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3. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Author

Warrington, Nicole M, Beaumont, Robin N, Horikoshi, Momoko, Day, Felix R, Helgeland, Øyvind, Laurin, Charles, Bacelis, Jonas, Peng, Shouneng, Hao, Ke, Feenstra, Bjarke, Wood, Andrew R, Mahajan, Anubha, Tyrrell, Jessica, Robertson, Neil R, Rayner, N William, Qiao, Zhen, Moen, Gunn-Helen, Vaudel, Marc, Marsit, Carmen J, Chen, Jia, Nodzenski, Michael, Schnurr, Theresia M, Zafarmand, Mohammad H, Bradfield, Jonathan P, Grarup, Niels, Kooijman, Marjolein N, Li-Gao, Ruifang, Geller, Frank, Ahluwalia, Tarunveer S, Paternoster, Lavinia, Rueedi, Rico, Huikari, Ville, Hottenga, Jouke-Jan, Lyytikäinen, Leo-Pekka, Cavadino, Alana, Metrustry, Sarah, Cousminer, Diana L, Wu, Ying, Thiering, Elisabeth, Wang, Carol A, Have, Christian T, Vilor-Tejedor, Natalia, Joshi, Peter K, Painter, Jodie N, Ntalla, Ioanna, Myhre, Ronny, Pitkänen, Niina, van Leeuwen, Elisabeth M, Joro, Raimo, Lagou, Vasiliki, Richmond, Rebecca C, Espinosa, Ana, Barton, Sheila J, Inskip, Hazel M, Holloway, John W, Santa-Marina, Loreto, Estivill, Xavier, Ang, Wei, Marsh, Julie A, Reichetzeder, Christoph, Marullo, Letizia, Hocher, Berthold, Lunetta, Kathryn L, Murabito, Joanne M, Relton, Caroline L, Kogevinas, Manolis, Chatzi, Leda, Allard, Catherine, Bouchard, Luigi, Hivert, Marie-France, Zhang, Ge, Muglia, Louis J, Heikkinen, Jani, Morgen, Camilla S, van Kampen, Antoine HC, van Schaik, Barbera DC, Mentch, Frank D, Langenberg, Claudia, Luan, Jian’an, Scott, Robert A, Zhao, Jing Hua, Hemani, Gibran, Ring, Susan M, Bennett, Amanda J, Gaulton, Kyle J, Fernandez-Tajes, Juan, van Zuydam, Natalie R, Medina-Gomez, Carolina, de Haan, Hugoline G, Rosendaal, Frits R, Kutalik, Zoltán, Marques-Vidal, Pedro, Das, Shikta, Willemsen, Gonneke, Mbarek, Hamdi, Müller-Nurasyid, Martina, Standl, Marie, Appel, Emil VR, Fonvig, Cilius E, and Trier, Caecilie

Subjects
Biological Sciences, Genetics, Cardiovascular, Perinatal Period - Conditions Originating in Perinatal Period, Nutrition, Prevention, Preterm, Low Birth Weight and Health of the Newborn, Pediatric, Obesity, Conditions Affecting the Embryonic and Fetal Periods, Infant Mortality, 2.1 Biological and endogenous factors, Aetiology, Reproductive health and childbirth, Good Health and Well Being, Adult, Birth Weight, Blood Pressure, Body Height, Diabetes Mellitus, Type 2, Female, Fetal Development, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Diseases, Humans, Infant, Newborn, Male, Maternal Inheritance, Maternal-Fetal Exchange, Metabolic Diseases, Models, Genetic, Polymorphism, Single Nucleotide, Pregnancy, Risk Factors, EGG Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

