rafael Simó, Alba Benaque, Ester Esteban de Antonio, Oscar Sotolongo-Grau, Alba Pérez-Cordón, Agustín Ruiz, Sergi Valero, Maitée Rosende-Roca, Isabel Hernández, Itziar de Rojas, Natalia Roberto, Mercè Boada, Andreea Ciudin, Marta Marquié, Montserrat Alegret, Lluís Tárraga, Ana Espinosa, Sonia Moreno-Grau, Cristina Hernández, Marta Gomez-Chiari, Javier Pavía, Gemma C Monté-Rubio, Octavio Rodriguez-Gomez, Juan Pablo Tartari, Silvia Gil, and Laura Montrreal
Subjects: Male, Neurology, Optical coherence tomography, lcsh:RC346-429, chemistry.chemical_compound, 0302 clinical medicine, β amyloid, Medicine, Cognitive decline, medicine.diagnostic_test, Brain, Middle Aged, Florbetaben, 3. Good health, medicine.anatomical_structure, Subjective cognitive decline, Positron emission tomography, Female, β-Amyloid, Retinal thickness, medicine.medical_specialty, Cognitive Neuroscience, Retina, lcsh:RC321-571, 03 medical and health sciences, Alzheimer Disease, Ophthalmology, Humans, Cognitive Dysfunction, Risk factor, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, lcsh:Neurology. Diseases of the nervous system, Aged, Amyloid beta-Peptides, business.industry, Research, Retinal, chemistry, Positron-Emission Tomography, ß-Amyloid, 030221 ophthalmology & optometry, Neurology (clinical), sense organs, business, 030217 neurology & neurosurgery
Abstract: Background: Optical coherence tomography (OCT) of the retina is a fast and easily accessible tool for the quantification of retinal structural measurements. Multiple studies show that patients with Alzheimer's disease (AD) exhibit thinning in several retinal layers compared to age-matched controls. Subjective cognitive decline (SCD) has been proposed as a risk factor for progression to AD. There is little data about retinal changes in preclinical AD and their correlation with amyloid-β (Aβ) uptake. Aims: We investigated the association of retinal thickness quantified by OCT with Aβ accumulation and conversion to mild cognitive impairment (MCI) over 24 months in individuals with SCD. Methods: One hundred twenty-nine individuals with SCD enrolled in Fundació ACE Healthy Brain Initiative underwent comprehensive neuropsychological testing, OCT scan of the retina and florbetaben (FBB) positron emission tomography (PET) at baseline (v0) and after 24 months (v2). We assessed the association of sixteen retinal thickness measurements at baseline with FBB-PET status (+/-) and global standardize uptake value ratio (SUVR) as a continuous measure at v0 and v2 and their predictive value on clinical status change (conversion to mild cognitive impairment (MCI)) at v2. Results: Mean age of the sample was 64.72 ± 7.27 years; 62.8% were females. Fifteen participants were classified as FBB-PET+ at baseline and 22 at v2. Every 1 μm of increased thickness in the inner nasal macular region conferred 8% and 6% higher probability of presenting a FBB-PET+ status at v0 (OR = 1.08, 95% CI = 1.02-1.14, p = 0.007) and v2 (OR = 1.06, 95% CI = 1.02-1.11, p = 0.004), respectively. Inner nasal macular thickness also positively correlated with global SUVR (at v0: β = 0.23, p = 0.004; at v2: β = 0.26, p = 0.001). No retinal measurements were associated to conversion to MCI over 24 months. Conclusions: Subtle retinal thickness changes in the macular region are already present in SCD and correlate with Aβ uptake. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 796706, and the Instituto de Salud Carlos III (ISCIII) grant PI19/00335 Acción Estratégica en Salud, integrated in the Spanish National R+D+I Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de hacer Europa") awarded to M.M. Funds were also obtained from donations from “La nit de l’Alzheimer”, a charity dinner initiative that takes place yearly as part of the “Festival Castell de Peralada” (2016-2018). The neuro-ophthalmology exam devices were acquired with a grant EFSD/Lilly Mental Health and Diabetes 2013 Programme of the European Foundation for the Study of Diabetes (EFSD) awarded to the project “Retinal neurodegeneration in type 2 diabetes as biomarker of Alzheimer’s disease” under the leadership of C.H. Funds from Fundació ACE Institut Català de Neurociències Aplicades, Grifols, Life Molecular Imaging, Araclon Biotech, Alkahest, Laboratorio de análisis Echevarne and IrsiCaixa are supporting the FACEHBI study. These sponsors were not involved in the study design, data collection, analysis or interpretation. The sponsors have reviewed the manuscript and have given their approval.
Published: 2020

15. Plasma Aβ42/40 ratio alone or combined with FDG-PET can accurately predict amyloid-PET positivity: a cross-sectional analysis from the AB255 Study

Author: Manuel Sarasa, Mar Buendía, Pablo Martinez-Lage, Mercè Boada, Oscar Sotolongo-Grau, Judith Romero, Inmaculada Monleón, Josep Munuera, Montserrat Alegret, Javier Arbizu, Isabel Hernández, Elena Prieto, Lluís Tárraga, Agustín Ruiz, Virginia Pérez-Grijalba, Fernando Guillen, Pedro Pesini, Itziar San-José, and Leticia Sarasa
Subjects: 0301 basic medicine, Oncology, Male, Neurology, Logistic regression, lcsh:RC346-429, Plasma, 0302 clinical medicine, Amyloid-beta, Mild cognitive impairment, Longitudinal Studies, FDG-PET, Aged, 80 and over, biology, Amyloidosis, Area under the curve, Amyloid-PET, Biomarker (medicine), Female, medicine.medical_specialty, Amyloid, Amyloid beta, Cognitive Neuroscience, lcsh:RC321-571, 03 medical and health sciences, Alzheimer Disease, Fluorodeoxyglucose F18, Internal medicine, medicine, Humans, Cognitive Dysfunction, Preclinical Alzheimer’s disease, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, lcsh:Neurology. Diseases of the nervous system, Aged, Amyloid beta-Peptides, Receiver operating characteristic, business.industry, Research, Biomarker, medicine.disease, Confidence interval, Peptide Fragments, 030104 developmental biology, Cross-Sectional Studies, Positron-Emission Tomography, biology.protein, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: BackgroundTo facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer’s disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (Aβ) levels with the presence of pathological accumulation of Aβ in the brain measured by amyloid-PET. Both plasma Aβ42/40 ratio alone or combined with an FDG-PET-based biomarker of neurodegeneration were assessed as potential AD biomarkers.MethodsWe included 39 cognitively normal subjects and 20 patients with mild cognitive impairment from the AB255 Study who had undergone PiB-PET scans. Total Aβ40 and Aβ42 levels in plasma (TP42/40) were quantified using ABtest kits. Subjects were dichotomized as Aβ-PET positive or negative, and the ability of TP42/40 to detect Aβ-PET positivity was assessed by logistic regression and receiver operating characteristic analyses. Combination of plasma Aβ biomarkers and FDG-PET was further assessed as an improvement for brain amyloidosis detection and diagnosis classification.ResultsEighteen (30.5%) subjects were Aβ-PET positive. TP42/40 ratio alone identified Aβ-PET status with an area under the curve (AUC) of 0.881 (95% confidence interval [CI] = 0.779–0.982). Discriminating performance of TP42/40 to detect Aβ-PET-positive subjects yielded sensitivity and specificity values at Youden’s cutoff of 77.8% and 87.5%, respectively, with a positive predictive value of 0.732 and negative predictive value of 0.900. All these parameters improved after adjusting the model for significant covariates. Applying TP42/40 as the first screening tool in a sequential diagnostic work-up would reduce the number of Aβ-PET scans by 64%. Combination of both FDG-PET scores and plasma Aβ biomarkers was found to be the most accurate Aβ-PET predictor, with an AUC of 0.965 (95% CI = 0.913–0.100).ConclusionsPlasma TP42/40 ratio showed a relevant and significant potential as a screening tool to identify brain Aβ positivity in preclinical and prodromal stages of Alzheimer’s disease.
Published: 2019

16. Automatized FACEmemory® scoring is related to Alzheimer's disease phenotype and biomarkers in early-onset mild cognitive impairment: the BIOFACE cohort

Author: Montserrat Alegret, Oscar Sotolongo-Grau, Ester Esteban de Antonio, Alba Pérez-Cordón, Adelina Orellana, Ana Espinosa, Silvia Gil, Daniel Jiménez, Gemma Ortega, Angela Sanabria, Natalia Roberto, Isabel Hernández, Maitee Rosende-Roca, Juan Pablo Tartari, Emilio Alarcon-Martin, Itziar de Rojas, Laura Montrreal, Xavier Morató, Amanda Cano, Dorene M. Rentz, Lluís Tárraga, Agustín Ruiz, Sergi Valero, Marta Marquié, and Mercè Boada
Subjects: Amyloid beta-Peptides, Cognitive Neuroscience, Memory, Episodic, tau Proteins, Neuropsychological Tests, Peptide Fragments, Phenotype, Neurology, Alzheimer Disease, Humans, Cognitive Dysfunction, Neurology (clinical), Diagnosis, Computer-Assisted, Biomarkers
Abstract: Background FACEmemory® is the first computerized, self-administered verbal episodic memory test with voice recognition. It can be conducted under minimal supervision and contains an automatic scoring system to avoid administrator errors. Moreover, it is suitable for discriminating between cognitively healthy and amnestic mild cognitive impairment (MCI) individuals, and it is associated with Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers. This study aimed to determine whether FACEmemory scoring is related to performance on classical memory tests and to AD biomarkers of brain magnetic resonance imaging (MRI) and CSF in patients with early-onset MCI (EOMCI). Methods Ninety-four patients with EOMCI from the BIOFACE study completed FACEmemory, classical memory tests (the Spanish version of the Word Free and Cued Selective Reminding Test -FCSRT-, the Word List from the Wechsler Memory Scale, third edition, and the Spanish version of the Rey–Osterrieth Complex Figure Test), and a brain MRI. Eighty-two individuals also underwent a lumbar puncture. Results FACEmemory scoring was moderately correlated with FCSRT scoring. With regard to neuroimaging MRI results, worse execution on FACEmemory was associated with lower cortical volume in the right prefrontal and inferior parietal areas, along with the left temporal and associative occipital areas. Moreover, the total FACEmemory score correlated with CSF AD biomarkers (Aβ1-42/Aβ1-40 ratio, p181-tau, and Aβ1-42/p181-tau ratio). When performance on FACEmemory was compared among the ATN classification groups, significant differences between the AD group and normal and SNAP groups were found. Conclusions FACEmemory is a promising tool for detecting memory deficits sensitive to early-onset AD, but it also allows the detection of memory-impaired cases due to other etiologies. Our findings suggest that FACEmemory scoring can detect the AD endophenotype and that it is also associated with AD-related changes in MRI and CSF in patients with EOMCI. The computerized FACEmemory tool might be an opportunity to facilitate early detection of MCI in younger people than 65, who have a growing interest in new technologies.
Published: 2021

17. Metabolic syndrome impact on cognitive composites domain scores and on white matter hyperintensities in subjective cognitive decline: The FACEHBI Cohort

Author: Gemma Ortega, Ana Espinosa, Montserrat Alegret, Gemma Monté‐Rubio, Oscar Sotolongo‐Grau, Angela Sanabria, Juan Pablo Tartari, Octavio Rodriguez‐Gomez, Marta Marquié, Assumpta Vivas, M Gómez‐Chiari, Emilio Alarcón‐Martín, Alba Pérez‐Cordón, Natalia Roberto, Isabel Hernandez, Maitee Rosende‐Roca, Liliana Vargas, Ana Mauleon, Carla Abdelnour, Ester Esteban‐De Antonio, Rogelio López‐Cuevas, S Alonso‐Lana, Sonia Moreno‐Grau, Itziar de Rojas, Adelina Orellana, Laura Montrreal, Lluis Tarraga, Agustin Ruiz, Mercè Boada, and Sergi Valero
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published: 2021

18. Early detection of amyloid load using 18F-florbetaben PET

Author: Susan De Santi, Audrey Perrotin, John Seibyl, Aleksandar Jovalekic, Christopher C. Rowe, Andre Müller, Vincent Dore, Andrew W. Stephens, Henryk Barthel, Juan Pablo Tartari, Marta Marquié, Lluís Tárraga, Mercè Boada, Oscar Sotolongo-Grau, Osama Sabri, Angela Sanabria, Susan M. Landau, Núria Roé-Vellvé, Norman Koglin, Santiago Bullich, and Victor L. Villemagne
Subjects: Pathology, medicine.medical_specialty, Amyloid, Amyloid beta, Cognitive Neuroscience, Population, Neuropathology, lcsh:RC346-429, lcsh:RC321-571, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, Dementia, Cognitive decline, education, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Florbetaben, lcsh:Neurology. Diseases of the nervous system, education.field_of_study, biology, business.industry, Mild cognitive impairment, Alzheimer's disease, medicine.disease, PET, Neurology, biology.protein, Neurology (clinical), Amyloid-beta, business, Subjective memory complainers, Alzheimer’s disease, 030217 neurology & neurosurgery
Abstract: Background A low amount and extent of Aβ deposition at early stages of Alzheimer’s disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using 18F-florbetaben PET. Quantitative thresholds for the early (SUVRearly) and established (SUVRestab) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition. Methods The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition (“gray zone”), and subjects with established Aβ pathology. Results SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the “gray zone” or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology. Conclusions This study supports the utility of using two cutoffs for amyloid PET abnormality defining a “gray zone”: a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention. Trial registration Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov (NCT00928304, NCT00750282, NCT01138111, NCT02854033) and EudraCT (2014-000798-38).
Published: 2021

19. Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Author: EADB contributors, The GR@ACE study group, DEGESCO consortium, IGAP (ADGC, CHARGE, EADI, GERAD), PGC-ALZ consortia, Itziar de Rojas, Sonia Moreno-Grau, Niccolò Tesi, Benjamin Grenier-Boley, Victor Andrade, I (Iris) Jansen, Nancy L. Pedersen, N (Najada) Stringa, Anna Zettergren, Isabel Hernández, Laura Montrreal, Carmen Antúnez, Anna Antonell, Rick M. Tankard, Joshua C. Bis, Rebecca Sims, Céline Bellenguez, Inés Quintela, Antonio González-Perez, Miguel Calero, Emilio Franco-Macías, Juan Macías, Rafael Blesa, Laura Cervera-Carles, Manuel Menéndez-González, Ana Frank-García, Jose Luís Royo, Fermin Moreno, Raquel Huerto Vilas, Miquel Baquero, Mónica Diez-Fairen, Carmen Lage, Sebastián García-Madrona, Pablo García-González, Emilio Alarcón-Martín, Sergi Valero, Oscar Sotolongo-Grau, Abbe Ullgren, Adam C. Naj, K (Kristel) Sleegers, M.A. (Arfan) Ikram, E Martin, M (Maria) Moreno, MS Marin, PJ Sanchez Juan, Henne Holstege, C.M. (Cornelia) van Duijn, D (Daniëlle) Posthuma, S.J. (Sven) van der Lee, EADB contributors, The GR@ACE study group, DEGESCO consortium, IGAP (ADGC, CHARGE, EADI, GERAD), PGC-ALZ consortia, Itziar de Rojas, Sonia Moreno-Grau, Niccolò Tesi, Benjamin Grenier-Boley, Victor Andrade, I (Iris) Jansen, Nancy L. Pedersen, N (Najada) Stringa, Anna Zettergren, Isabel Hernández, Laura Montrreal, Carmen Antúnez, Anna Antonell, Rick M. Tankard, Joshua C. Bis, Rebecca Sims, Céline Bellenguez, Inés Quintela, Antonio González-Perez, Miguel Calero, Emilio Franco-Macías, Juan Macías, Rafael Blesa, Laura Cervera-Carles, Manuel Menéndez-González, Ana Frank-García, Jose Luís Royo, Fermin Moreno, Raquel Huerto Vilas, Miquel Baquero, Mónica Diez-Fairen, Carmen Lage, Sebastián García-Madrona, Pablo García-González, Emilio Alarcón-Martín, Sergi Valero, Oscar Sotolongo-Grau, Abbe Ullgren, Adam C. Naj, K (Kristel) Sleegers, M.A. (Arfan) Ikram, E Martin, M (Maria) Moreno, MS Marin, PJ Sanchez Juan, Henne Holstege, C.M. (Cornelia) van Duijn, D (Daniëlle) Posthuma, and S.J. (Sven) van der Lee
Abstract: Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.
Published: 2021
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20. Early detection of amyloid load using

Author: Santiago, Bullich, Núria, Roé-Vellvé, Marta, Marquié, Susan M, Landau, Henryk, Barthel, Victor L, Villemagne, Ángela, Sanabria, Juan Pablo, Tartari, Oscar, Sotolongo-Grau, Vincent, Doré, Norman, Koglin, Andre, Müller, Audrey, Perrotin, Aleksandar, Jovalekic, Susan, De Santi, Lluís, Tárraga, Andrew W, Stephens, Christopher C, Rowe, Osama, Sabri, John P, Seibyl, and Mercè, Boada
Subjects: Amyloid beta-Peptides, Aniline Compounds, Research, Mild cognitive impairment, Florbetaben, PET, Alzheimer Disease, Positron-Emission Tomography, mental disorders, Stilbenes, Humans, Cognitive Dysfunction, Amyloid-beta, Subjective memory complainers, Alzheimer’s disease
Abstract: Background A low amount and extent of Aβ deposition at early stages of Alzheimer’s disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using 18F-florbetaben PET. Quantitative thresholds for the early (SUVRearly) and established (SUVRestab) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition. Methods The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition (“gray zone”), and subjects with established Aβ pathology. Results SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the “gray zone” or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology. Conclusions This study supports the utility of using two cutoffs for amyloid PET abnormality defining a “gray zone”: a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention. Trial registration Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov (NCT00928304, NCT00750282, NCT01138111, NCT02854033) and EudraCT (2014-000798-38).
Published: 2020

21. The Aβ42/Aβ40 ratio in plasma is associated with amyloid‐PET status and rate of progression in individuals with subjective cognitive decline: The Fundació ACE Healthy Brain Initiative

Author: Oscar Sotolongo-Grau, Mercè Boada, Marta Marquié, Judith Romero, Noelia Fandos, Angela Sanabria, Manuel Sarasa, Itziar de Rojas, Pedro Pesini, Juan Pablo Tartari, and Agustín Ruiz
Subjects: Oncology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Amyloid pet, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, medicine, Neurology (clinical), Geriatrics and Gerontology, Cognitive decline, business
Published: 2020

22. Quantitative thresholds for 18 F‐florbetaben PET for the detection of low amyloid load

Author: Lluís Tárraga, Osama Sabri, Aleksandar Jovalekic, Angela Sanabria, Marta Marquié, Oscar Sotolongo-Grau, Andre Mueller, Andrew W. Stephens, Victor L. Villemagne, Núria Roé-Vellvé, Henryk Barthel, Christopher C. Rowe, Vincent Dore, Juan Pablo Tartari, Audrey Perrotin, Mercè Boada, John Seibyl, Santiago Bullich, Susan De Santi, and Norman Koglin
Subjects: Amyloid, Epidemiology, business.industry, Health Policy, Early detection, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Neuroimaging, Medicine, Neurology (clinical), Geriatrics and Gerontology, business, Florbetaben, Neuroscience
Published: 2020

23. Common variants in Alzheimers disease: Novel association of six genetic variants with AD and risk stratification by polygenic risk scores

Author: Wiesje M. van der Flier, Rebecca Sims, Itziar de Rojas, Rick M. Tankard, Martijn A. Huisman, Victoria Alvarez, Joshua C. Bis, Sebastian Garcia-Madrona, Marta Marquié, Pascual Sánchez-Juan, Manuel Menéndez-González, Nancy L. Pedersen, Céline Bellenguez, R. Sanchez-Valle, María J. Bullido, Emilio Alarcón-Martín, Miquel Baquero, Sergi Valero, Luis Miguel Real, Laura Montrreal, Victor Andrade, Ole A. Andreassen, Anna Zettergren, Philip Scheltens, Cornelia M. van Duijn, Miguel Medina, Adolfo López de Munain, Anna Antonell, Julie Williams, Philippe Amouyel, Guillermo García-Ribas, Pablo Mir, Monica Diez-Fairen, Danielle Posthuma, Pablo García, Ana Frank-García, Karen A. Mather, Kaj Blennow, Antonio González-Pérez, Juan Macías, Alfredo Ramirez, Adelina Orellana, Mercè Boada, Niccolò Tesi, Jordi Clarimón, Lluís Tárraga, Alberto Lleó, Jordi Pérez-Tur, José María García-Alberca, Raquel Huerto, Iris E. Jansen, Sven J. van der Lee, Pgc-Alz Consortia, Fermin Moreno, Miguel Calero, Oscar Sotolongo-Grau, Rafael Blesa, María Eugenia Sáez, Carmen Lage, Henne Holstege, Benjamin Grenier-Boley, Isabel Hernández, Gerard Piñol-Ripoll, Ángel Carracedo, Sudha Seshadri, Jean-Charles Lambert, Sonia Moreno-Grau, Emilio Franco, Jose Luis Royo, Manuel Serrano-Ríos, Pau Pastor, Agustín Ruiz, Inés Quintela, Najada Stringa, and Carmen Antúnez
Subjects: Oncology, Apolipoprotein E, 0303 health sciences, medicine.medical_specialty, business.industry, Genomics, Heterozygote advantage, Genome-wide association study, Disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genotype, medicine, Missense mutation, business, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: BACKGROUNDDisentangling the genetic constellation underlying Alzheimer’s disease (AD) is important. Doing so allows us to identify biological pathways underlying AD, point towards novel drug targets and use the variants for individualised risk predictions in disease modifying or prevention trials. In the present work we report on the largest genome-wide association study (GWAS) for AD risk to date and show the combined utility of proven AD loci for precision medicine using polygenic risk scores (PRS).METHODSThree sets of summary statistics were included in our meta-GWAS of AD: an Spanish case-control study (GR@ACE/DEGESCO study, n = 12,386), the case-control study of International Genomics of Alzheimer project (IGAP, n = 82,771) and the UK Biobank (UKB) AD-by-proxy case-control study (n=314,278). Using these resources, we performed a fixed-effects inverse-variance-weighted meta-analysis. Detected loci were confirmed in a replication study of 19,089 AD cases and 39,101 controls from 16 European-ancestry cohorts not previously used. We constructed a weighted PRS based on the 39 AD variants. PRS were generated by multiplying the genotype dosage of each risk allele for each variant by its respective weight, and then summing across all variants. We first validated it for AD in independent data (assessing effects of sub-threshold signal, diagnostic certainty, age at onset and sex) and tested its effect on risk (odds for disease) and age at onset in the GR@ACE/DEGESCO study.FINDINGSUsing our meta-GWAS approach and follow-up analysis, we identified novel genome-wide significant associations of six genetic variants with AD risk (rs72835061-CHRNE, rs2154481-APP, rs876461-PRKD3/NDUFAF7, rs3935877-PLCG2 and two missense variants: rs34173062/rs34674752 in SHARPIN gene) and confirmed a stop codon mutation in the IL34 gene increasing the risk of AD (IL34-Tyr213Ter), and two other variants in PLCG2 and HS3ST1 regions. This brings the total number of genetic variants associated with AD to 39 (excluding APOE). The PRS based on these variants was associated with AD in an independent clinical AD-case control dataset (OR=1.30, per 1-SD increase in the PRS, 95%CI 1.18-1.44, p = 1.1×10−7), a similar effect to that in the GR@ACE/DEGESCO (OR=1.27, 95%CI 1.23-1.32, p = 7.4×10−39). We then explored the combined effects of these 39 variants in a PRS for AD risk and age-at-onset stratification in GR@ACE/DEGESCO. Excluding APOE, we observed a gradual risk increase over the 2% tiles; when comparing the extremes, those with the 2% highest risk had a 2.98-fold (95% CI 2.12–4.18, p = 3.2×10−10) increased risk compared to those with the 2% lowest risk (p = 5.9×10−10). Using the PRS we identified APOE ε33 carriers with a similar risk as APOE ε4 heterozygotes carriers, as well as APOE ε4 heterozygote carriers with a similar risk as APOE ε4 homozygote. Considering age at onset; there was a 9-year difference between median onset of AD the lowest risk group and the highest risk group (82 vs 73 years; p = 1.6×10−6); a 4-year median onset difference (81 vs 77 years; p = 6.9×10−5) within APOE ε4 heterozygotes and a 5.5-year median onset difference (78.5 vs 73 years; p = 4.6×10−5) within APOE ε4 carriers.INTERPRETATIONWe identified six novel genetic variants associated with AD-risk, among which one common APP variant. A PRS of all genetic loci reported to date could be a robust tool to predict the risk and age at onset of AD, beyond APOE alone. These properties make PRS instrumental in selecting individuals at risk in order to apply preventative strategies and might have potential use in diagnostic work-up.
Published: 2019
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24. Impact of Recruitment Methods in Subjective Cognitive Decline

Author: Ana Espinosa, Lluís Tárraga, Isabel Hernández, Alba Pérez-Cordón, Ana Mauleón, Angela Sanabria, Maitée Rosende-Roca, Marina Guitart, Domingo Sanchez, Sergi Valero, Gemma Ortega, Sonia Moreno-Grau, Agustín Ruiz, Oscar Sotolongo-Grau, Montserrat Alegret, Anna Gailhajanet, Liliana Vargas, Mercè Boada, Carla Abdelnour, Susana Diego, and Octavio Rodriguez-Gomez
Subjects: Male, Apolipoprotein E4, Neuropsychological Tests, Logistic regression, Diagnostic Self Evaluation, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Humans, Medicine, Dementia, Cognitive Dysfunction, Genetic Predisposition to Disease, 030212 general & internal medicine, Family history, Cognitive decline, Allele frequency, Depression (differential diagnoses), business.industry, Patient Selection, General Neuroscience, Neuropsychology, General Medicine, Middle Aged, medicine.disease, Patient recruitment, Psychiatry and Mental health, Clinical Psychology, Logistic Models, Educational Status, Female, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Demography
Abstract: BACKGROUND Recruitment methods can determine sample characteristics in mild cognitive impairment and Alzheimer's disease dementia, but little is known about its influence in subjective cognitive decline (SCD). OBJECTIVE To determine the influence of two types of recruitment methods in the characteristics of individuals with SCD. METHODS We select and compare clinical and neuropsychological features, and frequency of APOE ɛ4 allele of 326 subjects with SCD from two cohorts: Open House Initiative (OHI) versus Memory Unit (MU). A logistic regression analysis (LRA), using gender and years of education as covariates, was used to examine the neuropsychological variables. RESULTS The OHI sample were mostly women (75.9% versus 64.5%, p
Published: 2017

25. Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer’s disease and three causality networks of AD: the GR@ACE project

