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Alzheimer Disease: HELP
Articles by Lluís Tàrraga
Based on 50 articles published since 2010
(Why 50 articles?)
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Between 2010 and 2020, L. Tárraga wrote the following 50 articles about Alzheimer Disease.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Patient Engagement: The Fundació ACE Framework for Improving Recruitment and Retention in Alzheimer's Disease Research. 2018

Boada, Mercè / Santos-Santos, Miguel A / Rodríguez-Gómez, Octavio / Alegret, Montserrat / Cañabate, Pilar / Lafuente, Asunción / Abdelnour, Carla / Buendía, Mar / de Dios, Maria José / Morera, América / Sanabria, Ángela / Campo, Laura / Ruiz, Agustín / Tárraga, Lluís. ·Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain. · Cognition and Brain Plasticity Group, Bellvitge Biomedical Research Institute, IDIBELL, Spain. · International Corporate Affairs, Alzheimer's Disease, Eli Lilly and Co. ·J Alzheimers Dis · Pubmed #29562541.

ABSTRACT: Alzheimer's disease (AD) research is at a critical time. The global society is increasingly aware of the frightening rate of growth of the human and financial burden caused by this condition and of the urgent need to halt its progression. Consequently, the scientific community holds great responsibility to quickly put in place and optimize the machinery necessary for testing new treatments or interventions. In this context demand for participants for AD research is at an all-time high. In this review, we will focus on a methodological factor that is increasingly recognized as a key factor that shapes trial populations and affects validity of results in clinical trials: patient engagement, recruitment, and retention. We outline specific problems relevant to patient engagement in AD including recruiting enough participants, difficulties in participant retention, ensuring the recruited sample is representative of the general AD population, the burden of screening failures, and new challenges related to recruiting in preclinical disease. To address the urgent need for more research studying the applicability and cost-effectiveness of different recruitment strategies across different settings and nationalities, we describe the Models of Patient Engagement for Alzheimer's Disease (MOPEAD) project, a public-private partnership promoted by the Innovative Medicine Initiative (IMI), which will provide a large multinational quantitative analysis comparing different innovative recruitment models. We also discuss strategies that address each problem and draw on the experience of Fundació ACE to argue that focusing resources on comprehensive AD centers that offer coordinated clinical and social care and participate in basic and clinical research, is an effective and efficient way of implementing many of the discussed strategies.

2 Clinical Trial Safety, tolerability and immunogenicity of an active anti-Aβ 2018

Lacosta, Ana-María / Pascual-Lucas, María / Pesini, Pedro / Casabona, Diego / Pérez-Grijalba, Virginia / Marcos-Campos, Iván / Sarasa, Leticia / Canudas, Jesus / Badi, Hassnae / Monleón, Inmaculada / San-José, Itziar / Munuera, Josep / Rodríguez-Gómez, Octavio / Abdelnour, Carla / Lafuente, Asunción / Buendía, Mar / Boada, Mercè / Tárraga, Lluis / Ruiz, Agustín / Sarasa, Manuel. ·Araclon Biotech, Vía Hispanidad 21, 50009, Zaragoza, Spain. · Araclon Biotech, Vía Hispanidad 21, 50009, Zaragoza, Spain. ppesini@araclon.com. · Institut de Diagnòstic per la Imatge, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. · Memory Clinic and Research Centre, Fundació ACE Institut Català de Neurociències Aplicades, Barcelona, Spain. ·Alzheimers Res Ther · Pubmed #29378651.

ABSTRACT: BACKGROUND: Immunotherapy targeting the amyloid-β (Aβ) peptide is a promising strategy for the treatment of Alzheimer's disease (AD); however, none of the active or passive vaccines tested have been demonstrated to be effective to date. We have developed the first active vaccine against the C-terminal end of Aβ METHODS: A randomised, double-blind, placebo-controlled, parallel-group, phase I study of ABvac40 was conducted with patients aged 50-85 years with mild to moderate AD. Participants were entered into three separate groups according to time of study entry and were randomly allocated to receive ABvac40 or placebo (overall ratio 2:1). The first group received two half-doses of ABvac40 or placebo, whereas the second and third groups received two and three full doses, respectively. All treatments were administered subcutaneously at 4-week intervals. Patients, carers and investigators were blind to treatment allocation throughout the study. The primary objective was to assess the safety and tolerability of ABvac40 by registering all adverse events (AEs). All patients who received at least one dose of treatment were included in the safety analysis. The secondary objective was to evaluate the immunogenicity of ABvac40 by titration of specific anti-Aβ RESULTS: Twenty-four patients were randomly allocated: 16 patients to the ABvac40 group and 8 patients to the placebo group. All randomised patients completed the study, therefore the intention-to-treat and safety populations were identical. Overall, 71 AEs affecting 18 patients were recorded: 11 (69%) in the ABvac40 group and 7 (88%) in the placebo group (p = 0.6214). Neither incident vasogenic oedema nor sulcal effusion (amyloid-related imaging abnormalities corresponding to vasogenic oedema and sulcal effusions) nor microhaemorrhages (amyloid-related imaging abnormalities corresponding to microhaemorrhages and hemosiderin deposits) were detected throughout the study period in the ABvac40-treated patients. Eleven of 12 (~92%) individuals receiving three injections of ABvac40 developed specific anti-Aβ CONCLUSIONS: ABvac40 showed a favourable safety and tolerability profile while eliciting a consistent and specific immune response. An ongoing phase II clinical trial is needed to confirm these results and to explore the clinical efficacy of ABvac40. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03113812 . Retrospectively registered on 14 April 2017.

3 Clinical Trial Efficacy and Safety of Plasma Exchange with 5% Albumin to Modify Cerebrospinal Fluid and Plasma Amyloid-β Concentrations and Cognition Outcomes in Alzheimer's Disease Patients: A Multicenter, Randomized, Controlled Clinical Trial. 2017

Boada, Mercè / Anaya, Fernando / Ortiz, Pilar / Olazarán, Javier / Shua-Haim, Joshua R / Obisesan, Thomas O / Hernández, Isabel / Muñoz, Joan / Buendia, Mar / Alegret, Montserrat / Lafuente, Asunción / Tárraga, Lluís / Núñez, Laura / Torres, Mireia / Grifols, Joan Ramon / Ferrer, Isidre / Lopez, Oscar L / Páez, Antonio. ·Memory Clinic and Research Center of Fundació ACE, Institut Catalá de Neurociències Aplicades, Barcelona, Spain. · Neurology Service, Hospital General Universitari Vall d'Hebron, Barcelona, Spain. · Nephrology Service, Hospital General Universitario Gregorio Marañón, Madrid, Spain. · Banc de Sang i Teixits, Barcelona, Spain. · Neurology Service, Hospital General Universitario Gregorio Marañón, Madrid, Spain. · Alzheimer's Research Corporation, Mid Atlantic Geriatric Association, Manchester, NJ, USA. · Department of Internal Medicine, Howard University, Washington, DC, USA. · Clinical Trials Department, Instituto Grifols S.A., Barcelona, Spain. · Institut de Neuropatologia, Hospital Universitario Bellvitge, Barcelona, Spain. · Departments of Neurology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, USA. ·J Alzheimers Dis · Pubmed #27911295.

ABSTRACT: BACKGROUND: Studies conducted in animal models and humans suggest the presence of a dynamic equilibrium of amyloid-β (Aβ) peptide between cerebrospinal fluid (CSF) and plasma compartments. OBJECTIVE: To determine whether plasma exchange (PE) with albumin replacement was able to modify Aβ concentrations in CSF and plasma as well as to improve cognition in patients with mild-moderate Alzheimer's disease (AD). METHODS: In a multicenter, randomized, patient- and rater-blind, controlled, parallel-group, phase II study, 42 AD patients were assigned (1 : 1) to PE treatment or control (sham) groups. Treated patients received a maximum of 18 PE with 5% albumin (Albutein®, Grifols) with three different schedules: two PE/weekly (three weeks), one PE/weekly (six weeks), and one PE/bi- weekly (12 weeks), plus a six-month follow-up period. Plasma and CSF Aβ1-40 and Aβ1-42 levels, as well as cognitive, functional, and behavioral measures were determined. RESULTS: CSF Aβ1-42 levels after the last PE compared to baseline were marginally higher in PE-treated group versus controls (adjusted means of variation: 75.3 versus -45.5 pg/mL; 95% CI: -19.8, 170.5 versus 135.1, 44.2; p = 0.072). Plasma Aβ1-42 levels were lower in the PE-treated group after each treatment period (p < 0.05). Plasma Aβ1-40 levels showed a saw-tooth pattern variation associated with PE. PE-treated patients scored better in the Boston Naming Test and Semantic Verbal Fluency (p < 0.05) throughout the study. Neuropsychiatric Inventory scores were higher in controls during the PE phase (p < 0.05). CONCLUSION: PE with human albumin modified CSF and plasma Aβ1-42 levels. Patients treated with PE showed improvement in memory and language functions, which persisted after PE was discontinued.

4 Article A computerized version of the Short Form of the Face-Name Associative Memory Exam (FACEmemory®) for the early detection of Alzheimer's disease. 2020

Alegret, Montserrat / Muñoz, Nathalia / Roberto, Natalia / Rentz, Dorene M / Valero, Sergi / Gil, Silvia / Marquié, Marta / Hernández, Isabel / Riveros, Catalina / Sanabria, Angela / Perez-Cordon, Alba / Espinosa, Ana / Ortega, Gemma / Mauleón, Ana / Abdelnour, Carla / Rosende-Roca, Maitee / Papp, Kathryn V / Orellana, Adela / Benaque, Alba / Tarraga, Lluís / Ruiz, Agustín / Boada, Mercè. ·Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Gran Via de Carles III, 85 bis, 08028, Barcelona, Spain. malegret@fundacioace.com. · Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. malegret@fundacioace.com. · Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Gran Via de Carles III, 85 bis, 08028, Barcelona, Spain. · Department of Neurology, Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Boston, MA, USA. · Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. · Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. ·Alzheimers Res Ther · Pubmed #32178724.

ABSTRACT: BACKGROUND: Computerized neuropsychological tests for early detection of Alzheimer's disease (AD) have attracted increasing interest. Memory for faces and proper names is a complex task because its association is arbitrary. It implicates associative occipito-temporal cerebral regions, which are disrupted in AD. The short form of the Face-Name Associative Memory Exam (FNAME-12), developed to detect preclinical and prodromal AD, asks individuals to learn the names and occupations associated with 12 faces. The current work advances this field by using voice recognition and touchscreen response format. The purpose of this study is to create the first self-administered episodic memory test, FACEmemory®, by adapting the FNAME-12 for tablet use with voice recognition, touchscreen answers, and automatic scoring. The test was minimally supervised by a psychologist to avoid technological problems during execution and scored manually to assess the reliability of the automatic scoring. The aims of the present study were (1) to determine whether FACEmemory® is a sensitive tool for the detection of cognitive impairment, (2) to examine whether performances on FACEmemory® are correlated with those on the S-FNAME (paper-and-pencil version with 16 images), and (3) to determine whether performances on FACEmemory® are related to AD biomarkers in the cerebrospinal fluid (CSF) (Aβ42, p-tau, and Aβ42/p-tau ratio). METHODS: FACEmemory® was completed by 154 cognitively healthy (CH) individuals and 122 subjects with mild cognitive impairment, of whom 61 were non-amnestic (naMCI) and 61 amnestic (aMCI). A subsample of 65 individuals completed the S-FNAME, and 65 subjects received lumbar punctures. RESULTS: Performance on FACEmemory® was progressively worse from CH to the naMCI and aMCI groups. A cutoff of 31.5 in total FACEmemory® obtained 80.5% and 80.3% sensitivity and specificity values, respectively, for discriminating between CH and aMCI. Automatically corrected FACEmemory® scores were highly correlated with the manually corrected ones. FACEmemory® scores and AD CSF biomarker levels were significantly correlated as well, mainly in the aMCI group. CONCLUSIONS: FACEmemory® may be a promising memory prescreening tool for detecting subtle memory deficits related to AD. Our findings suggest FACEmemory® performance provides a useful gradation of impairment from normal aging to aMCI, and it is related to CSF AD biomarkers.