Author: María J. Bullido, Asunción Lafuente, Miguel A. Santos-Santos, Sergi Valero, Ana Mauleón, Adelina Orellana, Inés Quintela, Pascual Sánchez-Juan, Silvia Gil, Pablo Mir, Mercè Boada, Emilio Alarcón, Luis Miguel Real, Alba Pérez-Cordón, Juan Macías, Victoria Alvarez, Maitée Rosende-Roca, Nuria Aguilera, Oscar Sotolongo-Grau, Laura Madrid, Laura Montrreal, Montserrat Alegret, Jordi Clarimón, Carla Abdelnour, Isabel Hernández, José María García-Alberca, Gerard Piñol-Ripoll, Angela Sanabria, Angel Carracedo, Susana Ruiz, Carmen Antúnez, Alzheimer’s Disease Neuroimaging Initiative, Octavio Rodriguez-Gomez, Begoña Hernández-Olasagarre, Agustín Ruiz, Miguel Calero, Jose Luis Royo, Gemma Ortega, Marta Marquié, Miguel Medina, Juan A. Pineda, Emilio Franco, Sonia Moreno-Grau, Itziar de Rojas, María Eugenia Sáez, Antonio González-Pérez, Lluís Tárraga, Alberto Rábano, Gemma Monté-Rubio, Liliana Vargas, Olalla Maroñas, Pau Pastor, Jesús Avila, Ana Espinosa, and Guillermo García-Ribas
Subjects: Genetics, 0303 health sciences, Mechanism (biology), Genome-wide association study, Context (language use), Disease, Biology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Endophenotype, medicine, Dementia, Cerebral amyloid angiopathy, Genetic variability, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: BackgroundGenetics plays a major role in Alzheimer’s Disease (AD). To date, 40 genes associated with AD have been identified, although most remain undiscovered. Clinical, neuropathological and genetic variability might impact genetic discoveries and complicate dissection of the biological pathways underlying AD.MethodsGR@ACE is a genome-wide study of dementia and its clinical endophenotypes that encompasses 4,120 cases and 3,289 controls from Spain. GR@ACE phenotypes were defined according to AD’s clinical certainty and the presence of vascular co-morbidity. To explore whether clinical endophenotypes reflect variation in underlying biological pathways, we first assessed the impact of known AD loci across endophenotypes to generate three loci categories. Next, we incorporated gene co-expression data and conducted pathway analysis on each category. To assess the impact of heterogeneity in the GWAS findings, the GR@ACE series were meta-analyzed with: 1) genotype-level data from dbGaP (N=21,235); and 2) summary statistics from IGAP Stages I and II (n=61,571 and n=81,455 respectively).FindingsWe classified known AD loci in three categories, which might reflect the disease clinical heterogeneity, from vascular and mixed forms to pure AD pathology. Immune system pathways were detected in all categories. Intriguingly, vascular processes were only detected as a causal mechanism in probable AD. A meta-analysis of GR@ACE with additional GWAS datasets revealed theANKRD31-rs4704171signal in theHMGCRgenomic region. We confirmed NDUFAF6-rs10098778 andSCIMP-rs7225151, which were previously detected by IGAP, to be suggestive signals. We also confirmed CD33-rs3865444 to be genome-wide significant.InterpretationThe regulation of vasculature is a prominent causal component of probable AD. In that context, cerebral amyloid angiopathy, the unique identified link between the vascular and amyloid hypotheses, deserves further investigation. The GR@ACE meta-analysis revealed novel AD genetic signals. GWAS results are strongly driven by the presence of clinical heterogeneity in the AD series.FundingGrifols SA, Fundación bancaria “La Caixa”, Fundació ACE and ISCIII (Instituto de Salud Carlos III).
Published: 2019
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26. Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project

Author: Jordi Clarimón, G. Monté-Rubio, Miguel A. Santos-Santos, L. Vargas, E. Pelejà, M.T. Martínez, E. Alarcón-Martín, A. Mauleón, P. Martínez-Lage Álvarez, A. Carracedo, N. Aguilera, Goo Amer-Ferrer, M.J. Bullido, Pascual Sánchez-Juan, Olalla Maroñas, J.A. Pineda, Carmen Martínez, Carmen Lage, Antonio González-Pérez, V. Martínez, Angel Carracedo, Susana Ruiz, A. López de Munáin, E. L. Martin, O. Maroñas, Manuel Menéndez-González, Begoña Hernández-Olasagarre, Luis Miguel Real, S. Ruiz, Marta Marquié, Pablo Mir, Montse Alegret, María J. Bullido, Pilar Gómez-Garre, A. Sanabria, Carla Abdelnour, Silvia Jesús, M.M. de Pancorbo, J. Clarimón, Agustín Ruiz, M. Boada, José María García-Alberca, J.M. Cruz-Gamero, Ignacio Alvarez, P. Mir, Adelina Orellana, Alberto Rábano, J.L. Royo, Alberto Lleó, M.J. Casajeros, O. Sotolongo-Grau, R. Sanchez del Valle Díaz, Ana Espinosa, Nuria Aguilera, G. Piñol Ripoll, J. Pérez Tur, S. Manzanares, M. Marquié, Miguel Medina, S. Rodrigo, Teresa Periñán-Tocino, A. Rábano, A. Martín Montes, A. Gailhajenet, Daniel Macias, Ana Mauleón, E. Franco, Miguel Calero, Adela Orellana, P. Cañabate, M. Rosende-Roca, Jose Luis Royo, Gemma Ortega, M. Moreno, Juan A. Pineda, Marina Guitart, Marta Ibarria, A. Benaque, Maria Eugenia Sáez, Manuel Serrano-Ríos, A. Ruiz, Carmen Antúnez, Mariola Moreno, Juan Macías, Pilar Cañabate, L.M. Real, A. Lafuente, Astrid Adarmes-Gómez, Fátima Carrillo, A. Espinosa, T. Marín, S. Preckler, T. del Ser, Eloy Rodríguez-Rodríguez, S. Moreno-Grau, Susana Diego, Gemma Monté-Rubio, L. Montrreal, Rafael Blesa, Mercè Boada, M.P. Vicente, Asunción Lafuente, Emilio Franco, B. Martínez, Laura Montrreal, Itziar de Rojas, I. Hernández, Mario Carrión-Claro, Alba Benaque, I. de Rojas, Emilio Alarcón-Martín, Jesús Avila, S. Garcia Madrona, S. Valero, D. Real de Asúa, L. Vivancos, Ana Frank-García, J.A. Burguera, Liliana Vargas, Labrador Espinosa, Sara López-García, Angela Sanabria, Ana Pancho, A.B. Pastor, Juan Fortea, A. Legaz, Oscar Sotolongo-Grau, Laura Madrid, Sonia Moreno-Grau, J. Marín-Muñoz, M. Calero, Emilio Alarcón, Lluís Tárraga, M. Marín, Miquel Baquero, Sergi Valero, Mar Buendía, José-Luis Molinuevo, M. Mendioroz Iriarte, Alba Pérez-Cordón, C. Abdelnour, V. Álvarez, Pau Pastor, Silvia Gil, J.M. García-Alberca, A. González Pérez, A. Pérez-Cordon, Maitée Rosende-Roca, O. Rodríguez-Gómez, Victoria Alvarez, Isabel Sastre, Inés Quintela, Guillermo García-Ribas, Isabel Hernández, Octavio Rodriguez-Gomez, Arturo Corbatón, G. Ortega, C. Antúnez, P. García González, Monica Diez-Fairen, P. Pastor, P. Sánchez-Juan, L. Tárraga, G. Garcia-Ribas, Montserrat Alegret, S. Hevilla, Maria Jose Bernal, María Eugenia Sáez, M. Medina, I. Quintela, Silvia Preckler, M. Antequera, Dolores Buiza-Rueda, M.A. Santos-Santos, Gerard Piñol-Ripoll, S. Gil, European Commission, Universidad de Cantabria, Fundación La Caixa, Grifols (Spain), Fundació ACE, Instituto de Salud Carlos III, Ministerio de Sanidad (España), Unión Europea, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Regional Government of Andalusia (España), National Institutes of Health (Estados Unidos), United States Department of Defense, NIH - National Institute on Aging (NIA) (Estados Unidos), NIH - National Institute of Biomedical Imaging and Bioengineering (NIBIB) (Estados Unidos), Innovative Medicines Initiative, Unión Europea. Comisión Europea. 6 Programa Marco, Alzheimer's Disease Genetics Consortium, GRIFOLS, European Union, European Regional Development Fund (ERDF/FEDER), Gobierno de Andalucía, National Institutes of Health (United States), Department of Defense USA, National Institute on Aging, National Institute of Biomedical Imaging and Bioengineering, and 6º Programa Marco - Comisión Europea
Subjects: 0301 basic medicine, Male, Epidemiology, humanos, vascular pathology, enfermedad de Alzheimer, Genome-wide association study, Disease, demencia, 0302 clinical medicine, sitios genéticos, GWAS, Cerebrovascular disease, mediana edad, anciano, Health Policy, gwas, Alzheimer's disease, Middle Aged, rare, Causality, 3. Good health, Psychiatry and Mental health, Biological Pathway, alzheimer's disease, Female, Cerebral amyloid angiopathy, Malalties cerebrovasculars, biological pathway, metaanalysis, Endophenotypes, onset, Vascular Pathology, Computational biology, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, Developmental Neuroscience, Alzheimer Disease, medicine, Dementia, Humans, Genetic Predisposition to Disease, Alzheimer’s Disease, endofenotipos, gene, Gene, cerebral amyloid angiopathy, cognitive function, Aged, Mechanism (biology), predisposición genética a la enfermedad, medicine.disease, mutations, immunity, Cerebral Amyloid Angiopathy, 030104 developmental biology, Malaltia d'Alzheimer, Spain, Genetic Loci, Endophenotype, estudio de asociación genómica completa, Neurology (clinical), vascular risk, Geriatrics and Gerontology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series., The authors would like to thank patients and controls who participated in this project. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Fundacion bancaria La Caixa, Grifols SA, Fundacio ACE, and ISCIII (Ministry of Health, Spain). They also want to thank the private sponsors who support the basic and clinical projects of our institution (Piramal AG, Laboratorios Echevarne, Araclon Biotech S.A., and Fundacio ACE). They are indebted to the Trinitat Port-Carbo legacy and her family for their support of Fundacio ACE research programs. Fundacio ACE is a participating center in the Dementia Genetics Spanish Consortium (DEGESCO). A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, and PI17/01474. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de Hacer Europa). L.M.R. is supported by Consejeria de Salud de la Junta de Andalucia (grant PI-0001/2017). Control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.bancoadn.org, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed after standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. The present work was performed as part of the Biochemistry, Molecular Biology, and Biomedicine doctoral program of S. MorenoGrau at Universitat Autonoma de Barcelona (Barcelona, Spain).r Data collection and sharing for this project was partially funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). The ADNI is funded by the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering, as well as through generous contributions from the following: AbbVie; the Alzheimer's Association; the Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study was coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California.; r The AddNeuroMed data are from a public-private partnership supported by EFPIA companies and SMEs as part of InnoMed (Innovative Medicines in Europe), an integrated project funded by the European Union of the Sixth Framework program priority FP6-2004-LIFESCIHEALTH-5. Clinical leads responsible for data collection are Iwona K1oszewska (Lodz), Simon Lovestone (London), Patrizia Mecocci (Perugia), Hilkka Soininen (Kuopio), Magda Tsolaki (Thessaloniki), and Bruno Vellas (Toulouse). Imaging leads are Andy Simmons (London), Lars-Olad Wahlund (Stockholm), and Christian Spenger (Zurich). Bioinformatics leads are Richard Dobson (London) and Stephen Newhouse (London).r Funding support for the Alzheimer's Disease Genetics Consortium (ADGC) was provided through the NIA Division of Neuroscience (U01-AG032984).r The Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nilufer Ertekin-Taner and Dr. Steven G. Younkin at the Mayo Clinic in Jacksonville, FL, used samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, and R01 AG003949, NINDS grant R01 NS080820, the CurePSP Foundation, and support from the Mayo Foundation.r The Neocodex-Murcia study was funded by the Fundacion Alzheimur (Murcia), the Ministerio de Educacion y Ciencia (Gobierno de Espana), Corporacion Tecnologica de Andalucia, Agencia IDEA (Consejeria de Innovacion, Junta de Andalucia), the Diabetes Research Laboratory, and the Biomedical Research Foundation. University Hospital Clinico San Carlos has been supported by CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM); CIBERDEM is an ISCIII Project.r The ROS/MAP study data were provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984 and U01AG46152, the Illinois Department of Public Health, and the Translational Genomics Research Institute.r The TGEN study was supported by Kronos Life Science Laboratories, the National Institute on Aging (Arizona Alzheimer's Disease Center grants P30 AG19610 and RO1 AG023193, the Mayo Clinic Alzheimer's Disease Center grant P50 AG16574, and the Intramural Research Program), the National Alzheimer's Coordinating Center (U01 AG016976), and the state of Arizona.r The authors thank the International Genomics of Alzheimer's Project (IGAP) for providing summary result data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i-Select chip was funded by the French National Foundation on Alzheimer's disease and related disorders. European Alzheimer's Disease Initiative (EADI) was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Universite de Lille 2, and the Lille University Hospital. GERAD was supported by the Medical Research Council (grant no. 503480), Alzheimer's Research UK (grant no. 503176), the Wellcome Trust (grant no. 082604/2/07/Z), and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant no.; 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01-AG12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer's Association grant ADGC-10-196728.
Published: 2019

27. Genome-wide significant risk factors on chromosome 19 and the APOE locus

Author: A. Espinosa, Agustín Ruiz, Nuria Aguilera, Carla Abdelnour, Carmen Antúnez, W. Maier, Gemma Ortega, Sonia Moreno-Grau, Manuel Serrano-Ríos, Susana Ruiz, Maitée Rosende-Roca, Octavio Rodriguez-Gomez, López-Arrrieta J, Isabel Hernández, Mercè Boada, Lluís Tárraga, Neuroimaging Initiative Ad, Ana Mauleón, Liliana Vargas, Silvia Gil, Stefanie Heilmann-Heimbach, Montserrat Alegret, Alfredo Ramirez, and Oscar Sotolongo-Grau
Subjects: 0301 basic medicine, Apolipoprotein E, Linkage disequilibrium, Locus (genetics), ABCA7, 03 medical and health sciences, 0302 clinical medicine, medicine, Dementia, ddc:610, Genetic association, late onset Alzheimer’s disease, Gerotarget, Memory clinic, Research Papers: Gerotarget (Focus on Aging), Odds ratio, medicine.disease, 3. Good health, 030104 developmental biology, Oncology, Cohort, CD33, Psychology, 030217 neurology & neurosurgery, APOE, linkage disequilibrium, Demography
Abstract: // Sonia Moreno-Grau 1 , Isabel Hernandez 1 , Stefanie Heilmann-Heimbach 2, 3 , Susana Ruiz 1 , Maitee Rosende-Roca 1 , Ana Mauleon 1 , Liliana Vargas 1 , Octavio Rodriguez-Gomez 1 , Montserrat Alegret 1 , Ana Espinosa 1 , Gemma Ortega 1 , Nuria Aguilera 1 , Carla Abdelnour 1 , Alzheimer’s Disease Neuroimaging Initiative * , Silvia Gil 1 , Wolfgang Maier 4, 5 , Oscar Sotolongo-Grau 1 , Lluis Tarraga 1 , Alfredo Ramirez 2, 4, 6 , Jesus Lopez-Arrrieta 7 , Carmen Antunez 8 , Manuel Serrano-Rios 9 , Merce Boada 1 and Agustin Ruiz 1 1 Research Center and Memory Clinic of Fundacio ACE, Institut Catala de Neurociencies Aplicades, Univesitat Internacional de Catalunya, Barcelona, Spain 2 Institute of Human Genetics, University of Bonn, Bonn, Germany 3 Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany 4 Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany 5 German Center for Neurodegenerative Diseases, DZNE, Bonn, Germany 6 Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany 7 Memory Unit, University Hospital La Paz-Cantoblanco, Madrid, Spain 8 Dementia Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain 9 Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas, CIBERDEM, Spain, Hospital Clinico San Carlos, Madrid, Spain * Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or Provided data but did not participate in analysis or writing of this report Correspondence to: Agustin Ruiz, email: aruiz@fundacioace.com Keywords: late onset Alzheimer’s disease; ABCA7; APOE; CD33; linkage disequilibrium; Gerotarget Received: December 13, 2017 Accepted: March 22, 2018 Published: May 15, 2018 ABSTRACT The apolipoprotein E ( APOE ) gene on chromosome 19q13.32, was the first, and remains the strongest, genetic risk factor for Alzheimer’s disease (AD). Additional signals associated with AD have been located in chromosome 19, including ABCA7 (19p13.3) and CD33 (19q13.41). The ABCA7 gene has been replicated in most populations. However, the contribution to AD of other signals close to APOE gene remains controversial. Possible explanations for inconsistency between reports include long range linkage disequilibrium (LRLD). We analysed the contribution of ABCA7 and CD33 loci to AD risk and explore LRLD patterns across APOE region. To evaluate AD risk conferred by ABCA7 rs4147929:G>A and CD33 rs3865444:C>A, we used a large Spanish population (1796 AD cases, 2642 controls). The ABCA7 rs4147929:G>A SNP effect was nominally replicated in the Spanish cohort and reached genome-wide significance after meta-analysis (odds ratio (OR)=1.15, 95% confidence interval (95% CI)=1.12–1.19; P = 1.60 x 10 -19 ). CD33 rs3865444:C>A was not associated with AD in the dataset. The meta-analysis was also negative (OR=0.98, 95% CI=0.93–1.04; P =0.48). After exploring LRLD patterns between APOE and CD33 in several datasets, we found significant LD (D’ >0.20; P A in two of five datasets, suggesting the presence of a non-universal long range interaction between these loci affecting to some populations. In conclusion, we provide here evidence of genetic association of the ABCA7 locus in the Spanish population and also propose a plausible explanation for the controversy on the contribution of CD33 to AD susceptibility.
Published: 2018

28. FACEHBI: A Prospective Study of Risk Factors, Biomarkers and Cognition in a Cohort of Individuals with Subjective Cognitive Decline. Study Rationale and Research Protocols

Author: Octavio Rodriguez-Gomez, Marta Gomez-Chiari, Sanchez-Ruiz D, L. Tárraga, Tarragona M, Angela Sanabria, Assumpta Vivas, Gabriel Martínez, Oscar Sotolongo-Grau, Sonia Moreno-Grau, Francisco Lomeña, A. Espinosa, Miguel Angel Tejero, Carla Abdelnour, Anna Gailhajanet, E. Pelejà, Marina Guitart, Francisco Campos, Judit Serra, G. Ortega, Pedro Pesini, Joan Giménez, Isabel Hernández, Susana Ruiz, Sergi Valero, E. L. Martin, Liliana Vargas, Mercè Boada, Agustín Ruiz, Ana Mauleón, Manuel Sarasa, Alba Pérez-Cordón, Maitée Rosende-Roca, and Montserrat Alegret
Subjects: Gerontology, Longitudinal study, Amyloid, Neuropsychological Tests, Diagnostic Self Evaluation, Cognition, Risk Factors, Stilbenes, Medicine, Humans, Cognitive Dysfunction, Longitudinal Studies, Risk factor, Cognitive decline, Prospective cohort study, Florbetaben, Life Style, Aged, Aniline Compounds, business.industry, Memory clinic, Neuropsychology, Brain, Magnetic Resonance Imaging, Research Design, Positron-Emission Tomography, Observational study, Radiopharmaceuticals, business, Biomarkers, Tomography, Optical Coherence
Abstract: Background: Long-term longitudinal studies with multimodal biomarkers are needed to delve into the knowledge of preclinical AD. Subjective cognitive decline has been proposed as a risk factor for the development of cognitive impairment. Thus, including individuals with SCD in observational studies may be a cost-effective strategy to increase the prevalence of preclinical AD in the sample. Objectives: To describe the rationale, research protocols and baseline characteristics of participants in the Fundació ACE Healthy Brain Initiative (FACEHBI). Design: FACEHBI is a clinical trial (EudraCT: 2014-000798-38) embedded within a long-term observational study of individuals with SCD. Setting: Participants have been recruited at the memory clinic of Fundació ACE (Barcelona) from two different sources: patients referred by a general practitioner and individuals from an Open House Initiative. Participants: 200 individuals diagnosed with SCD with a strictly normal performance in a comprehensive neuropsychological battery. Measurements: Individuals will undergo an extensive neuropsychological protocol, risk factor assessment and a set of multimodal biomarkers including florbetaben PET, structural and functional MRI, diffusion tensor imaging, determination of amyloid species in plasma and neurophthalmologic assessment with optical coherence tomography. Results: Two hundred individuals have been recruited in 15 months. Mean age was 65.9 years; mean MMSE was 29.2 with a mean of 14.8 years of education. Conclusions: FACEHBI is a long-term study of cognition, biomarkers and lifestyle that has been designed upon an innovative symptom-based approach using SCD as target population. It will shed light on the pathophysiology of preclinical AD and the role of SCD as a risk marker for the development of cognitive impairment.
Published: 2017

29. Plasma extracellular vesicles reveal early molecular differences in amyloid positive patients with early-onset mild cognitive impairment