5 Article PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment. 2020

Kleineidam, Luca / Chouraki, Vincent / Próchnicki, Tomasz / van der Lee, Sven J / Madrid-Márquez, Laura / Wagner-Thelen, Holger / Karaca, Ilker / Weinhold, Leonie / Wolfsgruber, Steffen / Boland, Anne / Martino Adami, Pamela V / Lewczuk, Piotr / Popp, Julius / Brosseron, Frederic / Jansen, Iris E / Hulsman, Marc / Kornhuber, Johannes / Peters, Oliver / Berr, Claudine / Heun, Reinhard / Frölich, Lutz / Tzourio, Christophe / Dartigues, Jean-François / Hüll, Michael / Espinosa, Ana / Hernández, Isabel / de Rojas, Itziar / Orellana, Adelina / Valero, Sergi / Stringa, Najada / van Schoor, Natasja M / Huisman, Martijn / Scheltens, Philip / Anonymous421128 / Rüther, Eckart / Deleuze, Jean-Francois / Wiltfang, Jens / Tarraga, Lluis / Schmid, Matthias / Scherer, Martin / Riedel-Heller, Steffi / Heneka, Michael T / Amouyel, Philippe / Jessen, Frank / Boada, Merce / Maier, Wolfgang / Schneider, Anja / González-Pérez, Antonio / van der Flier, Wiesje M / Wagner, Michael / Lambert, Jean-Charles / Holstege, Henne / Sáez, Mª Eugenia / Latz, Eicke / Ruiz, Agustin / Ramirez, Alfredo. ·Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany. · Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany. · German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. · Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE-Facteurs de risque Et déterminants moléculaires des maladies liées au vieillissement, Lille, France. · Epidemiology and Public Health Department, Centre Hospitalier Universitaire de Lille, Lille, France. · Institute of Innate Immunity, University Hospitals Bonn, Bonn, Germany. · Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. · Department of Clinical Genetics, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. · Andalusian Bioinformatics Research Centre (CAEBi), Seville, Spain. · Institute of Medical Biometry, Informatics and Epidemiology, University Hospital of Bonn, Bonn, Germany. · Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Évry, France. · Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany. · Department of Neurodegeneration Diagnostics, Medical University of Białystok, Białystok, Poland. · Department of Biochemical Diagnostics, University Hospital of Białystok, Białystok, Poland. · Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland. · Department of Geriatric Psychiatry, University Hospital of Psychiatry Zurich, Zurich, Switzerland. · Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. · Department of Psychiatry, Charité - Universitätsmedizin Berlin, Berlin, Germany. · DZNE, German Center for Neurodegenerative Diseases, Berlin, Germany. · INSERM, University Montpellier, Neuropsychiatry: Epidemiological and Clinical Research, Montpellier, France. · Department of Psychiatry and Psychotherapy, University Hospital Bonn, 53127, Bonn, Germany. · Department of Geriatric Psychiatry, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany. · Inserm, Bordeaux Population Health Research Center, UMR1219, University of Bordeaux, Bordeaux, France. · Department of Psychiatry and Psychotherapy, Center for Psychiatry, Clinic for Geriatric Psychiatry and Psychotherapy Emmendingen, University of Freiburg, Freiburg, Germany. · Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya-Barcelona, Barcelona, Spain. · Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. · Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Amsterdam UMC-Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. · Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany. · German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany. · iBiMED, Medical Sciences Department, University of Aveiro, Aveiro, Portugal. · Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany. · Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA. · Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany. · Centre for Molecular Inflammation Research (CEMIR), Norwegian University of Science and Technology, Trondheim, Norway. · Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany. alfredo.ramirez@uk-koeln.de. · Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany. alfredo.ramirez@uk-koeln.de. ·Acta Neuropathol · Pubmed #32166339.

ABSTRACT: A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau

6 Article The 2019

Sánchez-Juan, Pascual / Moreno, Sonia / de Rojas, Itziar / Hernández, Isabel / Valero, Sergi / Alegret, Montse / Montrreal, Laura / García González, Pablo / Lage, Carmen / López-García, Sara / Rodrííguez-Rodríguez, Eloy / Orellana, Adelina / Tárraga, Lluís / Boada, Mercè / Ruiz, Agustín. ·Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain. · Service of Neurology, University Hospital Marqués de Valdecilla, IDIVAL, University of Cantabria, Santander, Spain. · Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain. ·Front Aging Neurosci · Pubmed #31866851.

ABSTRACT: An ancestral inversion of 900 kb on chromosome 17q21, which includes the microtubule-associated protein tau (

7 Article Plasma Aβ42/40 ratio alone or combined with FDG-PET can accurately predict amyloid-PET positivity: a cross-sectional analysis from the AB255 Study. 2019

Pérez-Grijalba, Virginia / Arbizu, Javier / Romero, Judith / Prieto, Elena / Pesini, Pedro / Sarasa, Leticia / Guillen, Fernando / Monleón, Inmaculada / San-José, Itziar / Martínez-Lage, Pablo / Munuera, Josep / Hernández, Isabel / Buendía, Mar / Sotolongo-Grau, Oscar / Alegret, Montserrat / Ruiz, Agustín / Tárraga, Lluis / Boada, Mercè / Sarasa, Manuel / Anonymous4071077. ·Araclon Biotech S.L., Vía Hispanidad 21, 50009, Zaragoza, Spain. · Servicio de Medicina Nuclear, Clínica Universidad de Navarra, Pamplona, Spain. · Araclon Biotech S.L., Vía Hispanidad 21, 50009, Zaragoza, Spain. ppesini@araclon.com. · Center for Research and Advanced Therapies and Memory Clinic, Fundación CITA-Alzheimer, San Sebastián, Spain. · Institut de recerca Sant Joan de Déu, Hospital Infantil Sant Joan de Déu, Barcelona, Spain. · Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya-Barcelona, Barcelona, Spain. · Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. ·Alzheimers Res Ther · Pubmed #31787105.

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.

8 Article 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. 2019

Moreno-Grau, Sonia / de Rojas, Itziar / Hernández, Isabel / Quintela, Inés / Montrreal, Laura / Alegret, Montserrat / Hernández-Olasagarre, Begoña / Madrid, Laura / González-Perez, Antonio / Maroñas, Olalla / Rosende-Roca, Maitée / Mauleón, Ana / Vargas, Liliana / Lafuente, Asunción / Abdelnour, Carla / Rodríguez-Gómez, Octavio / Gil, Silvia / Santos-Santos, Miguel Ángel / Espinosa, Ana / Ortega, Gemma / Sanabria, Ángela / Pérez-Cordón, Alba / Cañabate, Pilar / Moreno, Mariola / Preckler, Silvia / Ruiz, Susana / Aguilera, Nuria / Pineda, Juan Antonio / Macías, Juan / Alarcón-Martín, Emilio / Sotolongo-Grau, Oscar / Anonymous4911119 / Anonymous4921119 / Anonymous4931119 / Marquié, Marta / Monté-Rubio, Gemma / Valero, Sergi / Benaque, Alba / Clarimón, Jordi / Bullido, Maria Jesus / García-Ribas, Guillermo / Pástor, Pau / Sánchez-Juan, Pascual / Álvarez, Victoria / Piñol-Ripoll, Gerard / García-Alberca, Jose Maria / Royo, José Luis / Franco, Emilio / Mir, Pablo / Calero, Miguel / Medina, Miguel / Rábano, Alberto / Ávila, Jesús / Antúnez, Carmen / Real, Luis Miguel / Orellana, Adelina / Carracedo, Ángel / Sáez, María Eugenia / Tárraga, Lluís / Boada, Mercè / Ruiz, Agustín. ·Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain. · Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain. · Grupo de Medicina Xenómica, Centro Nacional de Genotipado (CEGEN-PRB3-ISCIII). Universidade de Santiago de Compostela, Santiago de Compostela, Spain. · CAEBI, Centro Andaluz de Estudios Bioinformáticos, Sevilla, Spain. · Unidad Clínica de Enfermedades Infecciosas y Microbiología. Hospital Universitario de Valme, Sevilla, Spain. · Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain; Department of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain. · CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. · CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; Centro de Biologia Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autonoma de Madrid, Madrid, Spain; Instituto de Investigacion Sanitaria "Hospital la Paz" (IdIPaz), Madrid, Spain. · Hospital Universitario Ramón y Cajal, Madrid, Spain. · Fundació per la Recerca Biomèdica i Social Mútua Terrassa, and Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, University of Barcelona School of Medicine, Terrassa, Spain. · CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; Neurology Service 'Marqués de Valdecilla' University Hospital (University of Cantabria and IDIVAL), Santander, Spain. · Laboratorio de Genética Hospital Universitario Central de Asturias, Oviedo, Spain; Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain. · CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; Unitat Trastorns Cognitius, Hospital Universitari Santa Maria de Lleida, Institut de Recerca Biomédica de Lleida (IRBLLeida), Lleida, Spain. · Alzheimer Research Center & Memory Clinic, Andalusian Institute for Neuroscience, Málaga, Spain. · Department of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain. · Unidad de Demencias, Servicio de Neurología y Neurofisiología. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. · CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. · CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; CIEN Foundation, Queen Sofia Foundation Alzheimer Center, Madrid, Spain; Instituto de Salud Carlos III (ISCIII), Madrid, Spain. · CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; CIEN Foundation, Queen Sofia Foundation Alzheimer Center, Madrid, Spain. · CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; CIEN Foundation, Queen Sofia Foundation Alzheimer Center, Madrid, Spain; BT-CIEN, Madrid, Spain. · CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain; Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC)/Universidad Autónoma de Madrid (UAM), Madrid, Spain. · Unidad de Demencias, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain. · Unidad Clínica de Enfermedades Infecciosas y Microbiología. Hospital Universitario de Valme, Sevilla, Spain; Department of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain. · Grupo de Medicina Xenómica, Centro Nacional de Genotipado (CEGEN-PRB3-ISCIII). Universidade de Santiago de Compostela, Santiago de Compostela, Spain; Fundación Pública Galega de Medicina Xenómica- CIBERER-IDIS, Santiago de Compostela, Spain. · Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain. Electronic address: aruiz@fundacioace.org. ·Alzheimers Dement · Pubmed #31473137.

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.