Author: Amanda Cano, Ester Esteban-de-Antonio, Mireia Bernuz, Raquel Puerta, Pablo García-González, Itziar de Rojas, Claudia Olivé, Alba Pérez-Cordón, Laura Montrreal, Raúl Núñez-Llaves, Óscar Sotolongo-Grau, Emilio Alarcón-Martín, Sergi Valero, Montserrat Alegret, Elvira Martín, Pamela V. Martino-Adami, Miren Ettcheto, Antonio Camins, Assumpta Vivas, Marta Gomez-Chiari, Miguel Ángel Tejero, Adelina Orellana, Lluís Tárraga, Marta Marquié, Alfredo Ramírez, Mercè Martí, María Isabel Pividori, Mercè Boada, and Agustín Ruíz
Subjects: Plasma exosomes, Extracellular vesicles, Cerebrospinal fluid, Proteomics, Alzheimer’s disease, Mild cognitive impairment, Biotechnology, TP248.13-248.65, Medical technology, R855-855.5
Abstract: Highlights The pEVs proteome revealed early molecular differences between EOMCI Aβ( +) and Aβ(-) subjects. Olink© neurology proteins from pEVs of EOMCI Aβ( +) patients exhibited a strong negative correlation with CSF p-tau181. The levels of pEVs and CSF Olink© proteins correlated with CSF p-tau181 levels and age. Brain MRI characteristics of EOMCI Aβ( +) patients correlated with pEVs protein levels. pEVs biomarkers only linked early signs of inflammation to brain atrophy in EOMCI Aβ( +) individuals. The correlation of cognitive status and pEVs biomarkers differed between EOMCI Aβ( +) and Aβ(-) patients.
Published: 2023
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30. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Author: John Hardy, Nick C. Fox, Lena Lilius, Christine Van Broeckhoven, Mindy J. Katz, Carlos Cruchaga, Joshua W. Miller, Carol Brayne, Letizia Concari, Christopher Shaw, Minerva M. Carrasquillo, Richard Mayeux, Anne Boland, Charles DeCarli, Helena C. Chui, Laura B. Cantwell, Yoland Aladro Benito, Chuang Kuo Wu, Elaine R. Peskind, Andrew McDavid, M. Ilyas Kamboh, Amanda Smith, Pascual Sánchez-Juan, Jean-François Deleuze, Jayanadra J. Himali, Thomas H. Mosley, Thomas J. Montine, Chuanhai Cao, Andreas J. Forstner, Thomas G. Beach, Robert Barber, Miquel Aguilar, Liming Qu, Jerome I. Rotter, Matthew J. Huentelman, Christiane Reitz, Christopher J. O'Donnell, Steven G. Younkin, Bradley T. Hyman, Bruce L. Miller, Rachelle S. Doody, Eric B. Larson, Ronald L. Hamilton, Todd E. Golde, Steven E. Arnold, Melissa E. Garcia, Rachel Raybould, Lena Kilander, Mark A. Sager, Kevin Morgan, Kathryn L. Lunetta, William Perry, Joseph D. Buxbaum, Craig S. Atwood, Thomas D. Bird, Michael Conlon O'Donovan, Robert Olaso, Juan Fortea, Susanne Moebus, Lisa L. Barnes, Rachel Marshall, Huntington Potter, Mercè Boada, Shahzad Ahmad, Paolo Caffarra, Daniel C. Marson, Jonathan L. Haines, Perrie M. Adams, John M Olichney, Lars Lannfelt, Stefanie Heilmann-Heimbach, Markus M. Nöthen, Shubhabrata Mukherjee, John Malamon, Xue Wang, Christopher S. Carlson, Karen Ritchie, Roger N. Rosenberg, Paul K. Crane, Alexa S. Beiser, Céline Bellenguez, Robert C. Green, Maria Urbano, Petra Proitsi, John Powell, Elisa Majounie, Ammar Al-Chalabi, Hakon Hakonarson, Yogen Patel, Martin Scherer, Julie Williams, Richard B. Lipton, Vincent Dermecourt, Adam L. Boxer, Gerard D. Schellenberg, David G. Clark, Anita L. DeStefano, Joel H. Kramer, Victoria Alvarez, Nandini Badarinarayan, Oscar L. Lopez, Chris Corcoran, Ubaldo Bonuccelli, Donald R. Royall, James Bowen, Monica Diez Fairen, Tricia A. Thornton-Wells, Nilufer Ertekin-Taner, Florence Pasquier, Martin Ingelsson, Yi Zhao, John R. Gilbert, Valentina Escott-Price, Amanda B. Kuzma, Fabienne Garzia, Reinhard Heun, Otto Valladares, Andrew J. Saykin, Sara Ortega-Cubero, Liana G. Apostolova, Henry L. Paulson, John K Kauwe, Imelda Barber, Carolina Ceballos Diaz, Douglas Galasko, M. Arfan Ikram, Lluís Tárraga, Carlo Caltagirone, Joan S. Reisch, Wolfgang Maier, Bruno Vellas, Rebecca Sims, Angela Hodges, Matthew P. Frosch, Isabel Henández, Annakaisa Haapasalo, Thor Aspelund, Håkan Thonberg, Aimee Pierce, Roger L. Albin, Wayne W. Poon, Rebecca Sussams, Amy Braddel, Ranjan Duara, Albert V. Smith, Kirk C. Wilhelmsen, Gianfranco Spalletta, Simon Lovestone, Peter Passmore, Ana Frank-García, Cynthia M. Carlsson, Jade Chapman, Nathan D. Price, Philip L. De Jager, John M. Ringman, Seung Hoan Choi, Nicola Denning, Michael John Owen, Clinton T. Baldwin, Amalia C. Bruni, Denis A. Evans, Rudolph E. Tanzi, Dominique Campion, Laura Fratiglioni, Alberto Lleó, Per Hoffmann, Carole Dufouil, Charlotte Forsell, Alun Meggy, Charlene Thomas, Robert S. Stern, James B. Leverenz, Tatiana Foroud, William W. Seeley, James J. Lah, Brian A. Lawlor, Kenneth B. Fallon, Matthias Riemenschneider, Ryan M. Huebinger, Regina M. Carney, Clinton B. Wright, Didier Hannequin, Deborah Blacker, Anne Kinhult-Ståhlbom, Ekaterina Rogaeva, Andrew P. Lieberman, Bernardino Ghetti, Linda J. Van Eldik, Bernadette McGuinness, Thomas Fairchild, Margaret A. Pericak-Vance, Ashok Raj, Reinhold Schmidt, Ronald C. Petersen, Harald Hampel, María J. Bullido, Steven L. Carroll, Maria Candida Deniz Naranjo, Kathleen A. Welsh-Bohmer, Myriam Fornage, Joseph F. Quinn, Caroline Graff, Claudia L. Satizabal, Patrice L. Whitehead, David Wallon, Christopher Medway, Lindsay A. Farrer, Vilmundur Gudnason, Peter St George-Hyslop, Pau Pastor, Frank Jessen, Erin L. Abner, Johanna Jakobsdottir, Hieab H.H. Adams, Roberta Cecchetti, Walter A. Kukull, Thomas S. Wingo, Michelle K. Lupton, Valur Emilsson, Susan M. McCurry, Simon Mead, Hilkka Soininen, Sandra Weintraub, Amy Gerrish, Lindy E. Harrell, Lina Keller, Jean-Charles Lambert, Denise Harold, Stephen Todd, Wei Gu, Maura Gallo, Najaf Amin, Lenore J. Launer, Eleonora Sacchinelli, Mikko Hiltunen, Cécile Dulary, Eliecer Coto, Xueqiu Jian, Nathalie Fievet, Patrizia Mecocci, Sarah Taylor, Eric Boerwinkle, Maria Serpente, Ronald G. Munger, Ina Giegling, Carlo Masullo, Aoibhinn Lynch, Eliezer Masliah, Anne M. Koivisto, Chang En Yu, Qiong Yang, Benedetta Nacmias, Wayne C. McCormick, Kristelle Brown, Alessio Squassina, Deborah C. Mash, Brian W. Kunkle, Makrina Daniilidou, Alison Goate, David Carrell, Kara L. Hamilton-Nelson, Sandra Barral, Vincent Chouraki, Kristel Sleegers, Frank J. Wolters, Joseph E. Parisi, Iwona Kłoszewska, Ronald C. Kim, Sonia Moreno-Grau, Marina Arcaro, Carmen Muñoz Fernadez, Vernon S. Pankratz, Duane Beekly, Sabrina Pichler, Gislain Septier, Delphine Bacq, Amanda J. Myers, Adam C. Naj, Frank Martiniuk, Sudha Seshadri, Badri N. Vardarajan, Joshua A. Sonnen, M.-Marsel Mesulam, Howard J. Rosen, James T. Becker, Chiara Fenoglio, Ge Li, Alberto Pilotto, Mary Sano, Olivier Hanon, Honghuang Lin, Jean Paul G. Vonsattel, W. T. Longstreth, Daniela Galimberti, David C. Rubinsztein, RoseMarie Brundin, Vilmantas Giedraitis, Christine M. Hulette, Peter Holmans, Martin Dichgans, Maria Vronskaya, Céline Derbois, Michelangelo Mancuso, Constantine G. Lyketsos, Christophe Tzourio, Jacques Epelbaum, Raffaele Maletta, Mariet Allen, Hong-Dong Li, James R. Burke, Rik Vandenberghe, David G. Mann, Bruce M. Psaty, Lawrence S. Honig, Beth A. Dombroski, Erik D. Roberson, Cornelia M. van Duijn, Benjamin Grenier-Boley, Seppo Helisalmi, Jean-François Dartigues, Russell H. Swerdlow, Paola Bossù, Ashley R. Winslow, Elio Scarpini, Lesley Jones, Sebastien Engelborghs, John Q. Trojanowski, Jeffrey Kaye, Jenny Lord, Chiara Cupidi, Janet A. Johnston, Dan Rujescu, Feroze Golamaully, Anne Braae, Rafael Blesa, L. Adrienne Cupples, Dennis W. Dickson, Gail P. Jarvik, David W. Fardo, David H. Cribbs, Michael Gill, Jose Bras, Allan I. Levey, Jennifer Williamson, Rhodri Thomas, John C. Morris, Lei Yu, Debby W. Tsuang, Annette M. Hartmann, John H. Growdon, John Collinge, Claudine Berr, Fernando Rivadeneira, Oliver Peters, Albert Hofman, Frank M. LaFerla, Vivianna M. Van Deerlin, James Uphill, David A. Bennett, Onofre Combarros, Gudny Eiriksdottir, Jeremy D. Burgess, Melanie L. Dunstan, Elizabeth Crocco, Keeley J. Brookes, Robert R. Graham, Lon S. Schneider, Eden R. Martin, Matt Hill, Neill R. Graff-Radford, Joseph T. Hughes, Vincenzo Solfrizzi, Taniesha Morgan, Antonio Ciaramella, Bruno Dubois, Juan C. Troncoso, Paolo Bosco, Jordi Clarimón, Daniel H. Geschwind, Virginia Boccardi, Barry Reisberg, Timothy W. Behrens, Annette L. Fitzpatrick, Salvatore Spina, Alexis Brice, Eileen H. Bigio, Marla Gearing, Jeffrey M. Burns, Carol A. Miller, Marilyn S. Albert, Sven J. van der Lee, Sandro Sorbi, C. Dirk Keene, Daniel Levy, Antonio Daniele, Eric M. Reiman, Paramita Chakrabarty, Oscar Sotolongo-Grau, Helena Schmidt, Francesco Panza, Murray A. Raskind, Rita Guerreiro, Gyungah Jun, Anna Karydas, Markus Leber, Harry V. Vinters, Cory C. Funk, Charles C. White, Jill R. Murrell, Sid E. O'Bryant, Nigel J. Cairns, Josée Dupuis, Ann C. McKee, Julie A. Schneider, Megan L. Grove, Malcolm B. Dick, Bradley F. Boeve, Jennifer A. Brody, Sanjay Asthana, Agustín Ruiz, Stefan Herms, Yuning Chen, David Craig, Neil W. Kowall, Maria Donata Orfei, JoAnn T. Tschanz, Florentino Sanchez Garcia, Manuel Mayhaus, Alfredo Ramirez, James Turton, André G. Uitterlinden, Davide Seripa, Lee-Way Jin, Kelley Faber, Maria C. Norton, Shuo Li, Steven H. Ferris, Steffi G. Riedel-Heller, Joshua C. Bis, Li-San Wang, Johannes Kornhuber, Peter Paul De Deyn, Martin R. Farlow, Randall L. Woltjer, Gary W. Beecham, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Icelandic Heart Association [Kopavogur, Iceland] (IHA), John P. Hussman Institute for Human Genomics [Miami, FL, USA], University of Miami [Coral Gables], Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Medicine, University of Washington [Seattle], Dr. John T. Macdonald Foundation [Miami, FL, USA] (Department of Human Genetics), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Department of Genomics [Bonn, Germany] (Institute of Human Genetics), University of Bonn-Institute of Human Genetics [Bonn, Germany], Department of Molecular Genetics, Institut Català de Neurociències Aplicades [Barcelona, Spain], Well Advanced Solutions, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], The University of Texas Health Science Center at Houston (UTHealth), Columbia University [New York], University of Eastern Finland, Life & Brain Center - Department of Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), John P. Hussman Institute for Human Genomics, Neurobiologie de la Croissance et de la Senescence, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Emmy Noether Project (SFB 833), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Boston University [Boston] (BU), Department of Genomics, Institute for Systems Biology [Seattle, WA, USA], Universitätsklinikum Bonn (UKB), Centre of Excellence for Robotic Vision [Canberra], Australian Research Council [Canberra] (ARC), Neuroscience and Mental Health Research Institute [Cardiff, UK] (School of Medicine), Boston University School of Medicine (BUSM), Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, University of Pennsylvania [Philadelphia], Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Department of Epidemiology and Biostatistics, ERASMUS, Hospital Universitario Doctor Negrín [Las Palmas de Gran Canaria, Spain], Department of Neurodegenerative Diseases, University of Mississippi Medical Center (UMMC), Pathology and Laboratory Medicine [Philadelphia, PA, USA] (Penn Neurodegeneration Genomics Center), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioinformatics, GlaxoSmithKline, Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], University of Nottingham, UK (UON), University of Texas Health Science Center, Department of Neurobiology, Caring Sciences and Society (NVS), University of Bari Aldo Moro (UNIBA), Ageing Group, Centre for Public Health, Queen's University [Belfast] (QUB), Mayo Clinic [Jacksonville], Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Università degli Studi di Perugia (UNIPG), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), CHU Rouen, Normandie Université (NU), Universidad Autonoma de Madrid (UAM), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), University of Florida [Gainesville] (UF), University of Parma = Università degli studi di Parma [Parme, Italie], Center for Cognitive Disorders AUSL [Parma, Italy], School of Public Health [Boston], Uppsala University, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Xi'an Jiaotong University (Xjtu), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Institute of Gerontology and Geriatrics, Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Geriatric Medicine and Metabolic Diseases, Departments of Nuclear Medicine, University Medical Centre Hamburg-Eppendorf [Hamburg, Germany], University of Texas Southwestern Medical Center [Dallas], University of Cologne, Laboratoire d'Etudes et de Recherche en Informatique d'Angers (LERIA), Université d'Angers (UA), Johns Hopkins University (JHU), Universität Leipzig [Leipzig], University of Iceland [Reykjavik], Metacohorts Consortium, Harvard School of Public Health, Catholic University of Rome, Medical University Graz, Baylor College of Medicine (BCM), Baylor University, University of North Texas Health Science Center [Fort Worth], Santa Lucia Foundation (IRCCS), Nextel S.A. [Bilbao], Massachusetts General Hospital [Boston], Department of Pathology and Laboratory Medicine and Indiana Alzheimer disease Center, Indiana University School of Medicine, Indiana University System-Indiana University System, Joint Institute for the Study of the Atmosphere and Ocean (JISAO), Beijing University of Technology, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Saul B. Korey Department of Neurology, Albert Einstein College of Medicine [New York]-Yeshiva University, Utah State University (USU), Fundació per la Recerca Biomèdica i Social Mútua Terrassa [Barcelona, Spain], Hospital Universitario Mutua de Terrassa, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Medical University of Łódź (MUL), University of Leicester, MRC Prion Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Milan, Fondazione Istituto di Ricerca e Cura Carattere Scientifico [Rome], Università degli Studi di Roma Tor Vergata [Roma], Saarland University Hospital, Universitat Autònoma de Barcelona (UAB), Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Universidade do Porto, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Experimental and Clinical Pharmacology, St. James Hospital and Trinity College [Dublin, Ireland], School of Medicine [Dublin], Trinity College Dublin, University of Sheffield [Sheffield], Lancaster University, University of Michigan [Ann Arbor], University of Michigan System, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, University of Wisconsin-Madison, Rush Alzheimer Disease Center [Chicago, IL, États-Unis], Rush University Medical Center [Chicago], Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), School of Engineering [Cardiff], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Northwestern University Feinberg School of Medicine, Mayo Clinic [Rochester], Swedish Medical Center [Seattle, WA, USA], University of California [San Francisco] (UCSF), University of California, Duke University [Durham], University of Kansas Medical Center [Lawrence], Laboratory of Molecular Neuropsychiatry, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Washington University in Saint Louis (WUSTL), University of South Florida [Tampa] (USF), Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Medical University of South Carolina [Charleston] (MUSC), University of Southern California (USC), Los Alamos National Laboratory (LANL), Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Neurology Department, University of California, Davis (UCDavis-Neuro), University of California [Davis] (UC Davis), University of California [Irvine] (UCI), Mount Sinai Medical Center, Indiana State University, University of Alabama at Birmingham [ Birmingham] (UAB), University of Kentucky, New York University [New York] (NYU), NYU System (NYU), Department of Medical and Molecular Genetics, Department of Epidemiology and biostatistics, VU University Medical Center [Amsterdam], Emory University [Atlanta, GA], Department of Neurology, University of California-University of California-David Geffen School of Medicine [Los Angeles], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Department of Medical Genetics, HMNC Brain Health, Alzheimer Disease Research Laboratory, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Laboratoire d'Informatique, Systèmes, Traitement de l'Information et de la Connaissance (LISTIC), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Department of Psychiatry, School of Medicine-Johns Hopkins University and Johns Hopkins Bayview Medical Center, Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Department of neurosciences, University of California [San Diego] (UC San Diego), Department of Physics and Astronomy [Fort Worth], Texas Christian University (TCU), Department of Computer Science [University of California, Davis], Indiana University System, Institute for Aging and Alzheimer’s Disease Research [Fort Worth] (IAADR), Department of Laboratory Medicine and Pathology, Mayo Clinic, Institute for Memory Impairments and Neurological Disorders [Irvine], University of Colorado Anschutz [Aurora], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Keck School of Medicine [Los Angeles], Indiana University [South Bend], Massachusetts General Hospital, Novartis Institutes for Biomedical Research [Cambridge, MA, USA], Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, UCLA Medical Center-David Geffen School of Medicine [Los Angeles], University of California-University of California-University of California [Los Angeles] (UCLA), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Institut de Génomique d'Evry (IG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Antwerp (UA), Institute Born-Bunge, Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], University of Kuopio, Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Laboratoire d'Analyse Génomique, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Inserm-U1167, Dpt Gériatrie [CHU Broca], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Epidemiology, University of Washington, School of Medicine [Los Angeles], Albert Einstein College of Medicine [New York], IdiPAZ - Instituto de Investigación La Paz [Madrid, Spain], Instituto de Física Teórica UAM/CSIC (IFT), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Department of Internal Medicine, University of Central Asturias [Oviedo, Spain], Human Genome Sequencing Center, Baylor College of Medicine, Baylor University-Baylor University, Department of Epidemiology, Erasmus Medical Centre, Translational Genomics Research Institute [Phoenix, AZ, USA], University of Arizona, Banner Alzheimer's Institute [Phoenix, AZ, États-Unis], University of Texas Health Science Center at San Antonio [San Antonio], Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department. of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico, Centre for Research in Neurodegenerative Diseases, VA Puget Sound Health Care System/GRECC [Seattle, WA, USA], University of Pisa - Università di Pisa, Pfizer Worldwide Research and Development [Cambridge, MA, USA], Università cattolica del Sacro Cuore [Piacenza e Cremona] (Unicatt), Texas Tech University Health Sciences Center, Texas Tech University [Lubbock] (TTU), Saarland University [Saarbrücken], University of Bonn, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Cambridge Institute for Medical Research (CIMR), Department of Molecular Neurosciences, Institute of Neurology, UCL, Institute of Psychiatry, Institute of psychiatry, University of British Columbia (UBC), the Clinical Neuroscience Research Group, University of Manchester [Manchester]-Greater Manchester Neurosciences Centre, Aristotle University of Thessaloniki, Memory and Dementia Centre, 3rd Department of Neurology, G. Pa, University of Barcelona, University of Southampton, Department of Psychiatry [Oxford] (POWIC), University of Oxford [Oxford]-The Warneford Hospital, School of Psychology [Cardiff University], Department of Medical Sciences, UCL, Institute of Neurology [London], Washington University School of Medicine, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), School of Medecine, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], School of Life Sciences, Department of Neuroscience, Mayo Clinic Jacksonville, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Klinik für Psychiatrie, Martin-Luther-University Halle-Wittenberg, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Clínica Universidad de Navarra [Pamplona], Neurodegenerative Brain Diseases Group, VIB, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University-Medical Research Council, Brigham Young University (BYU), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, The Gertrude H Sergivesky Center, Columbia University College of Physicians and Surgeons, Genetic Epidemiology Unit, Section of Clinical and Molecular Neurogenetics, Universität zu Lübeck [Lübeck], University of Pennsylvania - Department of Pathology & Laboratory Medecine, Framingham Heart Study [Framingham, MA, USA], ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), European Project: 29845,LSH-ACC-MENTOR, University of Pennsylvania-University of Pennsylvania, Universität Bonn = University of Bonn-Institute of Human Genetics [Bonn, Germany], Universität Leipzig-Universität Leipzig, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Università degli Studi di Perugia = University of Perugia (UNIPG), Universidad Autónoma de Madrid (UAM), Università degli studi di Parma = University of Parma (UNIPR), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Universität Leipzig, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Yeshiva University- Albert Einstein College of Medicine [New York], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Università degli Studi di Milano = University of Milan (UNIMI), Saarland University Hospital (UKS), Università degli Studi di Firenze = University of Florence (UniFI), Universidade do Porto = University of Porto, University of California (UC)-University of California (UC), University of California [San Francisco] (UC San Francisco), University of California (UC), University of Kansas Medical Center [Kansas City, KS, USA], Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of California [Irvine] (UC Irvine), University of Kentucky (UK), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Department of Computer Science [Univ California Davis] (CS - UC Davis), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Sorbonne Université (SU), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA], Universität Bonn = University of Bonn, University of Oxford-The Warneford Hospital, Medical Research Council-Cardiff University, Universität zu Lübeck = University of Lübeck [Lübeck], Epidemiology, Neurology, Gastroenterology & Hepatology, Internal Medicine, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Eberhard Karls Universität Tübingen, IRCCS 'Casa Sollievo della Sofferenza', Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas (Ciberned), University of Florida [Gainesville], University of Parma, Troubles cognitifs dégénératifs et vasculaires (U1171), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-INSERM, Yeshiva University- Albert Einstein College of Medicine, Institut d’Électronique, de Microélectronique et de Nanotechnologie (IEMN) - UMR 8520 (IEMN), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Université Polytechnique Hauts-de-France (UPHF)-Ecole Centrale de Lille-Université Polytechnique Hauts-de-France (UPHF)-Institut supérieur de l'électronique et du numérique (ISEN), Autonomous University of Barcelona (UAB), Università degli Studi di Firenze [Firenze], Universidade do Porto [Porto], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Washington University in St Louis, University of South Florida (USF), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, McGill University, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique, Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Albert Einstein College of Medicine, Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Università Cattolica del S. Cuore - Catholic University of the Sacred Hearth, University of Florence (UNIFI), CIBER de Enfermedades Neurodegenerativas (CIBERNED), Universität zu Lübeck [Lübeck] - University of Lübeck [Lübeck], [ANR-10-IAIHU-06],« Investissements d'avenir » ,Agence nationale de la recherche (ANR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Department of Psychiatry, van der Lee, Sven J [0000-0003-1606-8643], Naj, Adam C [0000-0002-9621-2942], Badarinarayan, Nandini [0000-0002-6944-748X], Chouraki, Vincent [0000-0002-4698-1794], Graham, Robert R [0000-0001-7151-4277], Hoffmann, Per [0000-0002-6573-983X], Smith, Albert V [0000-0003-1942-5845], Satizabal, Claudia L [0000-0002-1115-4430], Brody, Jennifer A [0000-0001-8509-148X], Wolters, Frank J [0000-0003-2226-4050], Lupton, Michelle K [0000-0002-7274-7299], Lin, Honghuang [0000-0003-3043-3942], Adams, Hieab H [0000-0003-3687-2508], Giedraitis, Vilmantas [0000-0003-3423-2021], Pasquier, Florence [0000-0001-9880-9788], Chen, Yuning [0000-0002-7358-7055], Bossù, Paola [0000-0002-1432-0078], Ghetti, Bernardino [0000-0002-1842-8019], Yang, Qiong [0000-0002-3658-1375], Aspelund, Thor [0000-0002-7998-5433], Bullido, María J [0000-0002-6477-1117], Rivadeneira, Fernando [0000-0001-9435-9441], Rubinsztein, David C [0000-0001-5002-5263], Al-Chalabi, Ammar [0000-0002-4924-7712], Tsolaki, Magda [0000-0002-2072-8010], De Jager, Philip L [0000-0002-8057-2505], Dickson, Dennis W [0000-0001-7189-7917], Van Broeckhoven, Christine [0000-0003-0183-7665], Ikram, M Arfan [0000-0003-0372-8585], Amouyel, Philippe [0000-0001-9088-234X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Berr, Claudine, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, and Mentoring of LifeSciHealth-Multipliers in the Accession Candidate Countries - LSH-ACC-MENTOR - 29845 - OLD
Subjects: 0301 basic medicine, Linkage disequilibrium, [SDV]Life Sciences [q-bio], Medizin, Sequence Homology, Genome-wide association study, genetics [Alzheimer Disease], metabolism [Microglia], Linkage Disequilibrium, 0302 clinical medicine, genetics [Protein Interaction Maps], genetics [Membrane Glycoproteins], Gene Frequency, Immunologic, genetics [Adaptor Proteins, Signal Transducing], Receptors, genetics [Exome], Odds Ratio, Innate, genetics [Receptors, Immunologic], Exome, Protein Interaction Maps, genetics [Genetic Predisposition to Disease], Receptors, Immunologic, ABI3 protein, human, Genetics, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Amino Acid Sequence, Case-Control Studies, Gene Expression Profiling, Genetic Predisposition to Disease, Genotype, Humans, Immunity, Innate, Membrane Glycoproteins, Microglia, Phospholipase C gamma, Sequence Homology, Amino Acid, Polymorphism, Single Nucleotide, Adaptor Proteins, Single Nucleotide, 3. Good health, [SDV] Life Sciences [q-bio], Amino Acid, Settore MED/26 - NEUROLOGIA, genetics [Phospholipase C gamma], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer's disease, Common disease-common variant, Biology, Article, 03 medical and health sciences, ddc:570, medicine, Journal Article, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Polymorphism, Allele frequency, TREM2 protein, human, TREM2, Case-control study, Signal Transducing, Immunity, medicine.disease, R1, Minor allele frequency, genetics [Immunity, Innate], 030104 developmental biology, Human medicine, 030217 neurology & neurosurgery
Abstract: International audience; We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
Published: 2017