9 Article A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity. 2019

van der Lee, Sven J / Conway, Olivia J / Jansen, Iris / Carrasquillo, Minerva M / Kleineidam, Luca / van den Akker, Erik / Hernández, Isabel / van Eijk, Kristel R / Stringa, Najada / Chen, Jason A / Zettergren, Anna / Andlauer, Till F M / Diez-Fairen, Monica / Simon-Sanchez, Javier / Lleó, Alberto / Zetterberg, Henrik / Nygaard, Marianne / Blauwendraat, Cornelis / Savage, Jeanne E / Mengel-From, Jonas / Moreno-Grau, Sonia / Wagner, Michael / Fortea, Juan / Keogh, Michael J / Blennow, Kaj / Skoog, Ingmar / Friese, Manuel A / Pletnikova, Olga / Zulaica, Miren / Lage, Carmen / de Rojas, Itziar / Riedel-Heller, Steffi / Illán-Gala, Ignacio / Wei, Wei / Jeune, Bernard / Orellana, Adelina / Then Bergh, Florian / Wang, Xue / Hulsman, Marc / Beker, Nina / Tesi, Niccolo / Morris, Christopher M / Indakoetxea, Begoña / Collij, Lyduine E / Scherer, Martin / Morenas-Rodríguez, Estrella / Ironside, James W / van Berckel, Bart N M / Alcolea, Daniel / Wiendl, Heinz / Strickland, Samantha L / Pastor, Pau / Rodríguez Rodríguez, Eloy / Anonymous1381184 / Anonymous1391184 / Anonymous1401184 / Anonymous1411184 / Anonymous1421184 / Anonymous1431184 / Boeve, Bradley F / Petersen, Ronald C / Ferman, Tanis J / van Gerpen, Jay A / Reinders, Marcel J T / Uitti, Ryan J / Tárraga, Lluís / Maier, Wolfgang / Dols-Icardo, Oriol / Kawalia, Amit / Dalmasso, Maria Carolina / Boada, Mercè / Zettl, Uwe K / van Schoor, Natasja M / Beekman, Marian / Allen, Mariet / Masliah, Eliezer / de Munain, Adolfo López / Pantelyat, Alexander / Wszolek, Zbigniew K / Ross, Owen A / Dickson, Dennis W / Graff-Radford, Neill R / Knopman, David / Rademakers, Rosa / Lemstra, Afina W / Pijnenburg, Yolande A L / Scheltens, Philip / Gasser, Thomas / Chinnery, Patrick F / Hemmer, Bernhard / Huisman, Martijn A / Troncoso, Juan / Moreno, Fermin / Nohr, Ellen A / Sørensen, Thorkild I A / Heutink, Peter / Sánchez-Juan, Pascual / Posthuma, Danielle / Anonymous1441184 / Clarimón, Jordi / Christensen, Kaare / Ertekin-Taner, Nilüfer / Scholz, Sonja W / Ramirez, Alfredo / Ruiz, Agustín / Slagboom, Eline / van der Flier, Wiesje M / Holstege, Henne. ·Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. s.j.vanderlee@amsterdamumc.nl. · Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. s.j.vanderlee@amsterdamumc.nl. · Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, 32224, USA. · Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. · Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. · Department for Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany. · DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany. · Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine, University Hospital Cologne, Cologne, Germany. · Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. · Pattern Recognition and Bioinformatics, Delft University of Technology, Delft, The Netherlands. · Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain. · Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. · Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. · Amsterdam UMC-Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands. · Interdepartmental Program in Bioinformatics, University of California, Los Angeles, USA. · Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AgeCap) at the University of Gothenburg, Gothenburg, Sweden. · Max Planck Institute of Psychiatry, Munich, Germany. · Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · German Competence Network Multiple Sclerosis (KKNMS), Munich, Germany. · Movement Disorders and Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, Barcelona, Spain. · Fundacio per la Recerca Biomedica I Social Mutua Terrassa, Terrassa, Barcelona, Spain. · German Center for Neurodegenerative Diseases (DZNE)-Tübingen, Tübingen, Germany. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain. · Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. · Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. · Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK. · The Danish Aging Research Center, Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, 20892-3707, USA. · Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark. · Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK. · Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, UK. · Institut für Neuroimmunologie und Multiple Sklerose (INIMS), Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. · Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USA. · Instituto Biodonostia, San Sebastian, Spain. · University Hospital "Marques de Valdecilla", Santander, Spain. · IDIVAL, Santander, Spain. · Institute of Social Medicine, Occupational Health and Public Health (ISAP), University of Leipzig, Leipzig, Germany. · Department of Neurology, University of Leipzig, Leipzig, Germany. · Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. · Newcastle Brain Tissue Resource, Edwardson Building, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK. · Cognitive Disorders Unit, Department of Neurology, Hospital Universitario San Sebastian, San Sebastian, Spain. · Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. · Department of Primary Medical Care, Center for Psychosocial Medicine, University Medical Center, Hamburg-Eppendorf, Germany. · Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH4 2XU, UK. · Department of Neurology, Klinik für Neurologie mit Institut für Translationale Neurologie, University of Münster, Münster, Germany. · Department of Neurology, Mayo Clinic Minnesota, Rochester, MN, 55905, USA. · Department of Psychiatry and Psychology, Mayo Clinic Florida, Jacksonville, FL, 32224, USA. · Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, 32224, USA. · Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands. · Fundación Instituto Leloir-IIBBA-CONICET, Buenos Aires, Argentina. · Department of Neurology, University of Rostock, Rostock, Germany. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Department of Neurology, Hospital Universitario San Sebastian, San Sebastian, Spain. · Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, 21287, USA. · Center of Neurology, Department of Neurodegenerative diseases, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany. · MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK. · Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. · Department of Sociology, VU University, Amsterdam, The Netherlands. · Research Unit of Gynecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark. · Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Copenhagen, Denmark. · Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · MRC Integrative Epidemiology Unit, Bristol University, Bristol, UK. · Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark. · Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. · Dutch Society for Research on Ageing, Leiden, The Netherlands. · Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. h.holstege@amsterdamumc.nl. · Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. h.holstege@amsterdamumc.nl. ·Acta Neuropathol · Pubmed #31131421.

ABSTRACT: The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

10 Article Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. 2019

Kunkle, Brian W / Grenier-Boley, Benjamin / Sims, Rebecca / Bis, Joshua C / Damotte, Vincent / Naj, Adam C / Boland, Anne / Vronskaya, Maria / van der Lee, Sven J / Amlie-Wolf, Alexandre / Bellenguez, Céline / Frizatti, Aura / Chouraki, Vincent / Martin, Eden R / Sleegers, Kristel / Badarinarayan, Nandini / Jakobsdottir, Johanna / Hamilton-Nelson, Kara L / Moreno-Grau, Sonia / Olaso, Robert / Raybould, Rachel / Chen, Yuning / Kuzma, Amanda B / Hiltunen, Mikko / Morgan, Taniesha / Ahmad, Shahzad / Vardarajan, Badri N / Epelbaum, Jacques / Hoffmann, Per / Boada, Merce / Beecham, Gary W / Garnier, Jean-Guillaume / Harold, Denise / Fitzpatrick, Annette L / Valladares, Otto / Moutet, Marie-Laure / Gerrish, Amy / Smith, Albert V / Qu, Liming / Bacq, Delphine / Denning, Nicola / Jian, Xueqiu / Zhao, Yi / Del Zompo, Maria / Fox, Nick C / Choi, Seung-Hoan / Mateo, Ignacio / Hughes, Joseph T / Adams, Hieab H / Malamon, John / Sanchez-Garcia, Florentino / Patel, Yogen / Brody, Jennifer A / Dombroski, Beth A / Naranjo, Maria Candida Deniz / Daniilidou, Makrina / Eiriksdottir, Gudny / Mukherjee, Shubhabrata / Wallon, David / Uphill, James / Aspelund, Thor / Cantwell, Laura B / Garzia, Fabienne / Galimberti, Daniela / Hofer, Edith / Butkiewicz, Mariusz / Fin, Bertrand / Scarpini, Elio / Sarnowski, Chloe / Bush, Will S / Meslage, Stéphane / Kornhuber, Johannes / White, Charles C / Song, Yuenjoo / Barber, Robert C / Engelborghs, Sebastiaan / Sordon, Sabrina / Voijnovic, Dina / Adams, Perrie M / Vandenberghe, Rik / Mayhaus, Manuel / Cupples, L Adrienne / Albert, Marilyn S / De Deyn, Peter P / Gu, Wei / Himali, Jayanadra J / Beekly, Duane / Squassina, Alessio / Hartmann, Annette M / Orellana, Adelina / Blacker, Deborah / Rodriguez-Rodriguez, Eloy / Lovestone, Simon / Garcia, Melissa E / Doody, Rachelle S / Munoz-Fernadez, Carmen / Sussams, Rebecca / Lin, Honghuang / Fairchild, Thomas J / Benito, Yolanda A / Holmes, Clive / Karamujić-Čomić, Hata / Frosch, Matthew P / Thonberg, Hakan / Maier, Wolfgang / Roshchupkin, Gennady / Ghetti, Bernardino / Giedraitis, Vilmantas / Kawalia, Amit / Li, Shuo / Huebinger, Ryan M / Kilander, Lena / Moebus, Susanne / Hernández, Isabel / Kamboh, M Ilyas / Brundin, RoseMarie / Turton, James / Yang, Qiong / Katz, Mindy J / Concari, Letizia / Lord, Jenny / Beiser, Alexa S / Keene, C Dirk / Helisalmi, Seppo / Kloszewska, Iwona / Kukull, Walter A / Koivisto, Anne Maria / Lynch, Aoibhinn / Tarraga, Lluís / Larson, Eric B / Haapasalo, Annakaisa / Lawlor, Brian / Mosley, Thomas H / Lipton, Richard B / Solfrizzi, Vincenzo / Gill, Michael / Longstreth, W T / Montine, Thomas J / Frisardi, Vincenza / Diez-Fairen, Monica / Rivadeneira, Fernando / Petersen, Ronald C / Deramecourt, Vincent / Alvarez, Ignacio / Salani, Francesca / Ciaramella, Antonio / Boerwinkle, Eric / Reiman, Eric M / Fievet, Nathalie / Rotter, Jerome I / Reisch, Joan S / Hanon, Olivier / Cupidi, Chiara / Andre Uitterlinden, A G / Royall, Donald R / Dufouil, Carole / Maletta, Raffaele Giovanni / de Rojas, Itziar / Sano, Mary / Brice, Alexis / Cecchetti, Roberta / George-Hyslop, Peter St / Ritchie, Karen / Tsolaki, Magda / Tsuang, Debby W / Dubois, Bruno / Craig, David / Wu, Chuang-Kuo / Soininen, Hilkka / Avramidou, Despoina / Albin, Roger L / Fratiglioni, Laura / Germanou, Antonia / Apostolova, Liana G / Keller, Lina / Koutroumani, Maria / Arnold, Steven E / Panza, Francesco / Gkatzima, Olymbia / Asthana, Sanjay / Hannequin, Didier / Whitehead, Patrice / Atwood, Craig S / Caffarra, Paolo / Hampel, Harald / Quintela, Inés / Carracedo, Ángel / Lannfelt, Lars / Rubinsztein, David C / Barnes, Lisa L / Pasquier, Florence / Frölich, Lutz / Barral, Sandra / McGuinness, Bernadette / Beach, Thomas G / Johnston, Janet A / Becker, James T / Passmore, Peter / Bigio, Eileen H / Schott, Jonathan M / Bird, Thomas D / Warren, Jason D / Boeve, Bradley F / Lupton, Michelle K / Bowen, James D / Proitsi, Petra / Boxer, Adam / Powell, John F / Burke, James R / Kauwe, John S K / Burns, Jeffrey M / Mancuso, Michelangelo / Buxbaum, Joseph D / Bonuccelli, Ubaldo / Cairns, Nigel J / McQuillin, Andrew / Cao, Chuanhai / Livingston, Gill / Carlson, Chris S / Bass, Nicholas J / Carlsson, Cynthia M / Hardy, John / Carney, Regina M / Bras, Jose / Carrasquillo, Minerva M / Guerreiro, Rita / Allen, Mariet / Chui, Helena C / Fisher, Elizabeth / Masullo, Carlo / Crocco, Elizabeth A / DeCarli, Charles / Bisceglio, Gina / Dick, Malcolm / Ma, Li / Duara, Ranjan / Graff-Radford, Neill R / Evans, Denis A / Hodges, Angela / Faber, Kelley M / Scherer, Martin / Fallon, Kenneth B / Riemenschneider, Matthias / Fardo, David W / Heun, Reinhard / Farlow, Martin R / Kölsch, Heike / Ferris, Steven / Leber, Markus / Foroud, Tatiana M / Heuser, Isabella / Galasko, Douglas R / Giegling, Ina / Gearing, Marla / Hüll, Michael / Geschwind, Daniel H / Gilbert, John R / Morris, John / Green, Robert C / Mayo, Kevin / Growdon, John H / Feulner, Thomas / Hamilton, Ronald L / Harrell, Lindy E / Drichel, Dmitriy / Honig, Lawrence S / Cushion, Thomas D / Huentelman, Matthew J / Hollingworth, Paul / Hulette, Christine M / Hyman, Bradley T / Marshall, Rachel / Jarvik, Gail P / Meggy, Alun / Abner, Erin / Menzies, Georgina E / Jin, Lee-Way / Leonenko, Ganna / Real, Luis M / Jun, Gyungah R / Baldwin, Clinton T / Grozeva, Detelina / Karydas, Anna / Russo, Giancarlo / Kaye, Jeffrey A / Kim, Ronald / Jessen, Frank / Kowall, Neil W / Vellas, Bruno / Kramer, Joel H / Vardy, Emma / LaFerla, Frank M / Jöckel, Karl-Heinz / Lah, James J / Dichgans, Martin / Leverenz, James B / Mann, David / Levey, Allan I / Pickering-Brown, Stuart / Lieberman, Andrew P / Klopp, Norman / Lunetta, Kathryn L / Wichmann, H-Erich / Lyketsos, Constantine G / Morgan, Kevin / Marson, Daniel C / Brown, Kristelle / Martiniuk, Frank / Medway, Christopher / Mash, Deborah C / Nöthen, Markus M / Masliah, Eliezer / Hooper, Nigel M / McCormick, Wayne C / Daniele, Antonio / McCurry, Susan M / Bayer, Anthony / McDavid, Andrew N / Gallacher, John / McKee, Ann C / van den Bussche, Hendrik / Mesulam, Marsel / Brayne, Carol / Miller, Bruce L / Riedel-Heller, Steffi / Miller, Carol A / Miller, Joshua W / Al-Chalabi, Ammar / Morris, John C / Shaw, Christopher E / Myers, Amanda J / Wiltfang, Jens / O'Bryant, Sid / Olichney, John M / Alvarez, Victoria / Parisi, Joseph E / Singleton, Andrew B / Paulson, Henry L / Collinge, John / Perry, William R / Mead, Simon / Peskind, Elaine / Cribbs, David H / Rossor, Martin / Pierce, Aimee / Ryan, Natalie S / Poon, Wayne W / Nacmias, Benedetta / Potter, Huntington / Sorbi, Sandro / Quinn, Joseph F / Sacchinelli, Eleonora / Raj, Ashok / Spalletta, Gianfranco / Raskind, Murray / Caltagirone, Carlo / Bossù, Paola / Orfei, Maria Donata / Reisberg, Barry / Clarke, Robert / Reitz, Christiane / Smith, A David / Ringman, John M / Warden, Donald / Roberson, Erik D / Wilcock, Gordon / Rogaeva, Ekaterina / Bruni, Amalia Cecilia / Rosen, Howard J / Gallo, Maura / Rosenberg, Roger N / Ben-Shlomo, Yoav / Sager, Mark A / Mecocci, Patrizia / Saykin, Andrew J / Pastor, Pau / Cuccaro, Michael L / Vance, Jeffery M / Schneider, Julie A / Schneider, Lori S / Slifer, Susan / Seeley, William W / Smith, Amanda G / Sonnen, Joshua A / Spina, Salvatore / Stern, Robert A / Swerdlow, Russell H / Tang, Mitchell / Tanzi, Rudolph E / Trojanowski, John Q / Troncoso, Juan C / Van Deerlin, Vivianna M / Van Eldik, Linda J / Vinters, Harry V / Vonsattel, Jean Paul / Weintraub, Sandra / Welsh-Bohmer, Kathleen A / Wilhelmsen, Kirk C / Williamson, Jennifer / Wingo, Thomas S / Woltjer, Randall L / Wright, Clinton B / Yu, Chang-En / Yu, Lei / Saba, Yasaman / Pilotto, Alberto / Bullido, Maria J / Peters, Oliver / Crane, Paul K / Bennett, David / Bosco, Paola / Coto, Eliecer / Boccardi, Virginia / De Jager, Phil L / Lleo, Alberto / Warner, Nick / Lopez, Oscar L / Ingelsson, Martin / Deloukas, Panagiotis / Cruchaga, Carlos / Graff, Caroline / Gwilliam, Rhian / Fornage, Myriam / Goate, Alison M / Sanchez-Juan, Pascual / Kehoe, Patrick G / Amin, Najaf / Ertekin-Taner, Nilifur / Berr, Claudine / Debette, Stéphanie / Love, Seth / Launer, Lenore J / Younkin, Steven G / Dartigues, Jean-Francois / Corcoran, Chris / Ikram, M Arfan / Dickson, Dennis W / Nicolas, Gael / Campion, Dominique / Tschanz, JoAnn / Schmidt, Helena / Hakonarson, Hakon / Clarimon, Jordi / Munger, Ron / Schmidt, Reinhold / Farrer, Lindsay A / Van Broeckhoven, Christine / C O'Donovan, Michael / DeStefano, Anita L / Jones, Lesley / Haines, Jonathan L / Deleuze, Jean-Francois / Owen, Michael J / Gudnason, Vilmundur / Mayeux, Richard / Escott-Price, Valentina / Psaty, Bruce M / Ramirez, Alfredo / Wang, Li-San / Ruiz, Agustin / van Duijn, Cornelia M / Holmans, Peter A / Seshadri, Sudha / Williams, Julie / Amouyel, Phillippe / Schellenberg, Gerard D / Lambert, Jean-Charles / Pericak-Vance, Margaret A / Anonymous1811199 / Anonymous1821199 / Anonymous1831199 / Anonymous1841199 / and others. ·John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA. bkunkle@miami.edu. · Inserm, U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France. · Institut Pasteur de Lille, Lille, France. · Univ. Lille, U1167-Excellence Laboratory LabEx DISTALZ, Lille, France. · Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. · UK Dementia Research Institute at Cardiff, Cardiff University, Cardiff, UK. · Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA. · Department of Biostatistics and Epidemiology/Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. · Centre National de Recherche en Génomique Humaine, Institut de Biologie François Jacob, CEA, Université Paris-Saclay, and LabEx GENMED, Evry, France. · Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. · Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. · Framingham Heart Study, Framingham, MA, USA. · Department of Neurology, Boston University School of Medicine, Boston, MA, USA. · John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA. · Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium. · Laboratory for Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. · Icelandic Heart Association, Kopavogur, Iceland. · Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain. · Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain. · Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. · Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland. · Department of Neurology, Kuopio University Hospital, Kuopio, Finland. · Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY, USA. · Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA. · Department of Neurology, Columbia University, New York, NY, USA. · UMR 894, Center for Psychiatry and Neuroscience, Inserm, Université Paris Descartes, Paris, France. · Institute of Human Genetics, University of Bonn, Bonn, Germany. · Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany. · Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland. · School of Biotechnology, Dublin City University, Dublin, Ireland. · Department of Family Medicine, University of Washington, Seattle, WA, USA. · Department of Epidemiology, University of Washington, Seattle, WA, USA. · Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK. · Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA. · Faculty of Medicine, University of Iceland, Reykjavik, Iceland. · Brown Foundation Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, TX, USA. · Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy. · UK Dementia Research Institute at UCL, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK. · Neurology Service and CIBERNED, 'Marqués de Valdecilla' University Hospital (University of Cantabria and IDIVAL), Santander, Spain. · Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. · Department of Immunology, Hospital Universitario Doctor Negrín, Las Palmas de Gran Canaria, Spain. · Department of Neurology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece. · Department of Medicine, University of Washington, Seattle, WA, USA. · Normandie University, UNIROUEN, Inserm U1245, and Rouen University Hospital, Department of Neurology, Department of Genetics and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France. · Department of Neurodegenerative Disease, MRC Prion Unit at UCL, Institute of Prion Diseases, London, UK. · Centre for Public Health, University of Iceland, Reykjavik, Iceland. · Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy. · University of Milan, Centro Dino Ferrari, Milan, Italy. · Clinical Division of Neurogeriatrics, Department of Neurology, Medical University Graz, Graz, Austria. · Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria. · Institute for Computational Biology, Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany. · Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA. · Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA. · Laboratory for Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. · Department of Neurology and Memory Clinic, Hospital Network Antwerp, Antwerp, Belgium. · Department of Psychiatry and Psychotherapy, University Hospital, Saarland, Germany. · Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA. · Laboratory for Cognitive Neurology, Department of Neurology, University Hospital and University of Leuven, Leuven, Belgium. · Department of Neurology, Johns Hopkins University, Baltimore, MD, USA. · National Alzheimer's Coordinating Center, University of Washington, Seattle, WA, USA. · Department of Psychiatry, Martin Luther University Halle-Wittenberg, Halle, Germany. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA. · Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA. · Department of Psychiatry, University of Oxford, Oxford, UK. · Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD, USA. · Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, TX, USA. · Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK. · Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. · Office of Strategy and Measurement, University of North Texas Health Science Center, Fort Worth, TX, USA. · C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, MA, USA. · Theme Aging, Unit for Hereditary Dementias, Karolinska University Hospital-Solna, Stockholm, Sweden. · Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Alzheimer Research Center, Division of Neurogeriatrics, Solna, Sweden. · German Center for Neurodegenerative Diseases, Bonn, Germany. · Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany. · Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN, USA. · Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden. · Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany. · Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA. · Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany. · Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA. · Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA, USA. · Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK. · Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA. · Section of Neuroscience, DIMEC-University of Parma, Parma, Italy. · FERB-Alzheimer Center, Gazzaniga (Bergamo), Italy. · Department of Pathology, University of Washington, Seattle, WA, USA. · Elderly and Psychiatric Disorders Department, Medical University of Lodz, Lodz, Poland. · Mercer's Institute for Research on Aging, St. James's Hospital and Trinity College, Dublin, Ireland. · St. James's Hospital and Trinity College, Dublin, Ireland. · Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA. · A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland. · Departments of Medicine, Geriatrics, Gerontology and Neurology, University of Mississippi Medical Center, Jackson, MS, USA. · Interdisciplinary Department of Medicine, Geriatric Medicine and Memory Unity, University of Bari, Bari, Italy. · Department of Neurology, University of Washington, Seattle, WA, USA. · Department of Geriatrics, Center for Aging Brain, University of Bari, Bari, Italy. · Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain. · Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain. · Department of Internal Medicine, Erasmus University Medical Center, Rotterdamt, the Netherlands. · Netherlands Consortium on Health Aging and National Genomics Initiative, Leiden, the Netherlands. · Department of Neurology, Mayo Clinic, Rochester, MN, USA. · CHU Lille, Memory Center of Lille (Centre Mémoire de Ressources et de Recherche), Lille, France. · Department of Clinical and Behavioral Neurology, Experimental Neuropsychobiology Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy. · School of Public Health, Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA. · Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. · Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA. · Arizona Alzheimer's Consortium, Phoenix, AZ, USA. · Banner Alzheimer's Institute, Phoenix, AZ, USA. · Department of Psychiatry, University of Arizona, Phoenix, AZ, USA. · Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA. · Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA. · University Paris Descartes, EA 4468, AP-HP, Geriatrics Department, Hôpital Broca, Paris, France. · Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy. · Departments of Psychiatry, Medicine, Family & Community Medicine, South Texas Veterans Health Administration Geriatric Research Education & Clinical Center (GRECC), UT Health Science Center at San Antonio, San Antonio, TX, USA. · University of Bordeaux, Inserm 1219, Bordeaux, France. · Department of Neurology, Bordeaux University Hospital / CHU de Bordeaux, Bordeaux, France. · Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. · Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06, UMRS 1127, Institut du Cerveau et de la Moelle Épinière, Paris, France. · AP-HP, Department of Genetics, Pitié-Salpêtrière Hospital, Paris, France. · Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy. · Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. · Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada. · Inserm U1061 Neuropsychiatry, La Colombière Hospital, Montpellier, France. · Montpellier University, Montpellier, France. · Department of Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. · VA Puget Sound Health Care System/>GRECC, Seattle, WA, USA. · Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA. · Institut de la Mémoire et de la Maladie d'Alzheimer and Institut du Cerveau et de la Moelle Épinière, Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France. · Institut des Neurosciences Translationnelles de Paris, Institut du Cerveau et de la Moelle Épinière, Paris, France. · Inserm, CNRS, UMR-S975, Institut du Cerveau et de la Moelle Epinière, Paris, France. · Sorbonne Universités, Université Pierre et Marie Curie, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France. · Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK. · Departments of Neurology, Pharmacology & Neuroscience, Texas Tech University Health Science Center, Lubbock, TX, USA. · Department of Neurology, University of Michigan, Ann Arbor, MI, USA. · Geriatric Research, Education and Clinical Center (GRECC), VA Ann Arbor Healthcare System (VAAAHS), Ann Arbor, MI, USA. · Michigan Alzheimer Disease Center, Ann Arbor, MI, USA. · Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden. · Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA. · Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA. · Department of Neurology, Indiana University, Indianapolis, IN, USA. · Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, IN, USA. · Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. · Geriatric Research, Education and Clinical Center (GRECC), University of Wisconsin, Madison, WI, USA. · Department of Medicine, University of Wisconsin, Madison, WI, USA. · Wisconsin Alzheimer's Disease Research Center, Madison, WI, USA. · AXA Research Fund & Sorbonne University Chair, Paris, France. · Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France. · Brain & Spine Institute, Inserm U 1127, CNRS UMR 7225, Paris, France. · Institute of Memory and Alzheimer's Disease, Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France. · Grupo de Medicina Xenomica, Universidade de Santiago de Compostela, Centro Nacional de Genotipado, Centro de Investigación Biomédica en Red de Enfermedades Raras, Santiago de Compostela, Spain. · UK Dementia Research Institute, University of Cambridge, Cambridge, UK. · Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA. · Department of Behavioral Sciences, Rush University Medical Center, Chicago, IL, USA. · Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA. · Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. · Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Phoenix, AZ, USA. · Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Psychology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. (and more) ·Nat Genet · Pubmed #30820047.

ABSTRACT: Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10

11 Article Plasma Aβ42/40 Ratio Detects Early Stages of Alzheimer's Disease and Correlates with CSF and Neuroimaging Biomarkers in the AB255 Study. 2019

Pérez-Grijalba, V / Romero, J / Pesini, P / Sarasa, L / Monleón, I / San-José, I / Arbizu, J / Martínez-Lage, P / Munuera, J / Ruiz, A / Tárraga, L / Boada, M / Sarasa, M. ·Pedro Pesini, PhD. Vía Hispanidad 21, 50009 Zaragoza, Spain; Telephone number: +34 976 796 562; Fax: (+34) 976 217 802; Email: ppesini@araclon.com. ·J Prev Alzheimers Dis · Pubmed #30569084.

ABSTRACT: BACKGROUND: Easily accessible biomarkers are needed for the early identification of individuals at risk of developing Alzheimer's disease (AD) in large population screening strategies. OBJECTIVES: This study evaluated the potential of plasma β-amyloid (Aβ) biomarkers in identifying early stages of AD and predicting cognitive decline over the following two years. DESIGN: Total plasma Aβ42/40 ratio (TP42/40) was determined in 83 cognitively normal individuals (CN) and 145 subjects with amnestic mild cognitive impairment (a-MCI) stratified by an FDG-PET AD-risk pattern. RESULTS: Significant lower TP42/40 ratio was found in a-MCI patients compared to CN. Moreover, a-MCIs with a high-risk FDG-PET pattern for AD showed even lower plasma ratio levels. Low TP42/40 at baseline increased the risk of progression to dementia by 70%. Furthermore, TP42/40 was inversely associated with neocortical amyloid deposition (measured with PiB-PET) and was concordant with the AD biomarker profile in cerebrospinal fluid (CSF). CONCLUSIONS: TP42/40 demonstrated value in the identification of individuals suffering a-MCI, in the prediction of progression to dementia, and in the detection of underlying AD pathology revealed by FDG-PET, Amyloid-PET and CSF biomarkers, being, thus, consistently associated with all the well-established indicators of AD.