31. [P3–233]: CORRELATIONS BETWEEN PLASMA AND BRAIN BETA‐AMYLOID LEVELS IN INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE: THE FUNDACIÓ ACE HEALTHY BRAIN INITIATIVE (FACEHBI)

Author: Gemma Ortega, Agustín Ruiz, Virginia Pérez-Grijalba, Carla Abdelnour, Sonia Moreno, Susana Ruiz, Angela Sanabria, Marina Tarragona, Monserrat Alegret, Oscar Sotolongo-Grau, E. L. Martin, Marina Guitart, Anna Gailhajanet, Francisco Lomeña, Pedro Pesini, Judith Romero, Miguel Angel Tejero, Marta Gómez Chiari, Francisco Campos, Domingo Sanchez, Isabel Hernández, Ana Mauleón, Esther Palejà, Alba Pérez, Mercè Boada, Sergi Valero, Maitée Rosende-Roca, Assumpta Vivas, Manuel Sarasa, Adelina Orellana, Itziar de Rojas, Lluís Tárraga, Octavio Rodriguez-Gomez, Ana Espinosa, Joan Giménez, and Liliana Vargas
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Amyloid, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology, Cognitive decline, Beta (finance), Psychology, Neuroscience
Published: 2017

32. [P1–141]: EXPLORING APOE GENOTYPE EFFECTS ON AD RISK AND BETA‐AMYLOID BURDEN IN INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE: THE FACEHBI STUDY RESULTS

Author: Sonia Moreno‐Grau, Octavio Rodriguez, Angela Sanabria, Alba Perez, Domingo Sanchez, Carla Abdelnour, Sergi Valero, Isabel Hernandez, Maitee Rosende‐Roca, Ana Mauleon, Liliana Vargas, Monserrat Alegret, Ana Espinosa, Gemma Ortega, Marina Guitart, Anna Gailhajanet, Itziar Rojas, Oscar Sotolongo‐Grau, Susana Ruiz, Marina Tarragona, Judit Serra, Elvira Martín, Esther Peleja, Francisco Lomeña, Francisco Campos, Assumpta Vivas, Miguel Angel Tejero, Joan Giménez, Pedro Pesini, Manuel Sarasa, Gabriel Martinez, Marta Gómez Chiari, Adelina Orellana, Lluis Tarraga, Agustín Ruiz, and Mercè Boada
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published: 2017

33. [O1–13–06]: THE SPANISH VERSION OF FACE‐NAME ASSOCIATIVE MEMORY EXAM (S‐FNAME) PERFORMANCE IS RELATED TO AMYLOID BURDEN IN SUBJECTIVE COGNITIVE DECLINE

Author: Maitée Rosende-Roca, Mercè Boada, Francisco Lomeña, Octavio Rodriguez-Gomez, Sergi Valero, Liliana Vargas, Silvia Gil, Lluís Tárraga, Gemma Ortega, Marta Ibarria, Oscar Sotolongo-Grau, Susana Diego, Miguel Santos, Anna Gailhajanet, E. L. Martin, Carla Abdelnour, Marina Guitart, Monserrat Alegret, Ana Mauleón, Alba Pérez, Isabel Hernández, Angela Sanabria, Agustín Ruiz, Domingo Sanchez, and Ana Espinosa
Subjects: Epidemiology, Health Policy, Face (sociological concept), Spanish version, Content-addressable memory, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Amyloid burden, Neurology (clinical), Geriatrics and Gerontology, Cognitive decline, Psychology, Social psychology, Cognitive psychology
Published: 2017

34. The Spanish version of Face-Name Associative Memory Exam (S-FNAME) performance is related to amyloid burden in Subjective Cognitive Decline

Author: Angela, Sanabria, Montserrat, Alegret, Octavio, Rodriguez-Gomez, Sergi, Valero, Oscar, Sotolongo-Grau, Gemma, Monté-Rubio, Carla, Abdelnour, Ana, Espinosa, Gemma, Ortega, Alba, Perez-Cordon, Anna, Gailhajanet, Isabel, Hernandez, Maitee, Rosende-Roca, Liliana, Vargas, Ana, Mauleon, Domingo, Sanchez, Elvira, Martin, Dorene M, Rentz, Francisco, Lomeña, Agustin, Ruiz, Lluis, Tarraga, Merce, Boada, and A, Vivas
Subjects: Cingulate cortex, Male, medicine.medical_specialty, Amyloid beta, lcsh:Medicine, Disease, Audiology, Neuropsychological Tests, 050105 experimental psychology, Article, 03 medical and health sciences, 0302 clinical medicine, Memory, Activities of Daily Living, Medicine, Humans, 0501 psychology and cognitive sciences, Cognitive Dysfunction, Cognitive decline, lcsh:Science, Episodic memory, Aged, Language, Aged, 80 and over, Multidisciplinary, Amyloid beta-Peptides, biology, business.industry, 05 social sciences, lcsh:R, Neuropsychology, Cognition, Content-addressable memory, Middle Aged, Positron-Emission Tomography, biology.protein, lcsh:Q, Female, business, 030217 neurology & neurosurgery
Abstract: The Face-Name Associative Memory Exam (FNAME) is a paired associative memory test created to detect memory deficits in individuals with preclinical Alzheimer’s disease (AD). Worse performance on FNAME in cognitively healthy individuals were found related to higher amyloid beta (Aβ) burden measured with Positron-Emission-Tomography using 11C-PiB (PiB-PET). We previously reported normative data of a Spanish version of FNAME (S-FNAME) in cognitively healthy Spanish-speaking subjects. The aim of the present study was to determine whether performance on S-FNAME was associated with Aβ burden in subjective cognitive decline (SCD) individuals. 200 SCD subjects received neurological and neuropsychological assessments, including the S-FNAME and the Word List task from the Wechsler-Memory-Scale-III (WMS-III). Moreover, they received an MRI and (18)F-Florbetaben Positron-Emission-Tomography (FBB-PET) to measure Aβ burden. Three cognitive factor composites were derived for the episodic memory measures (face-name [SFN-N], face-occupation [SFN-O] and WMS-III) to determine whether episodic memory performance was related to Aβ deposition. Higher global Aβ deposition was significantly related to worse performance on SFN-N but not with SFN-O or WMS-III Composite. Moreover, worse SFN-N performance was significantly related to higher Aβ deposition in bilateral Posterior Cingulate Cortex. The S-FNAME may be a promising neuropsychological tool for detecting SCD individuals with preclinical AD.
Published: 2017