12 Article Correlations between plasma and PET beta-amyloid levels in individuals with subjective cognitive decline: the Fundació ACE Healthy Brain Initiative (FACEHBI). 2018

de Rojas, Itziar / Romero, J / Rodríguez-Gomez, O / Pesini, P / Sanabria, A / Pérez-Cordon, A / Abdelnour, C / Hernández, I / Rosende-Roca, M / Mauleón, A / Vargas, L / Alegret, M / Espinosa, A / Ortega, G / Gil, S / Guitart, M / Gailhajanet, A / Santos-Santos, M A / Moreno-Grau, Sonia / Sotolongo-Grau, O / Ruiz, S / Montrreal, L / Martín, E / Pelejà, E / Lomeña, F / Campos, F / Vivas, A / Gómez-Chiari, M / Tejero, M A / Giménez, J / Pérez-Grijalba, V / Marquié, G M / Monté-Rubio, G / Valero, S / Orellana, A / Tárraga, L / Sarasa, M / Ruiz, A / Boada, M / Anonymous390971. ·Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya-Barcelona, C/ Marquès de Sentmenat, 57, 08029, Barcelona, Spain. · Araclon Biotech©, Zaragoza, Spain. · Servei de Medicina Nuclear, Hospital Clínic i Provincial, Barcelona, Spain. · Departament de Diagnòstic per la Imatge, Clínica Corachan, Barcelona, Spain. · Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya-Barcelona, C/ Marquès de Sentmenat, 57, 08029, Barcelona, Spain. aruiz@fundacioace.org. ·Alzheimers Res Ther · Pubmed #30497535.

ABSTRACT: BACKGROUND: Peripheral biomarkers that identify individuals at risk of developing Alzheimer's disease (AD) or predicting high amyloid beta (Aβ) brain burden would be highly valuable. To facilitate clinical trials of disease-modifying therapies, plasma concentrations of Aβ species are good candidates for peripheral AD biomarkers, but studies to date have generated conflicting results. METHODS: The Fundació ACE Healthy Brain Initiative (FACEHBI) study uses a convenience sample of 200 individuals diagnosed with subjective cognitive decline (SCD) at the Fundació ACE (Barcelona, Spain) who underwent amyloid florbetaben( RESULTS: FBB-PET global SUVR correlated weakly but significantly with Aβ42/40 plasma ratios. For TP42/40, this observation persisted after controlling for age and APOE ε4 allele carrier status (R CONCLUSION: Brain and plasma Aβ levels are partially correlated in individuals diagnosed with SCD. Aβ plasma measurements, particularly the TP42/40 ratio, could generate a new recruitment strategy independent of the APOE genotype that would improve identification of SCD subjects with brain amyloidosis and reduce the rate of screening failures in preclinical AD studies. Independent replication of these findings is warranted.

13 Article Exploring Genetic Associations of Alzheimer's Disease Loci With Mild Cognitive Impairment Neurocognitive Endophenotypes. 2018

Espinosa, Ana / Hernández-Olasagarre, Begoña / Moreno-Grau, Sonia / Kleineidam, Luca / Heilmann-Heimbach, Stefanie / Hernández, Isabel / Wolfsgruber, Steffen / Wagner, Holger / Rosende-Roca, Maitée / Mauleón, Ana / Vargas, Liliana / Lafuente, Asunción / Rodríguez-Gómez, Octavio / Abdelnour, Carla / Gil, Silvia / Marquié, Marta / Santos-Santos, Miguel A / Sanabria, Ángela / Ortega, Gemma / Monté-Rubio, Gemma / Pérez, Alba / Ibarria, Marta / Ruiz, Susana / Kornhuber, Johannes / Peters, Oliver / Frölich, Lutz / Hüll, Michael / Wiltfang, Jens / Luck, Tobias / Riedel-Heller, Steffi / Montrreal, Laura / Cañabate, Pilar / Moreno, Mariola / Preckler, Silvia / Aguilera, Nuria / de Rojas, Itziar / Orellana, Adelina / Alegret, Montserrat / Valero, Sergi / Nöthen, Markus M / Wagner, Michael / Jessen, Frank / Tárraga, Lluis / Boada, Mercè / Ramírez, Alfredo / Ruiz, Agustín. ·Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain. · Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany. · German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. · Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany. · Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany. · Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany. · Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany. · Department of Psychiatry and Psychotherapy, University Clinic Erlangen, Erlangen, Germany. · Department of Psychiatry, Charité University Medicine, Berlin, Germany. · Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. · Center for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany. · Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany. · Department of Economic and Social Sciences & Institute of Social Medicine, Rehabilitation Sciences and Healthcare Research (ISRV), University of Applied Sciences Nordhausen, Nordhausen, Germany. · Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany. ·Front Aging Neurosci · Pubmed #30425636.

ABSTRACT: The role of genetic risk markers for Alzheimer's disease (AD) in mediating the neurocognitive endophenotypes (NEs) of subjects with mild cognitive impairment (MCI) has rarely been studied. The aim of the present study was to investigate the relationship between well-known AD-associated single-nucleotide polymorphisms (SNPs) and individual NEs routinely evaluated during diagnosis of MCI, AD, and other dementias. The Fundació ACE (ACE) dataset, comprising information from 1245 patients with MCI, was analyzed, including the total sample, amnestic MCI (aMCI) (

14 Article Usefulness of peripapillary nerve fiber layer thickness assessed by optical coherence tomography as a biomarker for Alzheimer's disease. 2018

Sánchez, Domingo / Castilla-Marti, Miguel / Rodríguez-Gómez, Octavio / Valero, Sergi / Piferrer, Albert / Martínez, Gabriel / Martínez, Joan / Serra, Judit / Moreno-Grau, Sonia / Hernández-Olasagarre, Begoña / De Rojas, Itziar / Hernández, Isabel / Abdelnour, Carla / Rosende-Roca, Maitée / Vargas, Liliana / Mauleón, Ana / Santos-Santos, Miguel A / Alegret, Montserrat / Ortega, Gemma / Espinosa, Ana / Pérez-Cordón, Alba / Sanabria, Ángela / Ciudin, Andrea / Simó, Rafael / Hernández, Cristina / Villoslada, Pablo / Ruiz, Agustín / Tàrraga, Lluís / Boada, Mercè. ·Alzheimer Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain. dsanchez@fundacioace.com. · Clínica Oftalmológica Dr. Castilla, Barcelona, Spain. · Valles Ophthalmology Research, Hospital General de Catalunya, Sant Cugat del Vallès, Spain. · Alzheimer Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain. · Psychiatry Department, Hospital Universitari Vall d'Hebron, CIBERSAM, Universitat Autònoma de Barcelona, Barcelona, Spain. · Topcon España Clinical Affairs, Sant Just Desvern, Spain. · Faculty of Medicine and Dentistry. Faculty of Medicine and Dentistry, Universidad de Antofagasta, Antofagasta, Chile. · Iberoamerican Cochrane Centre, Barcelona, Spain. · Diabetes and Metabolism Research Unit and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólica Asociada (CIBERDEM), Vall d'Hebron Research Institute, Barcelona, Spain. · Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain. ·Sci Rep · Pubmed #30397251.

ABSTRACT: The use of optical coherence tomography (OCT) has been suggested as a potential biomarker for Alzheimer's Disease based on previously reported thinning of the retinal nerve fiber layer (RNFL) in Alzheimer's disease's (AD) and Mild Cognitive Impairment (MCI). However, other studies have not shown such results. 930 individuals (414 cognitively healthy individuals, 192 probable amnestic MCI and 324 probable AD) attending a memory clinic were consecutively included and underwent spectral domain OCT (Maestro, Topcon) examinations to assess differences in peripapillary RNFL thickness, using a design of high ecological validity. Adjustment by age, education, sex and OCT image quality was performed. We found a non-significant decrease in mean RNFL thickness as follows: control group: 100,20 ± 14,60 µm, MCI group: 98,54 ± 14,43 µm and AD group: 96,61 ± 15,27 µm. The multivariate adjusted analysis revealed no significant differences in mean overall (p = 0.352), temporal (p = 0,119), nasal (p = 0,151), superior (p = 0,435) or inferior (p = 0,825) quadrants between AD, MCI and control groups. These results do not support the usefulness of peripapillary RNFL analysis as a marker of cognitive impairment or in discriminating between cognitive groups. The analysis of other OCT measurements in other retinal areas and layers as biomarkers for AD should be tested further.

15 Article Genome-wide significant risk factors on chromosome 19 and the 2018

Moreno-Grau, Sonia / Hernández, Isabel / Heilmann-Heimbach, Stefanie / Ruiz, Susana / Rosende-Roca, Maitée / Mauleón, Ana / Vargas, Liliana / Rodríguez-Gómez, Octavio / Alegret, Montserrat / Espinosa, Ana / Ortega, Gemma / Aguilera, Nuria / Abdelnour, Carla / Neuroimaging Initiative, Alzheimer's Disease / Gil, Silvia / Maier, Wolfgang / Sotolongo-Grau, Oscar / Tárraga, Lluís / Ramirez, Alfredo / López-Arrrieta, Jesús / Antúnez, Carmen / Serrano-Ríos, Manuel / Boada, Mercè / Ruiz, Agustín. ·Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Univesitat Internacional de Catalunya, Barcelona, Spain. · Institute of Human Genetics, University of Bonn, Bonn, Germany. · Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany. · Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany. · German Center for Neurodegenerative Diseases, DZNE, Bonn, Germany. · Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany. · Memory Unit, University Hospital La Paz-Cantoblanco, Madrid, Spain. · Dementia Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain. · Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Spain, Hospital Clínico San Carlos, Madrid, Spain. ·Oncotarget · Pubmed #29872490.

ABSTRACT: The apolipoprotein E (

16 Article The Role of Verb Fluency in the Detection of Early Cognitive Impairment in Alzheimer's Disease. 2018

Alegret, Montserrat / Peretó, Mar / Pérez, Alba / Valero, Sergi / Espinosa, Ana / Ortega, Gemma / Hernández, Isabel / Mauleón, Ana / Rosende-Roca, Maitée / Vargas, Liliana / Rodríguez-Gómez, Octavio / Abdelnour, Carla / Berthier, Marcelo L / Bak, Thomas H / Ruíz, Agustín / Tárraga, Lluís / Boada, Mercè. ·Memory Clinic and Research Center of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain. · Mental Health Research Group, IMIM (Hospital del Mar Research Institute), CIBERSAM (Centro de Investigación Biomédica en Red de Salud Mental), Barcelona, Spain. · Department of Psychiatry, Hospital Universitari Vall d'Hebron, CIBERSAM, Universitat Autònoma de Barcelona, Barcelona, Spain. · Cognitive Neurology and Aphasia Unit and Cathedra ARPA of Aphasia, Centro de Investigaciones Médico-Sanitarias (CIMES) and Instituto de Investigación Biomédica de Málaga (IBIMA), University of Malaga, Malaga, Spain. · Department of Psychology and Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. ·J Alzheimers Dis · Pubmed #29480180.

ABSTRACT: BACKGROUND: Verb fluency (VF) is the less commonly used fluency test, despite several studies suggesting its potential as a neuropsychological assessment tool. OBJECTIVE: To investigate the presence of VF deficits in mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) dementia; to assess the usefulness of VF in the detection of cognitively healthy (CH) people who will convert to MCI, and from MCI to dementia; and to establish the VF cut-offs useful in the cognitive assessment of Spanish population. METHODS: 568 CH, 885 MCI, and 367 mild AD dementia individuals were administered the VF test and a complete neuropsychological battery. Longitudinal analyses were performed in 231 CH and 667 MCI subjects to search for VF predictors of diagnosis conversion. RESULTS: A worsening on VF performance from CH, MCI to AD dementia groups was found. Lower performances on VF were significantly related to conversion from CH to MCI/MCI to dementia. When the effect of time to conversion was analyzed, a significant effect of VF was found on the faster conversion from CH to MCI, but not from MCI to dementia. Moreover, VF cut-off scores and sensitivity/specificity values were calculated for 6 conditions (3 age ranges by 2 educational levels). CONCLUSION: The VF test may be a useful tool for the differential diagnosis of cognitive failure in the elderly. Since VF deficits seem to take place in early stages of the disease, it is a suitable neuropsychological tool for the detection not only of CH people who will convert to MCI, but also from MCI to dementia.

17 Article 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. 2018

Moreno-Grau, Sonia / Rodríguez-Gómez, Octavio / Sanabria, Ángela / Pérez-Cordón, Alba / Sánchez-Ruiz, Domingo / Abdelnour, Carla / Valero, Sergi / Hernández, Isabel / Rosende-Roca, Maitée / Mauleón, Ana / Vargas, Liliana / Lafuente, Asunción / Gil, Silvia / Santos-Santos, Miguel Ángel / Alegret, Montserrat / Espinosa, Ana / Ortega, Gemma / Guitart, Marina / Gailhajanet, Anna / de Rojas, Itziar / Sotolongo-Grau, Óscar / Ruiz, Susana / Aguilera, Nuria / Papasey, Judith / Martín, Elvira / Peleja, Esther / Anonymous4090927 / Lomeña, Francisco / Campos, Francisco / Vivas, Assumpta / Gómez-Chiari, Marta / Tejero, Miguel Ángel / Giménez, Joan / Serrano-Ríos, Manuel / Orellana, Adelina / Tárraga, Lluís / Ruiz, Agustín / Boada, Mercè / Anonymous4100927. ·Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain. · Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain; Department of Psychiatry, Hospital Universitari Vall d'Hebron, CIBERSAM, Universitat Autònoma de Barcelona, Barcelona, Spain. · Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain; Cognition and brain plasticity group [Bellvitge Biomedical Research Institute-IDIBELL], L'Hospitalet de Llobregat, Barcelona, Spain. · Servei de Medicina Nuclear, Hospital Clínic i Provincial, Barcelona, Spain. · Departament de Diagnòstic per la Imatge, Clínica Corachan, Barcelona, Spain. · CIBERDEM-Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. · Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain. Electronic address: aruiz@fundacioace.com. ·Alzheimers Dement · Pubmed #29156223.

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) ε4'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 ε4 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 ε4 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.

18 Article Longitudinal Neuroimaging Analysis in Mild-Moderate Alzheimer's Disease Patients Treated with Plasma Exchange with 5% Human Albumin. 2018

Cuberas-Borrós, Gemma / Roca, Isabel / Boada, Mercè / Tárraga, Lluís / Hernández, Isabel / Buendia, Mar / Rubio, Lourdes / Torres, Gustavo / Bittini, Ángel / Guzmán-de-Villoria, Juan A / Pujadas, Francesc / Torres, Mireia / Núñez, Laura / Castell, Joan / Páez, Antonio. ·Department of Nuclear Medicine, Institut de Diagnòstic per la Imatge (IDI), Hospital General Universitari Vall d'Hebrón, Universitat Autònoma de Barcelona, Barcelona, Spain. · Department of Nuclear Medicine, Gammagrafía Corachan, Barcelona, Spain. · Department of Neurology, Hospital General Universitari Vall d'Hebrón, Barcelona, Spain. · Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain. · Department of Nuclear Medicine, Hospital General Universitario Gregorio Marañón, Madrid, Spain. · Department of Radiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain. · Department of Clinical, Instituto Grifols, S.A., Barcelona, Spain. ·J Alzheimers Dis · Pubmed #29154283.

ABSTRACT: BACKGROUND: Recently, modifications of Aβ1-42 levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer's disease (AD) treated with plasma exchange (PE) with albumin replacement. OBJECTIVE: To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial. METHODS: Patients received between 3 and 18 PE with albumin (Albutein® 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam®) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline. RESULTS: 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls. CONCLUSIONS: Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion.

19 Article Genetic risk for schizophrenia and psychosis in Alzheimer disease. 2018

DeMichele-Sweet, M A A / Weamer, E A / Klei, L / Vrana, D T / Hollingshead, D J / Seltman, H J / Sims, R / Foroud, T / Hernandez, I / Moreno-Grau, S / Tárraga, L / Boada, M / Ruiz, A / Williams, J / Mayeux, R / Lopez, O L / Sibille, E L / Kamboh, M I / Devlin, B / Sweet, R A. ·Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Computational Biology, Carnegie Mellon University, Pittsburgh, PA, USA. · Genomics Research Core of the Health Sciences Core Research Facilities, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA. · Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK. · Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. · Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain. · Departments of Neurology, Psychiatry and Epidemiology, Columbia University, New York, NY, USA. · Department of Psychiatry and Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. · Campbell Family Mental Health Research Institute of CAMH, Toronto, ON, Canada. · Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA. · VISN 4 Mental Illness Research, Education and Clinical Center (MIRECC), VA Pittsburgh Healthcare System, Pittsburgh, PA, USA. ·Mol Psychiatry · Pubmed #28461698.

ABSTRACT: Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.