35. Exploring APOE genotype effects on Alzheimer's disease risk and amyloid β burden in individuals with subjective cognitive decline: The FundacioACE Healthy Brain Initiative (FACEHBI) study baseline results

Author: O. Rodríguez-Gómez, O. Sotolongo-Grau, M. Berthier, Francisco Lomeña, Miguel A. Santos-Santos, M. Boada, Assumpta Vivas, J. Martínez, C. Abdelnour, S. Preckler, Adelina Orellana, M. Moreno, I. de Rojas, G. Ortega, S. Diego, S. Ruiz, A. Mauleón, Judith Papasey, M. Rosende-Roca, A. Orellana, S. Bullich, J. Giménez, M. Torres, P. Pesini, Marina Guitart, Octavio Rodriguez-Gomez, A. Pérez-Cordon, M. Gómez-Chiari, J. Romero, Itziar de Rojas, Montserrat Alegret, A. Páez, P. Cañabate, Marta Gómez-Chiari, Lluís Tárraga, Liliana Vargas, Asunción Lafuente, M. Guitart, Carla Abdelnour, M. Buendia, Miguel Angel Tejero, Anna Gailhajanet, F. Lomeña, Isabel Hernández, L. Vargas, E. Martín, Agustín Ruiz, Sergi Valero, M.A. Santos-Santos, L. Tárraga, F. Campos, Oscar Sotolongo-Grau, M.A. Tejero, Esther Peleja, L. Núñez, Ana Mauleón, Silvia Gil, Alba Pérez-Cordón, Sonia Moreno–Grau, A. Vivas, V. Pérez-Grijalba, E. Pelejà, M. Ibarria, A. Ruiz, N. Aguilera, M. Sarasa, A. Sanabria, C. Cuevas, Ana Espinosa, Joan Giménez, A. Espinosa, Angela Sanabria, Domingo Sánchez-Ruiz, Nuria Aguilera, R. Gismondi, A. Lafuente, G. Monté, A. Pancho, Gemma Ortega, J. Pavía, Manuel Serrano-Ríos, D. Sánchez-Ruiz, S. Moreno-Grau, Mercè Boada, S. Gil, I. Hernández, Maitée Rosende-Roca, M. Alegret, S. Valero, A. Gailhajenet, B. Hernández-Olasagarre, Francisco Campos, Susana Ruiz, and E. L. Martin
Subjects: Male, 0301 basic medicine, Apolipoprotein E, Oncology, Amyloid, medicine.medical_specialty, Genotype, Epidemiology, Apolipoprotein E4, Neuroimaging, Disease, Diagnostic Self Evaluation, 03 medical and health sciences, Cellular and Molecular Neuroscience, Malalties del sistema nerviós, 0302 clinical medicine, Meta-Analysis as Topic, Developmental Neuroscience, Alzheimer Disease, Risk Factors, Internal medicine, medicine, Humans, Cognitive Dysfunction, Cognitive decline, Allele, Psychiatry, Alleles, business.industry, Health Policy, Brain, Middle Aged, Alzheimer's disease, Nervous system diseases, Psychiatry and Mental health, Cross-Sectional Studies, 030104 developmental biology, Malaltia d'Alzheimer, Spain, Endophenotype, Cohort, Biomarker (medicine), Female, Neurology (clinical), Geriatrics and Gerontology, business, Biomarkers, 030217 neurology & neurosurgery
Abstract: Introduction Subjective cognitive decline (SCD) has been proposed as a potential preclinical stage of Alzheimer's disease (AD). Nevertheless, the genetic and biomarker profiles of SCD individuals remain mostly unexplored. Methods We evaluated apolipoprotein E ( APOE ) e4's effect in the risk of presenting SCD, using the Fundacio ACE Healthy Brain Initiative (FACEHBI) SCD cohort and Spanish controls, and performed a meta-analysis addressing the same question. We assessed the relationship between APOE dosage and brain amyloid burden in the FACEHBI SCD and Alzheimer's Disease Neuroimaging Initiative cohorts. Results Analysis of the FACEHBI cohort and the meta-analysis demonstrated SCD individuals presented higher allelic frequencies of APOE e4 with respect to controls. APOE dosage explained 9% (FACEHBI cohort) and 11% (FACEHBI and Alzheimer's Disease Neuroimaging Initiative cohorts) of the variance of cerebral amyloid levels. Discussion The FACEHBI sample presents APOE e4 enrichment, suggesting that a pool of AD patients is nested in our sample. Cerebral amyloid levels are partially explained by the APOE allele dosage, suggesting that other genetic or epigenetic factors are involved in this AD endophenotype.
Published: 2017

36. Genome-wide significant risk factors for Alzheimer's disease: role in progression to dementia due to Alzheimer's disease among subjects with mild cognitive impairment

Author: A. Espinosa, André Lacour, Steffen Wolfsgruber, Isabel Hernández, W. Maier, Octavio Rodriguez-Gomez, J. Kornhuber, Eva Louwersheimer, Mercè Boada, Holger Wagner, SG Riedel-Heller, G. Ortega, Yolande A.L. Pijnenburg, Oscar Sotolongo-Grau, Tim Becker, Teddy Koene, Markus M. Nöthen, Oliver Peters, Susana Ruiz, Henne Holstege, W.M. van der Flier, Sonia Moreno-Grau, Victoria Fernández, Lutz Frölich, Frank Jessen, Agustín Ruiz, Philip Scheltens, Montserrat Alegret, Martin Scherer, Ana Mauleón, Maitée Rosende-Roca, L. Tárraga, Jens Wiltfang, Michael Wagner, E. Rüther, Michael Hüll, Stefanie Heilmann, Alfredo Ramirez, Liliana Vargas, Neurology, Amsterdam Neuroscience - Neurodegeneration, Medical psychology, Human genetics, APH - Personalized Medicine, APH - Methodology, and Epidemiology and Data Science
Subjects: 0301 basic medicine, Oncology, Male, Apolipoprotein E4, Genome-wide association study, genetics [Alzheimer Disease], methods [Genome-Wide Association Study], 0302 clinical medicine, Risk Factors, genetics [Apolipoprotein E4], Aged, 80 and over, biology, Hazard ratio, Middle Aged, 3. Good health, Psychiatry and Mental health, Disease Progression, genetics [Polymorphism, Single Nucleotide], Original Article, Female, Alzheimer's disease, Psychology, genetics [Clusterin], medicine.medical_specialty, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, Alzheimer Disease, genetics [Dementia], Internal medicine, mental disorders, CLU protein, human, medicine, Dementia, SNP, Humans, Cognitive Dysfunction, Genetic Predisposition to Disease, ddc:610, Psychiatry, Molecular Biology, Aged, Clusterin, Proportional hazards model, genetics [Cognitive Dysfunction], medicine.disease, 030104 developmental biology, biology.protein, 030217 neurology & neurosurgery, Biomarkers, Genome-Wide Association Study, Follow-Up Studies
Abstract: Few data are available concerning the role of risk markers for Alzheimer's disease (AD) in progression to AD dementia among subjects with mild cognitive impairment (MCI). We therefore investigated the role of well-known AD-associated single-nucleotide polymorphism (SNP) in the progression from MCI to AD dementia. Four independent MCI data sets were included in the analysis: (a) the German study on Aging, Cognition and Dementia in primary care patients (n=853); (b) the German Dementia Competence Network (n=812); (c) the Fundació ACE from Barcelona, Spain (n=1245); and (d) the MCI data set of the Amsterdam Dementia Cohort (n=306). The effects of single markers and combined polygenic scores were measured using Cox proportional hazards models and meta-analyses. The clusterin (CLU) locus was an independent genetic risk factor for MCI to AD progression (CLU rs9331888: hazard ratio (HR)=1.187 (1.054-1.32); P=0.0035). A polygenic score (PGS1) comprising nine established genome-wide AD risk loci predicted a small effect on the risk of MCI to AD progression in APOE-ϵ4 (apolipoprotein E-ϵ4) carriers (HR=1.746 (1.029-2.965); P=0.038). The novel AD loci reported by the International Genomics of Alzheimer's Project were not implicated in MCI to AD dementia progression. SNP-based polygenic risk scores comprising currently available AD genetic markers did not predict MCI to AD progression. We conclude that SNPs in CLU are potential markers for MCI to AD progression.
Published: 2017

37. P1‐321: White Matter Microstructure Disruption Could Be an Early Phenomenon in The Pathophysiology of Preclinical Alzheimer's Disease: FundaciÓ ACE Healthy Brain Initiative

Author: Francisco Lomeña, Miguel Angel Tejero, Francisco Campos, Marta Gómez Chiari, Lluís Tárraga, Gemma Ortega, Isabel Hernández, Javier Pavía, Carla Abdelnour, Domingo Sanchez, Susana Ruiz, Monserrat Alegret, Agustín Ruiz, Assumpta Vivas, Oscar Sotolongo-Grau, Alba Pérez, Ana Espinosa, Joan Giménez, Mercè Boada, Angela Sanabria, Marina Tarragona, and Octavio Rodriguez-Gomez
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Phenomenon, Neurology (clinical), Disease, Geriatrics and Gerontology, Psychology, White matter microstructure, Neuroscience, Pathophysiology
Published: 2016

38. P2‐141: FundaciÓ ACE Healthy Brain Initiative: A Study of Cognition and Biomarkers in Individuals with Subjective Cognitive Decline

Author: Miguel Angel Tejero, Susana Ruiz, Octavio Rodriguez-Gomez, Oscar Sotolongo-Grau, Isabel Hernández, Marina Tarragona, Marta Gómez Chiari, Angela Sanabria, Francisco Lomeña, Mercè Boada, Domingo Sanchez, Lluís Tárraga, Monserrat Alegret, Gemma Ortega, Carla Abdelnour, Assumpta Vivas, Agustín Ruiz, Alba Pérez, Javier Pavía, Ana Espinosa, Joan Giménez, and Francisco Campos
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Cognition, Neurology (clinical), Geriatrics and Gerontology, Cognitive decline, Psychology, Developmental psychology
Published: 2016

39. P3‐209: Impact of Biomarkers On Diagnostic Confidence in Clinical Assessment of Patients with Suspected Alzheimer's Disease and High Diagnostic Uncertainty: An EADC Study

Author: Luca Pelini, Samantha Galluzzi, Paolo Bosco, Sebastiaan Engelborghs, Luiza Spiru, Anna Mega, Christine Bastin, Derya Durusu Emek-Savaş, Agnese Picco, Milica G. Kramberger, Timo Grimmer, Alberto Redolfi, José Luis Molinuevo, Clarissa Ferrari, Görsev Yener, Patrizia Mecocci, Frédéric Assal, Anastasia Bougea, Isabel Santana, Flavio Nobili, Eric Salmon, Mircea Balasa, George P. Paraskevas, Brian A. Lawlor, Mihaela Marinescu, Oscar Sotolongo-Grau, Galina Grosu, Ellis Niemantsverdriet, Konstantinos Ntovas, Magda Tsolaki, Dina Zekry, Martina Bocchetta, Gorana Mandic Stojmenovic, Katarina Surlan Popovic, Giovanni B. Frisoni, Sarah O'Dwyer, Panteleimon Giannakopoulos, Elka Stefanova, Gabriel Gold, and Ricardo Morais
Subjects: Oncology, medicine.medical_specialty, Pathology, Epidemiology, business.industry, Health Policy, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, medicine, Biomarker (medicine), Neurology (clinical), Geriatrics and Gerontology, business
Published: 2016

40. Whole exome sequencing analysis reveals TRPV3 as a risk factor for cardioembolic stroke

Author: Joan Montaner, Elena Muiño, Israel Fernandez-Cadenas, B. B. Worrall, Jordi Jimenez-Conde, Caty Carrera, Sergi Beltran, Oscar Sotolongo-Grau, Jin-Moo Lee, Rainer Malik, Silvia Tur, Agustín Ruiz, Kelly Rabionet, Marina Mola-Caminal, Jurek Krupinski, Carolina Soriano-Tárrega, Sophia Derdak, Pilar Delgado, Cristina Gallego-Fabrega, Sudha Seshadri, Rosa Díaz-Navarro, Cristofol Vives-Bauza, Carlos Cruchaga, Jaume Roquer, and Eva Giralt-Steinhauer
Subjects: 0301 basic medicine, TRPV Cation Channels, Hematology, Odds ratio, Biology, medicine.disease, Bioinformatics, Polymorphism, Single Nucleotide, Transcriptome, Stroke, 03 medical and health sciences, 030104 developmental biology, Phenotype, Risk Factors, Case-Control Studies, Genotype, Cohort, Exome Sequencing, medicine, Humans, Exome, Risk factor, Exome sequencing
Abstract: SummaryGenetic studies suggest that hundreds of genes associated with stroke remain unidentified. Exome sequencing proves useful for finding new genes associated with stroke. We aimed to find new genetic risk factors for cardioembolic stroke by analysing exome sequence data using new strategies. For discovery, we analysed 42 cardioembolic stroke cases and controls with extreme phenotypes (cohort 1), and for replication, 32 cardioembolic stroke cases and controls (cohort 2) using the SeqCapExome capture kit. We then analysed the replicated genes in two new cohorts that comprised 834 cardioembolic strokes and controls (cohort 3) and 64,373 cardioembolic strokes and controls (cohort 4). Transcriptomic in-silico functional analyses were also performed. We found 26 coding regions with a higher frequency of mutations in cardioembolic strokes after correcting for the number of mutations found in the whole exome of every patient. The TRPV3 gene was associated with cardioembolic stroke after replication of exome sequencing analysis (p-value-discovery: 0.018, p-value-replication: 0.014). The analysis of the TRPV3 gene using polymorphisms in cohort 3 and 4 revealed two polymorphisms associated with cardioembolic stroke in both cohorts, the most significant polymorphism being rs151091899 (p-value: 3.1 × 10−05; odds ratio: 5.4) in cohort 3. The genotype of one polymorphism of TRPV3 was associated with a differential expression of genes linked to cardiac malformations. In conclusion, new strategies using exome sequence data have revealed TRPV3 as a new gene associated with cardioembolic stroke. This strategy among others might be useful in finding new genes associated with complex genetic diseases.
Published: 2016