20 Article Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. 2017

Sims, Rebecca / van der Lee, Sven J / Naj, Adam C / Bellenguez, Céline / Badarinarayan, Nandini / Jakobsdottir, Johanna / Kunkle, Brian W / Boland, Anne / Raybould, Rachel / Bis, Joshua C / Martin, Eden R / Grenier-Boley, Benjamin / Heilmann-Heimbach, Stefanie / Chouraki, Vincent / Kuzma, Amanda B / Sleegers, Kristel / Vronskaya, Maria / Ruiz, Agustin / Graham, Robert R / Olaso, Robert / Hoffmann, Per / Grove, Megan L / Vardarajan, Badri N / Hiltunen, Mikko / Nöthen, Markus M / White, Charles C / Hamilton-Nelson, Kara L / Epelbaum, Jacques / Maier, Wolfgang / Choi, Seung-Hoan / Beecham, Gary W / Dulary, Cécile / Herms, Stefan / Smith, Albert V / Funk, Cory C / Derbois, Céline / Forstner, Andreas J / Ahmad, Shahzad / Li, Hongdong / Bacq, Delphine / Harold, Denise / Satizabal, Claudia L / Valladares, Otto / Squassina, Alessio / Thomas, Rhodri / Brody, Jennifer A / Qu, Liming / Sánchez-Juan, Pascual / Morgan, Taniesha / Wolters, Frank J / Zhao, Yi / Garcia, Florentino Sanchez / Denning, Nicola / Fornage, Myriam / Malamon, John / Naranjo, Maria Candida Deniz / Majounie, Elisa / Mosley, Thomas H / Dombroski, Beth / Wallon, David / Lupton, Michelle K / Dupuis, Josée / Whitehead, Patrice / Fratiglioni, Laura / Medway, Christopher / Jian, Xueqiu / Mukherjee, Shubhabrata / Keller, Lina / Brown, Kristelle / Lin, Honghuang / Cantwell, Laura B / Panza, Francesco / McGuinness, Bernadette / Moreno-Grau, Sonia / Burgess, Jeremy D / Solfrizzi, Vincenzo / Proitsi, Petra / Adams, Hieab H / Allen, Mariet / Seripa, Davide / Pastor, Pau / Cupples, L Adrienne / Price, Nathan D / Hannequin, Didier / Frank-García, Ana / Levy, Daniel / Chakrabarty, Paramita / Caffarra, Paolo / Giegling, Ina / Beiser, Alexa S / Giedraitis, Vilmantas / Hampel, Harald / Garcia, Melissa E / Wang, Xue / Lannfelt, Lars / Mecocci, Patrizia / Eiriksdottir, Gudny / Crane, Paul K / Pasquier, Florence / Boccardi, Virginia / Henández, Isabel / Barber, Robert C / Scherer, Martin / Tarraga, Lluis / Adams, Perrie M / Leber, Markus / Chen, Yuning / Albert, Marilyn S / Riedel-Heller, Steffi / Emilsson, Valur / Beekly, Duane / Braae, Anne / Schmidt, Reinhold / Blacker, Deborah / Masullo, Carlo / Schmidt, Helena / Doody, Rachelle S / Spalletta, Gianfranco / Longstreth, W T / Fairchild, Thomas J / Bossù, Paola / Lopez, Oscar L / Frosch, Matthew P / Sacchinelli, Eleonora / Ghetti, Bernardino / Yang, Qiong / Huebinger, Ryan M / Jessen, Frank / Li, Shuo / Kamboh, M Ilyas / Morris, John / Sotolongo-Grau, Oscar / Katz, Mindy J / Corcoran, Chris / Dunstan, Melanie / Braddel, Amy / Thomas, Charlene / Meggy, Alun / Marshall, Rachel / Gerrish, Amy / Chapman, Jade / Aguilar, Miquel / Taylor, Sarah / Hill, Matt / Fairén, Mònica Díez / Hodges, Angela / Vellas, Bruno / Soininen, Hilkka / Kloszewska, Iwona / Daniilidou, Makrina / Uphill, James / Patel, Yogen / Hughes, Joseph T / Lord, Jenny / Turton, James / Hartmann, Annette M / Cecchetti, Roberta / Fenoglio, Chiara / Serpente, Maria / Arcaro, Marina / Caltagirone, Carlo / Orfei, Maria Donata / Ciaramella, Antonio / Pichler, Sabrina / Mayhaus, Manuel / Gu, Wei / Lleó, Alberto / Fortea, Juan / Blesa, Rafael / Barber, Imelda S / Brookes, Keeley / Cupidi, Chiara / Maletta, Raffaele Giovanni / Carrell, David / Sorbi, Sandro / Moebus, Susanne / Urbano, Maria / Pilotto, Alberto / Kornhuber, Johannes / Bosco, Paolo / Todd, Stephen / Craig, David / Johnston, Janet / Gill, Michael / Lawlor, Brian / Lynch, Aoibhinn / Fox, Nick C / Hardy, John / Anonymous10931124 / Albin, Roger L / Apostolova, Liana G / Arnold, Steven E / Asthana, Sanjay / Atwood, Craig S / Baldwin, Clinton T / Barnes, Lisa L / Barral, Sandra / Beach, Thomas G / Becker, James T / Bigio, Eileen H / Bird, Thomas D / Boeve, Bradley F / Bowen, James D / Boxer, Adam / Burke, James R / Burns, Jeffrey M / Buxbaum, Joseph D / Cairns, Nigel J / Cao, Chuanhai / Carlson, Chris S / Carlsson, Cynthia M / Carney, Regina M / Carrasquillo, Minerva M / Carroll, Steven L / Diaz, Carolina Ceballos / Chui, Helena C / Clark, David G / Cribbs, David H / Crocco, Elizabeth A / DeCarli, Charles / Dick, Malcolm / Duara, Ranjan / Evans, Denis A / Faber, Kelley M / Fallon, Kenneth B / Fardo, David W / Farlow, Martin R / Ferris, Steven / Foroud, Tatiana M / Galasko, Douglas R / Gearing, Marla / Geschwind, Daniel H / Gilbert, John R / Graff-Radford, Neill R / Green, Robert C / Growdon, John H / Hamilton, Ronald L / Harrell, Lindy E / Honig, Lawrence S / Huentelman, Matthew J / Hulette, Christine M / Hyman, Bradley T / Jarvik, Gail P / Abner, Erin / Jin, Lee-Way / Jun, Gyungah / Karydas, Anna / Kaye, Jeffrey A / Kim, Ronald / Kowall, Neil W / Kramer, Joel H / LaFerla, Frank M / Lah, James J / Leverenz, James B / Levey, Allan I / Li, Ge / Lieberman, Andrew P / Lunetta, Kathryn L / Lyketsos, Constantine G / Marson, Daniel C / Martiniuk, Frank / Mash, Deborah C / Masliah, Eliezer / McCormick, Wayne C / McCurry, Susan M / McDavid, Andrew N / McKee, Ann C / Mesulam, Marsel / Miller, Bruce L / Miller, Carol A / Miller, Joshua W / Morris, John C / Murrell, Jill R / Myers, Amanda J / O'Bryant, Sid / Olichney, John M / Pankratz, Vernon S / Parisi, Joseph E / Paulson, Henry L / Perry, William / Peskind, Elaine / Pierce, Aimee / Poon, Wayne W / Potter, Huntington / Quinn, Joseph F / Raj, Ashok / Raskind, Murray / Reisberg, Barry / Reitz, Christiane / Ringman, John M / Roberson, Erik D / Rogaeva, Ekaterina / Rosen, Howard J / Rosenberg, Roger N / Sager, Mark A / Saykin, Andrew J / Schneider, Julie A / Schneider, Lon S / Seeley, William W / Smith, Amanda G / Sonnen, Joshua A / Spina, Salvatore / Stern, Robert A / Swerdlow, Russell H / Tanzi, Rudolph E / Thornton-Wells, Tricia A / Trojanowski, John Q / Troncoso, Juan C / Van Deerlin, Vivianna M / Van Eldik, Linda J / Vinters, Harry V / Vonsattel, Jean Paul / Weintraub, Sandra / Welsh-Bohmer, Kathleen A / Wilhelmsen, Kirk C / Williamson, Jennifer / Wingo, Thomas S / Woltjer, Randall L / Wright, Clinton B / Yu, Chang-En / Yu, Lei / Garzia, Fabienne / Golamaully, Feroze / Septier, Gislain / Engelborghs, Sebastien / Vandenberghe, Rik / De Deyn, Peter P / Fernadez, Carmen Muñoz / Benito, Yoland Aladro / Thonberg, Hakan / Forsell, Charlotte / Lilius, Lena / Kinhult-Stählbom, Anne / Kilander, Lena / Brundin, RoseMarie / Concari, Letizia / Helisalmi, Seppo / Koivisto, Anne Maria / Haapasalo, Annakaisa / Dermecourt, Vincent / Fievet, Nathalie / Hanon, Olivier / Dufouil, Carole / Brice, Alexis / Ritchie, Karen / Dubois, Bruno / Himali, Jayanadra J / Keene, C Dirk / Tschanz, JoAnn / Fitzpatrick, Annette L / Kukull, Walter A / Norton, Maria / Aspelund, Thor / Larson, Eric B / Munger, Ron / Rotter, Jerome I / Lipton, Richard B / Bullido, María J / Hofman, Albert / Montine, Thomas J / Coto, Eliecer / Boerwinkle, Eric / Petersen, Ronald C / Alvarez, Victoria / Rivadeneira, Fernando / Reiman, Eric M / Gallo, Maura / O'Donnell, Christopher J / Reisch, Joan S / Bruni, Amalia Cecilia / Royall, Donald R / Dichgans, Martin / Sano, Mary / Galimberti, Daniela / St George-Hyslop, Peter / Scarpini, Elio / Tsuang, Debby W / Mancuso, Michelangelo / Bonuccelli, Ubaldo / Winslow, Ashley R / Daniele, Antonio / Wu, Chuang-Kuo / Anonymous10941124 / Peters, Oliver / Nacmias, Benedetta / Riemenschneider, Matthias / Heun, Reinhard / Brayne, Carol / Rubinsztein, David C / Bras, Jose / Guerreiro, Rita / Al-Chalabi, Ammar / Shaw, Christopher E / Collinge, John / Mann, David / Tsolaki, Magda / Clarimón, Jordi / Sussams, Rebecca / Lovestone, Simon / O'Donovan, Michael C / Owen, Michael J / Behrens, Timothy W / Mead, Simon / Goate, Alison M / Uitterlinden, Andre G / Holmes, Clive / Cruchaga, Carlos / Ingelsson, Martin / Bennett, David A / Powell, John / Golde, Todd E / Graff, Caroline / De Jager, Philip L / Morgan, Kevin / Ertekin-Taner, Nilufer / Combarros, Onofre / Psaty, Bruce M / Passmore, Peter / Younkin, Steven G / Berr, Claudine / Gudnason, Vilmundur / Rujescu, Dan / Dickson, Dennis W / Dartigues, Jean-François / DeStefano, Anita L / Ortega-Cubero, Sara / Hakonarson, Hakon / Campion, Dominique / Boada, Merce / Kauwe, John Keoni / Farrer, Lindsay A / Van Broeckhoven, Christine / Ikram, M Arfan / Jones, Lesley / Haines, Jonathan L / Tzourio, Christophe / Launer, Lenore J / Escott-Price, Valentina / Mayeux, Richard / Deleuze, Jean-François / Amin, Najaf / Holmans, Peter A / Pericak-Vance, Margaret A / Amouyel, Philippe / van Duijn, Cornelia M / Ramirez, Alfredo / Wang, Li-San / Lambert, Jean-Charles / Seshadri, Sudha / Williams, Julie / Schellenberg, Gerard D / and others. ·Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. · Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. · Department of Biostatistics and Epidemiology/Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. · INSERM, U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France. · Institut Pasteur de Lille, Lille, France. · University Lille, U1167-Excellence Laboratory LabEx DISTALZ, Lille, France. · Icelandic Heart Association, Kopavogur, Iceland. · John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA. · CEA/Institut de Génomique, Centre National de Génotypage, Evry, France. · Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA. · Dr. John T. Macdonald Foundation, Department of Human Genetics, University of Miami, Miami, Florida, USA. · Institute of Human Genetics, University of Bonn, Bonn, Germany. · Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany. · Boston University School of Medicine, Boston, Massachusetts, USA. · Framingham Heart Study, Framingham, Massachusetts, USA. · Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. · Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium. · Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. · Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain. · Immunology Biomarkers Group, Genentech, South San Francisco, California, USA. · Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland. · School of Public Health, Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA. · Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, New York, USA. · Gertrude H. Sergievsky Center, Columbia University, New York, New York, USA. · Department of Neurology, Columbia University, New York, New York, USA. · Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland. · Department of Neurology, Kuopio University Hospital, Kuopio, Finland. · Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA. · UMR 894, Center for Psychiatry and Neuroscience, INSERM, Université Paris Descartes, Paris, France. · German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. · Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany. · Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. · Faculty of Medicine, University of Iceland, Reykjavik, Iceland. · Institute for Systems Biology, Seattle, Washington, USA. · School of Biotechnology, Dublin City University, Dublin, Ireland. · Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy. · Neurology Service and CIBERNED, 'Marqués de Valdecilla' University Hospital (University of Cantabria and IFIMAV), Santander, Spain. · Department of Immunology, Hospital Universitario Doctor Negrín, Las Palmas de Gran Canaria, Spain. · Brown Foundation Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas, USA. · Departments of Medicine, Geriatrics, Gerontology and Neurology, University of Mississippi Medical Center, Jackson, Mississippi, USA. · Centre Hospitalier du Rouvray, Sotteville les Rouen, France. · INSERM U1079, Rouen University, IRIB, Normandy University, Rouen, France. · Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. · Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. · Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden. · Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden. · Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK. · Department of Medicine, University of Washington, Seattle, Washington, USA. · Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA. · Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy. · Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, UK. · Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA. · Geriatric Medicine-Memory Unit and Rare Disease Centre, University of Bari Aldo Moro, Bari, Italy. · Geriatric Unit and Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. · Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy. · Department of Neurology, Rouen University Hospital, Rouen, France. · Department of Neurology, University Hospital La Paz, Universidad Autónoma de Madrid, Madrid, Spain. · Instituto de Investigación Sanitaria Hospital la Paz (IdiPAZ), Madrid, Spain. · Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. · National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA. · Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, Florida, USA. · Department of Neuroscience, University of Parma, Parma, Italy. · Center for Cognitive Disorders AUSL, Parma, Italy. · Department of Psychiatry, Martin Luther University Halle-Wittenberg, Halle, Germany. · Department of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden. · AXA Research Fund and UPMC Chair, Paris, France. · Sorbonne Universités, Université Pierre et Marie Curie, Paris, France. · Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A) and Institut du Cerveau et de la Moelle Épinière (ICM), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France. · Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, USA. · Centre Hospitalier Universitaire de Lille, Epidemiology and Public Health Department, Lille, France. · INSERM UMRS 1171, CNR-Maj, Lille, France. · Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA. · Department of Primary Medical Care, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. · Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA. · Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany. · Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA. · Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany. · Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland. · National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, USA. · Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, UK. · Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz, Austria. · Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. · Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA. · Department of Neurology, Catholic University of Rome, Rome, Italy. · Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria. · Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, Texas, USA. · Experimental Neuropsychiatry Laboratory, IRCCS Santa Lucia Foundation, Department of Clinical and Behavioural Neurology, Rome, Italy. · Department of Neurology, University of Washington, Seattle, Washington, USA. · Department of Epidemiology, University of Washington, Seattle, Washington, USA. · Office of Strategy and Measurement, University of North Texas Health Science Center, Fort Worth, Texas, USA. · Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, Massachusetts, USA. · Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, USA. · Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA. · Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA. · Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, Missouri, USA. · Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA. · Department of Mathematics and Statistics, Utah State University, Logan, Utah, USA. · Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain. · Memory Unit, Department of Neurology, Hospital Universitario Mútua Terrassa, Terrassa, Barcelona, Spain. · Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. · INSERM U558, University of Toulouse, Toulouse, France. · Elderly and Psychiatric Disorders Department, Medical University of Lodz, Lodz, Poland. · Department of Health Sciences, Psychiatry for the Elderly, University of Leicester, Leicester, UK. · Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK. · Department of Pathophysiology and Transplantation, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy. · Department of Psychiatry and Psychotherapy, University Hospital, Saarland, Germany. · Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain. · Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy. · Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA. · NEUROFARBA (Department of Neuroscience, Psychology, Drug Research and Child Health), University of Florence, Florence, Italy. · IRCCS 'Don Carlo Gnocchi', Florence, Italy. · Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany. · Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Associazione Oasi Maria Santissima Srl, Troina, Italy. · Mercers Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland. · Department of Molecular Neuroscience, UCL, Institute of Neurology, London, UK. · Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA. · Geriatric Research, Education and Clinical Center (GRECC), VA Ann Arbor Healthcare System (VAAAHS), Ann Arbor, Michigan, USA. · Michigan Alzheimer Disease Center, Ann Arbor, Michigan, USA. · Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, Indiana, USA. · Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, USA. · Department of Neurology, Indiana University, Indianapolis, Indiana, USA. · Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, Indiana, USA. · Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. · Geriatric Research, Education and Clinical Center (GRECC), University of Wisconsin, Madison, Wisconsin, USA. · Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA. · Wisconsin Alzheimer's Disease Research Center, Madison, Wisconsin, USA. · Department of Medicine (Genetics Program), Boston University, Boston, Massachusetts, USA. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA. · Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois, USA. · Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA. · Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Phoenix, Arizona, USA. · Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. · Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. · Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. · VA Puget Sound Health Care System/GRECC, Seattle, Washington, USA. · Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA. · Swedish Medical Center, Seattle, Washington, USA. · Department of Neurology, University of California, San Francisco, San Francisco, California, USA. · Department of Medicine, Duke University, Durham, North Carolina, USA. · University of Kansas Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, Kansas, USA. · Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA. · Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA. · Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA. · Department of Pathology and Immunology, Washington University, St. Louis, Missouri, USA. · USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida, USA. · Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, Florida, USA. · Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA. · Department of Neurology, University of Southern California, Los Angeles, California, USA. · Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA. · Department of Neurology, Ralph H. Johnson VA Medical Center, Charleston, South Carolina, USA. · Department of Neurology, University of California, Irvine, Irvine, California, USA. · Department of Neurology, University of California, Davis, Sacramento, California, USA. · Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, California, USA. · Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Florida, USA. · Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA. · Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA. · Sanders-Brown Center on Aging, Department of Biostatistics, University of Kentucky, Lexington, Kentucky, USA. · Department of Psychiatry, New York University, New York, New York, USA. · Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. · Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA. · Emory Alzheimer's Disease Center, Emory University, Atlanta, Georgia, USA. · Neurogenetics Program, University of California, Los Angeles, Los Angeles, California, USA. · Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA. · Division of Genetics, Department of Medicine and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA. · Department of Pathology (Neuropathology), University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA. · Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, USA. · Department of Pathology, Duke University, Durham, North Carolina, USA. · Department of Genome Sciences, University of Washington, Seattle, Washington, USA. · Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington, USA. · Sanders-Brown Center on Aging, College of Public Health, Department of Epidemiology, University of Kentucky, Lexington, Kentucky, USA. · Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, California, USA. · Department of Biostatistics, Boston University, Boston, Massachusetts, USA. · Department of Ophthalmology, Boston University, Boston, Massachusetts, USA. · Department of Neurology, Oregon Health &Science University, Portland, Oregon, USA. · Department of Neurology, Portland Veterans Affairs Medical Center, Portland, Oregon, USA. · Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, California, USA. · Department of Neurology, Boston University, Boston, Massachusetts, USA. · Department of Pathology, Boston University, Boston, Massachusetts, USA. · Department of Neuropsychology, University of California, San Francisco, San Francisco, California, USA. · Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California, USA. · Department of Neurology, Emory University, Atlanta, Georgia, USA. · Cleveland Clinic Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, Ohio, USA. · Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. · Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Medicine-Pulmonary, New York University, New York, New York, USA. · Department of Neurology, University of Miami, Miami, Florida, USA. · Department of Pathology, University of California, San Diego, La Jolla, California, USA. · School of Nursing Northwest Research Group on Aging, University of Washington, Seattle, Washington, USA. · Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. · Department of Pathology, University of Southern California, Los Angeles, California, USA. · Department of Neurology, Washington University, St. Louis, Missouri, USA. · Internal Medicine, Division of Geriatrics, University of North Texas Health Science Center, Fort Worth, Texas, USA. · Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA. · Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA. · Alzheimer's Disease Center, New York University, New York, New York, USA. · Department of Epidemiology, Columbia University, New York, New York, USA. · Department of Neurology, University of California, Los Angeles, Los Angeles, California, USA. · Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada. · Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. · Department of Pathology (Neuropathology), Rush University Medical Center, Chicago, Illinois, USA. · Department of Psychiatry, University of Southern California, Los Angeles, California, USA. · Department of Pathology, University of Washington, Seattle, Washington, USA. · Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA. · Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. · Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. · Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, USA. · Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA. · Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Pathology, Columbia University, New York, New York, USA. · Department of Psychiatry, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. · Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina, USA. · Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. · Department of Pathology, Oregon Health &Science University, Portland, Oregon, USA. · Evelyn F. McKnight Brain Institute, Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida, USA. · Department of Neurology and Memory Clinic, Hospital Network Antwerp, Antwerp, Belgium. · Laboratory for Cognitive Neurology, Department of Neurology, University of Leuven, Leuven, Belgium. (and more) ·Nat Genet · Pubmed #28714976.

ABSTRACT: 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

21 Article Social Representation of Dementia: An Analysis of 5,792 Consecutive Cases Evaluated in a Memory Clinic. 2017

Cañabate, Pilar / Martínez, Gabriel / Rosende-Roca, Maitée / Moreno, Mariola / Preckler, Silvia / Valero, Sergi / Sotolongo, Oscar / Hernández, Isabel / Alegret, Montserrat / Ortega, Gemma / Espinosa, Ana / Mauleón, Ana / Vargas, Liliana / Rodríguez, Octavio / Abdelnour, Carla / Sánchez, Domingo / Martín, Elvira / Ruiz, Agustín / Tárraga, Lluís / Boada, Mercè. ·Memory Clinic and Research Center of Fundació ACE. Institut Català de Neurociènces Aplicades, Barcelona, Spain. · Iberoamerican Cochrane Centre, Barcelona, Spain. · Faculty of Medicine and Dentistry, University of Antofagasta, Antofagasta, Chile. · Department of Psychiatry, Hospital Universitari Vall d'Hebron, CIBERSAM, Universitat Autònoma de Barcelona, Barcelona, Spain. ·J Alzheimers Dis · Pubmed #28527206.

ABSTRACT: BACKGROUND: Different interpretations of cognitive impairment and dementia due to differences in health structures, such as cultural differences could affect the diagnosis and treatment of the condition. it is reasonable to expect that the social and family impact of the disease and coping strategies will differ among societies. OBJECTIVE: The general aim of this study is to understand the social representations of dementia, its associated practices, and the effects they imply. METHODS: People diagnosed with clinical dementia and their families were assessed from 2005 to 2015 in the memory clinic of the Fundació ACE, Institut Català de Neurociències Aplicades in Barcelona, Spain. RESULTS: 9,898 people were examined and 5,792 were diagnosed with dementia. For those with a caregiver (71%), the decision-making fell on the person with dementia in 16.2% of the cases; and for those without a caregiver, in 26.4% of the cases the family did not perceive the deficits as a disease, which led to multiple risk situations (74.6%). CONCLUSIONS: The recognition of dementia as part of aging is common among families. Consequently, risk situations may arise and diagnosis and access to treatment may be delayed. The incorporation of a social appraisal to the diagnostic process is a necessity to evaluate these situations.

22 Article Cognitive Composites Domain Scores Related to Neuroimaging Biomarkers within Probable-Amnestic Mild Cognitive Impairment-Storage Subtype. 2017

Espinosa, Ana / Alegret, Montserrat / Pesini, Pedro / Valero, Sergi / Lafuente, Asunción / Buendía, Mar / San José, Itziar / Ibarria, Marta / Tejero, Miguel A / Giménez, Joan / Ruiz, Susana / Hernández, Isabel / Pujadas, Francesc / Martínez-Lage, Pablo / Munuera, Josep / Arbizu, Javier / Tárraga, Lluis / Hendrix, Suzanne B / Ruiz, Agustín / Becker, James T / Landau, Susan M / Sotolongo-Grau, Oscar / Sarasa, Manuel / Boada, Mercè / Anonymous6980898 / Anonymous6990898. ·Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Alzheimer Barcelona, Spain. · Araclon Biotech S.L., Zaragoza, Spain. · Deparment of Psychiatry, Hospital Universitari Vall d'Hebron, CIBERSAM, Universitat Autònoma de Barcelona, Barcelona, Spain. · Clínica Corachán, Barcelona, Spain. · Department of Neurology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. · Fundación CITA, Centro de Investigación y Terapias Avanzadas, Alzheimer, San Sebastián, Spain. · Hospital Universitari Germans Trias i Pujol, Unitat RM Badalona, Institut de diagnòstic per la imatge, Badalona, Spain. · Clínica Universitaria de Pamplona, Pamplona, Spain. · Pentara Corporation, Salt Lake City, UT, USA. · Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA, USA. · Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA. ·J Alzheimers Dis · Pubmed #28269787.

ABSTRACT: The probable-amnestic (Pr-a) mild cognitive impairment (MCI)-storage subtype is a phenotype with 8.5 times more risk of conversion to dementia, mainly Alzheimer's disease (AD), than the possible non-amnestic (Pss-na) MCI. The aim of this study was to find the optimized cognitive composites (CCs) domain scores most related to neuroimaging biomarkers within Pr-aMCI-storage subtype patients. The Fundació ACE (ACE) study with 20 Pr-aMCI-storage subtype subjects (MCI) were analyzed. All subjects underwent a neuropsychological assessment, a structural MRI, FDG-PET, and PIB-PET. The adjusted hippocampal volume (aHV) on MRI, the standard uptake value ratio (SUVR) on FDG-PET and PIB-PET SUVR measures were analyzed. The construction of the CCs domain scores, and the aHV on MRI and FDG-PET SUVR measures, were replicated in the parental AB255 study database (n = 133 MCI). Partial correlations adjusted by age, gender, and education were calculated with the associated p-value among every CC domain score and the neuroimaging biomarkers. The results were replicated in the "MCI due to AD" with memory storage impairments from ADNI. Delayed Recall CC domain score was significantly correlated with PIB-PET SUVR (β= -0.61, p = 0.003) in the ACE study and also with aHV on MRI (β= 0.27, p = 0.01) and FDG-PET SUVR (β= 0.27, p = 0.01) in the AB255 study. After a median survival time of 20.6 months, 85% from the ACE MCI converted to AD. The replication of our results in the ADNI dataset also confirmed our findings. Delayed Recall is the CC domain score best correlated with neuroimaging biomarkers associated with prodromal AD diagnosis.

23 Article Impact of Recruitment Methods in Subjective Cognitive Decline. 2017

Abdelnour, Carla / Rodríguez-Gómez, Octavio / Alegret, Montserrat / Valero, Sergi / Moreno-Grau, Sonia / Sanabria, Ángela / Hernández, Isabel / Rosende-Roca, Maitee / Vargas, Liliana / Mauleón, Ana / Sánchez, Domingo / Espinosa, Ana / Ortega, Gemma / Pérez-Cordón, Alba / Diego, Susana / Gailhajanet, Anna / Guitart, Marina / Sotolongo-Grau, Óscar / Ruiz, Agustín / Tárraga, Lluís / Boada, Mercè. ·Alzheimer Research Center and Memory Clinic of Fundació ACE, Institut Catalá de Neurociències Aplicades, Barcelona, Spain. · Department of Psychiatry, Hospital Universitari Vall d'Hebron, CIBERSAM, Universitat Autònoma de Barcelona, Barcelona, Spain. ·J Alzheimers Dis · Pubmed #28269773.

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 < 0.05), with higher educational level (12.15 [3.71] versus 10.70 [3.80] years, p = 0.001), and more family history of dementia (138 [62.7%] versus 44 [41.5%], p < 0.001) than the MU sample. Also, the OHI sample showed better overall neuropsychological performance than the MU sample, and after a LRA, this trend continued in automatic response inhibition capacity, abstract reasoning, and recognition memory. We did not find differences in age, depression history, and/or APOE ɛ4 allele frequency. CONCLUSION: SCD subjects showed different demographic and neuropsychological characteristics depending on the recruitment method, which should be taken into account in the design of research studies with this target population.

24 Article 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. 2017

Lacour, A / Espinosa, A / Louwersheimer, E / Heilmann, S / Hernández, I / Wolfsgruber, S / Fernández, V / Wagner, H / Rosende-Roca, M / Mauleón, A / Moreno-Grau, S / Vargas, L / Pijnenburg, Y A L / Koene, T / Rodríguez-Gómez, O / Ortega, G / Ruiz, S / Holstege, H / Sotolongo-Grau, O / Kornhuber, J / Peters, O / Frölich, L / Hüll, M / Rüther, E / Wiltfang, J / Scherer, M / Riedel-Heller, S / Alegret, M / Nöthen, M M / Scheltens, P / Wagner, M / Tárraga, L / Jessen, F / Boada, M / Maier, W / van der Flier, W M / Becker, T / Ramirez, A / Ruiz, A. ·German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. · Memory Clinic and Research Center of Fundación ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain. · Department of Neurology and Alzheimer Centre, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. · Institute of Human Genetics, University of Bonn, Bonn, Germany. · Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany. · Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany. · Alzheimer Center and Department of Clinical Genetics, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. · Department of Psychiatry and Psychotherapy, University Clinic Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. · Department of Psychiatry, Charité University Medicine, Berlin, Germany. · Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. · Center for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany. · Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany. · Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany. · Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany. · Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. · Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany. ·Mol Psychiatry · Pubmed #26976043.

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-ɛ4 (apolipoprotein E-ɛ4) 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.

25 Article Alzheimer's disease risk variants modulate endophenotypes in mild cognitive impairment. 2016

Louwersheimer, Eva / Wolfsgruber, Steffen / Espinosa, Ana / Lacour, André / Heilmann-Heimbach, Stefanie / Alegret, Montserrat / Hernández, Isabel / Rosende-Roca, Maitée / Tárraga, Lluís / Boada, Mercè / Kornhuber, Johannes / Peters, Oliver / Frölich, Lutz / Hüll, Michael / Rüther, Eckart / Wiltfang, Jens / Scherer, Martin / Riedel-Heller, Steffi / Jessen, Frank / Nöthen, Markus M / Maier, Wolfgang / Koene, Ted / Scheltens, Philip / Holstege, Henne / Wagner, Michael / Ruiz, Agustín / van der Flier, Wiesje M / Becker, Tim / Ramirez, Alfredo. ·Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands. Electronic address: e.louwersheimer@vumc.nl. · Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. · Alzheimer Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain. · German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. · Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany. · Department of Psychiatry and Psychotherapy, University Clinic Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. · Department of Psychiatry, Charité University Medicine, Berlin, Germany. · Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. · Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany. · Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany. · Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany. · Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany. · Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands; Alzheimer Center and Department of Medical Psychology, VU University Medical Center, Amsterdam, The Netherlands. · Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands. · Alzheimer Center and Department of Clinical Genetics, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands. · Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands; Department of Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. · Institute for Community Medicine, Ernst Moritz Arndt University Greifswald, Greifswald, Germany. · Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; Institute of Human Genetics, University of Bonn, Bonn, Germany. Electronic address: alfredo.ramirez@ukb.uni-bonn.de. ·Alzheimers Dement · Pubmed #26921674.

ABSTRACT: INTRODUCTION: We evaluated the effect of Alzheimer's disease (AD) susceptibility loci on endophenotypes closely related with AD pathology in patients with mild cognitive impairment (MCI). METHODS: We selected 1730 MCI patients from four independent data sets. Weighted polygenic risk scores (PGS) were constructed of 18 non-apolipoprotein E (APOE) AD risk variants. In addition, we determined APOE genotype. AD endophenotypes were cognitive decline over time and cerebrospinal fluid (CSF) biomarkers (aβ, tau, ptau). RESULTS: PGS was modestly associated with cognitive decline over time, as measured by mini-mental state examination (MMSE) (β ± SE:-0.24 ± 0.10; P = .012), and with CSF levels of tau and ptau (tau: 1.38 ± 0.36, P = 1.21 × 10(-4); ptau: 1.40 ± 0.36, P = 1.02 × 10(-4)). DISCUSSION: In MCI, we observed a joint effect of AD susceptibility loci on nonamyloid endophenotypes, suggesting a link of these genetic loci with neuronal degeneration in general rather than with Alzheimer-related amyloid deposition.

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