41. Radiotherapy and the role of the immune system

Author: Oscar Sotolongo Grau, Daniel Rodriguez Pérez, J. C. Antoranz, Luis M. Gaggero Sager, and Oscar Sotolongo Costa
Subjects: lcsh:Social Sciences, lcsh:H, lcsh:Q, lcsh:H1-99, lcsh:Social sciences (General), lcsh:Science, lcsh:Science (General), lcsh:Q1-390
Abstract: Se simuló computacionalmente un gran número de pacientes bajo tratamiento de radioterapia, mediante un sistema dinámico. De los resultados, se halló un método para cambiar el número de sesiones de radiación manteniendo óptimo el tratamiento. Además, se obtuvo que la relación entre la fracción sistema inmune-eficiencia tumoral para un paciente dado y la máxima probabilidad de éxito del tratamiento sigue una ley de potencias.
Published: 2012

42. Immune system-tumour efficiency ratio as a new oncological index for radiotherapy treatment optimization

Author: José Carlos Antoranz, Oscar Sotolongo-Costa, Daniel Rodríguez-Pérez, J. A. Santos-Miranda, and Oscar Sotolongo-Grau
Subjects: medicine.medical_specialty, Pathology, Time Factors, medicine.medical_treatment, Large population, Cell Count, Models, Biological, General Biochemistry, Genetics and Molecular Biology, Neoplasms, medicine, Humans, Computer Simulation, Lymphocytes, Probability, General Environmental Science, Pharmacology, General Immunology and Microbiology, business.industry, Applied Mathematics, General Neuroscience, General Medicine, Radiation therapy, Treatment success, Dose optimization, Patient classification, Immune System, Modeling and Simulation, Radiotherapy treatment, Dose Fractionation, Radiation, Radiology, business, Algorithms
Abstract: A dynamical system model for tumour-immune system interaction together with a method to mimic radiation therapy are proposed. A large population of virtual patients is simulated following an ideal radiation treatment. A characteristic parameter, the immune system-tumor efficiency ratio (ISTER) is introduced. ISTER dependence of treatment success and other features are studied. Radiotherapy treatment dose optimization, following ALARA (As Low As Reasonably Achievable) criterion, as well as a patient classification are drawn from the statistics results.
Published: 2009

43. O5‐06‐03: The cognitive network as dependent on metabolic activity and synaptic structure: A trip through cognitive decline to dementia

Author: Fernando Maestú, Oscar Sotolongo-Costa, James T. Becker, Oscar Sotolongo-Grau, and L. M. Gaggero-Sager
Subjects: Epidemiology, Health Policy, medicine.disease, Cognitive network, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Dementia, Neurology (clinical), Geriatrics and Gerontology, Cognitive decline, Metabolic activity, Psychology, Cognitive psychology
Published: 2015

44. P3‐196: Cognitive composites and prodromal Alzheimer's disease

Author: Lluís Tárraga, Monserrat Alegret, Isabel Hernández, Pedro Pesini, Asunción Lafuente, Manuel Sarasa, Oscar Sotolongo-Grau, Sergi Valero, Ana Espinosa, Mercè Boada, Marta Ibarria, Itziar San José, Susana Ruiz, Agustín Ruiz, and Mar Buendía
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, Medicine, Cognition, Neurology (clinical), Disease, Geriatrics and Gerontology, business, Clinical psychology
Published: 2015

45. Evaluation of Candidate Genes Related to Neuronal Apoptosis in Late-Onset Alzheimer’s Disease

Author: Juan Marín, Ana Mauleón, Octavio Rodriguez, Oscar Sotolongo-Grau, Isabel Hernández, Liliana Vargas, Montserrat Alegret, Gemma Ortega, Paulina Carriba, Bruna Barneda, Maria Victoria Fernandez, Joan X. Comella, Mercè Boada, Joaquín Aguirre López, Jesús López-Arrieta, Carmen Antúnez, Ana Espinosa, Lluís Tárraga, Agustín Ruiz, Sonia Moreno-Grau, and Maitée Rosende-Roca
Subjects: Male, Candidate gene, Fas Ligand Protein, Locus (genetics), Genome-wide association study, Single-nucleotide polymorphism, Apoptosis, Human leukocyte antigen, Biology, Apolipoproteins E, Meta-Analysis as Topic, Piperidines, Alzheimer Disease, Predictive Value of Tests, Genetic variation, Humans, Donepezil, Longitudinal Studies, Gene, Genetic association, Aged, Genetics, Aged, 80 and over, Analysis of Variance, Polymorphism, Genetic, Tumor Necrosis Factor-alpha, General Neuroscience, General Medicine, Psychiatry and Mental health, Clinical Psychology, Treatment Outcome, Cytochrome P-450 CYP2D6, Pharmacogenetics, Indans, Female, Cholinesterase Inhibitors, Geriatrics and Gerontology, Mental Status Schedule
Abstract: The objective of this study was to identify genetic variation in genes encoding death receptors and signals that modulate their activity. After conducting a meta-analysis with five previous genome-wide association studies and aggregated data, the most significant signals, (TNF locus: rs2395488, rs2534672, and rs9267445; and FASLG locus: rs730278), were replicated in 1,046 cases and 372 controls. The rs2395488 and rs2534672 markers showed a modest protective effect (OR = 0.849, p = 0.49780;OR= 0.687, p = 0.11335), in contrast to rs730278 marker (OR = 1.146, p = 0.17212), which did not follow the previous effect direction; in any case it reached the significance level. Final meta-analysis, adding the replication sample, confirmed these observations. We concluded that FASLG marker is not etiologically linked to Alzheimer’s disease. However, single nucleotide polymorphisms around TNF locus require further analyses in order to explain the association between Alzheimer’s disease and human leukocyte antigen.
Published: 2015

46. A physical model for dementia

Author: Fernando Maestú, Oscar Sotolongo-Grau, Oscar Sotolongo-Costa, L. M. Gaggero-Sager, and James T. Becker
Subjects: Statistics and Probability, 05 social sciences, FOS: Physical sciences, Statistical and Nonlinear Physics, Disease, medicine.disease, 050105 experimental psychology, Article, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, Biological Physics (physics.bio-ph), FOS: Biological sciences, Quantitative Biology - Neurons and Cognition, mental disorders, medicine, Dementia, 0501 psychology and cognitive sciences, Neurons and Cognition (q-bio.NC), Physics - Biological Physics, Psychology, 030217 neurology & neurosurgery, Cognitive psychology
Abstract: Aging associated brain decline often result in some kind of dementia. Even when this is a complex brain disorder a physical model can be used in order to describe its general behavior. This model is based in first principles. A probabilistic model for the development of dementia is obtained and fitted to some experimental data obtained from the Alzheimer's Disease Neuroimaging Initiative. It is explained how dementia appears as a consequence of aging and why it is irreversible., 12 pages, 4 figures. submitted for publication
Published: 2014

47. Association between cell-bound blood amyloid-β(1 - 40) levels and hippocampus volume

Author: Miguel Angel Tejero, Itziar San José, Joan Giménez, Virginia Pérez-Grijalba, Lluís Tárraga, Mercè Boada, Sergi Valero, Mar Buendía, Marta Ibarria, Pedro Pesini, Asunción Lafuente, Oscar Sotolongo-Grau, Manuel Sarasa, Agustín Ruiz, and Isabel Hernández
Subjects: Secondary prevention, medicine.medical_specialty, Neurology, Amyloid β, business.industry, Research, Cognitive Neuroscience, Cell, Clinical Neurology, Hippocampus, Disease, Bioinformatics, 3. Good health, medicine.anatomical_structure, Hippocampal volume, Medicine, Biomarker (medicine), Neurology (clinical), business
Abstract: Introduction The identification of early, preferably presymptomatic, biomarkers and true etiologic factors for Alzheimer’s disease (AD) is the first step toward establishing effective primary and secondary prevention programs. Consequently, the search for a relatively inexpensive and harmless biomarker for AD continues. Despite intensive research worldwide, to date there is no definitive plasma or blood biomarker indicating high or low risk of conversion to AD. Methods Magnetic resonance imaging and β-amyloid (Aβ) levels in three blood compartments (diluted in plasma, undiluted in plasma and cell-bound) were measured in 96 subjects (33 with mild cognitive impairment, 14 with AD and 49 healthy controls). Pearson correlations were completed between 113 regions of interest (ROIs) (45 subcortical and 68 cortical) and Aβ levels. Pearson correlation analyses adjusted for the covariates age, sex, apolipoprotein E (ApoE), education and creatinine levels showed neuroimaging ROIs were associated with Aβ levels. Two statistical methods were applied to study the major relationships identified: (1) Pearson correlation with phenotype added as a covariate and (2) a meta-analysis stratified by phenotype. Neuroimaging data and plasma Aβ measurements were taken from 630 Alzheimer’s Disease Neuroimaging Initiative (ADNI) subjects to be compared with our results. Results The left hippocampus was the brain region most correlated with Aβ(1–40) bound to blood cell pellets (partial correlation (pcor) = −0.37, P = 0.0007) after adjustment for the covariates age, gender and education, ApoE and creatinine levels. The correlation remained almost the same (pcor = −0.35, P = 0.002) if phenotype is also added as a covariate. The association between both measurements was independent of cognitive status. The left hemisphere entorhinal cortex also correlated with Aβ(1–40) cell-bound fraction. AB128 and ADNI plasma Aβ measurements were not related to any brain morphometric measurement. Conclusions Association of cell-bound Aβ(1–40) in blood with left hippocampal volume was much stronger than previously observed in Aβ plasma fractions. If confirmed, this observation will require careful interpretation and must be taken into account for blood amyloid-based biomarker development.
Published: 2014

48. Association of TMEM106B rs1990622 marker and frontotemporal dementia: evidence for a recessive effect and meta-analysis

Author: Montserrat Alegret, Lluís Tárraga, Agustín Ruiz, Mercè Boada, Maitée Rosende-Roca, Isabel Hernández, Ana Mauleón, Oscar Sotolongo-Grau, Ana Espinosa, and Liliana Vargas
Subjects: Male, Genome-wide association study, Genes, Recessive, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, White People, mental disorders, Genotype, medicine, SNP, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Aged, Genetics, Models, Genetic, General Neuroscience, nutritional and metabolic diseases, Membrane Proteins, General Medicine, Odds ratio, Frontotemporal lobar degeneration, Sequence Analysis, DNA, medicine.disease, nervous system diseases, Psychiatry and Mental health, Clinical Psychology, Study heterogeneity, Spain, Meta-analysis, Case-Control Studies, Frontotemporal Dementia, Female, Geriatrics and Gerontology, Psychology, Frontotemporal dementia
Abstract: Transmembrane Protein 106B SNP rs1990622 was recently shown to modify the risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTD-TDP). An independent replication study of this genetic variant was performed in 381 individuals from Catalonia (Spain). By applying a recessive model, a tendency toward an association with FTD risk was observed in our case-control study (age- and gender-adjusted odds ratio = 0.57; p = 0.082). Importantly, meta-analysis of available studies also supports a recessive effect for rs1990622 CC genotype (OR = 0.70; CI 95% [0.57-0.85]; p = 0.0003) and demonstrates the existence of statistical heterogeneity due to an inherent pathological heterogeneity between series (p = 0.00014). We conclude that TMEM106B is associated with FTD, although the extent of this effect is difficult to be estimated by using clinical FTD series.
Published: 2014

49. O4‐04‐04: TOWARD FINE MAPPING AND FUNCTIONAL CHARACTERIZATION OF GENOME‐WIDE ASSOCIATION STUDY‐IDENTIFIED LOCUS RS74615166 (TRIP4) FOR ALZHEIMER'S DISEASE

Author: Markus Leber, Markus M. Nöthen, Wolfgang Maier, Stefanie Heilmann, Alfredo Ramirez, Frank Jessen, Lluís Tárraga, Maitée Rosende-Roca, Montse Alegret, Isabel Hernández, Tim Becker, Holger Wagner, Mercè Boada, Ana Espinosa, André Lacour, Monique M.B. Breteler, Agustín Ruiz, Peter Nürnberg, Ana Mauleón, Jose Luis Royo, Mathias Thelen, Mohammad R. Toliat, J Becker, and Oscar Sotolongo Grau
Subjects: Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Locus (genetics), Genome-wide association study, Neurology (clinical), Disease, Geriatrics and Gerontology, Biology
Published: 2014

50. Correction: Blood Amyloid Beta Levels in Healthy, Mild Cognitive Impairment and Alzheimer’s Disease Individuals: Replication of Diastolic Blood Pressure Correlations and Analysis of Critical Covariates

Author: AgustÃn Ruiz, Pedro Pesini, Ana Espinosa, Virginia PÃ©rez-Grijalba, Sergi Valero, Oscar Sotolongo-Grau, Montserrat Alegret, Inmaculada MonleÃ³n, AsunciÃ³n Lafuente, Mar BuendÃa, Marta Ibarria, Susana Ruiz, Isabel HernÃ¡ndez, Itziar San JosÃ©, LluÃs TÃ¡rraga, MercÃ¨ Boada, and Manuel Sarasa
Subjects: Multidisciplinary, Science, lcsh:R, Medicine, Correction, lcsh:Medicine, lcsh:Q, lcsh:Science
Published: 2014

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