Published
2019

4. Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms

Author

Jami, Eshim S., Hammerschlag, Anke R., Ip, Hill F., Allegrini, Andrea G., Benyamin, Beben, Border, Richard, Diemer, Elizabeth W., Jiang, Chang, Karhunen, Ville, Lu, Yi, Lu, Qing, Mallard, Travis T., Mishra, Pashupati P., Nolte, Ilja M., Palviainen, Teemu, Peterson, Roseann E., Sallis, Hannah M., Shabalin, Andrey A., Tate, Ashley E., Thiering, Elisabeth, Vilor-Tejedor, Natàlia, Wang, Carol, Zhou, Ang, Adkins, Daniel E., Alemany, Silvia, Ask, Helga, Chen, Qi, Corley, Robin P., Ehli, Erik A., Evans, Luke M., Havdahl, Alexandra, Hagenbeek, Fiona A., Hakulinen, Christian, Henders, Anjali K., Hottenga, Jouke Jan, Korhonen, Tellervo, Mamun, Abdullah, Marrington, Shelby, Neumann, Alexander, Rimfeld, Kaili, Rivadeneira, Fernando, Silberg, Judy L., van Beijsterveldt, Catharina E., Vuoksimaa, Eero, Whipp, Alyce M., Tong, Xiaoran, Andreassen, Ole A., Boomsma, Dorret I., Brown, Sandra A., Burt, S. Alexandra, Copeland, William, Dick, Danielle M., Harden, K. Paige, Harris, Kathleen Mullan, Hartman, Catharina A., Heinrich, Joachim, Hewitt, John K., Hopfer, Christian, Hypponen, Elina, Jarvelin, Marjo-Riitta, Kaprio, Jaakko, Keltikangas-Järvinen, Liisa, Klump, Kelly L., Krauter, Kenneth, Kuja-Halkola, Ralf, Larsson, Henrik, Lehtimäki, Terho, Lichtenstein, Paul, Lundström, Sebastian, Maes, Hermine H., Magnus, Per, Munafò, Marcus R., Najman, Jake M., Njølstad, Pål R., Oldehinkel, Albertine J., Pennell, Craig E., Plomin, Robert, Reichborn-Kjennerud, Ted, Reynolds, Chandra, Rose, Richard J., Smolen, Andrew, Snieder, Harold, Stallings, Michael, Standl, Marie, Sunyer, Jordi, Tiemeier, Henning, Wadsworth, Sally J., Wall, Tamara L., Whitehouse, Andrew J.O., Williams, Gail M., Ystrøm, Eivind, Nivard, Michel G., Bartels, Meike, and Middeldorp, Christel M.

Published
2022
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5. Genetically predicted telomere length and Alzheimer’s disease endophenotypes: a Mendelian randomization study

Author

Rodríguez-Fernández, Blanca, Vilor-Tejedor, Natalia, Arenaza-Urquijo, Eider M., Sánchez-Benavides, Gonzalo, Suárez-Calvet, Marc, Operto, Grégory, Minguillón, Carolina, Fauria, Karine, Kollmorgen, Gwendlyn, Suridjan, Ivonne, de Moura, Manuel Castro, Piñeyro, David, Esteller, Manel, Blennow, Kaj, Zetterberg, Henrik, De Vivo, Immaculata, Molinuevo, José Luis, Navarro, Arcadi, Gispert, Juan Domingo, Sala-Vila, Aleix, and Crous-Bou, Marta

Published
2022
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6. CSF glial biomarkers are associated with cognition in individuals at risk of Alzheimer's disease.

Author

Warmenhoven, Noëlle, Sánchez‐Benavides, Gonzalo, González‐Escalante, Armand, Milà‐Alomà, Marta, Shekari, Mahnaz, López‐Martos, David, Ortiz‐Romero, Paula, Kollmorgen, Gwendlyn, Quijano‐Rubio, Clara, Minguillón, Carolina, Gispert, Juan Domingo, Vilor‐Tejedor, Natalia, Arenaza‐Urquijo, Eider, Palpatzis, Eleni, Ashton, Nicholas J, Zetterberg, Henrik, Blennow, Kaj, Suárez‐Calvet, Marc, and Grau‐Rivera, Oriol

Published
2024
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9. Lipid-regulatory mechanisms drive cerebrovascular disease in asymptomatic individuals at low risk for late-life dementia

Author

Genius, Patricia, primary, Rodriguez-Fernandez, Blanca, additional, Minguillon, Carolina, additional, Brugulat, Anna, additional, Huguet, Jordi, additional, Esteller, Manel, additional, Sudre, Carole, additional, Cortes-Canteli, Marta, additional, Tristao-Pereira, Catarina, additional, Garcia-Lunar, Ines, additional, Navarro, Arcadi, additional, Gispert, Juan Domingo, additional, and Vilor-Tejedor, Natalia, additional

Published
2024
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10. Compositional structural brain signatures capture Alzheimer's genetic risk on brain structure along the diseasecontinuum

Author

Genius, Patricia, primary, Calle, Maria Luz, additional, Rodriguez-Fernandez, Blanca, additional, Minguillon, Carolina, additional, Cacciaglia, Raffaele, additional, Garrido-Martin, Diego, additional, Esteller, Manel, additional, Navarro, Arcadi, additional, Gispert, Juan Domingo, additional, and Vilor-Tejedor, Natalia, additional

Published
2024
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12. Amyloid-β positive individuals with subjective cognitive decline present increased CSF neurofilament light levels that relate to lower hippocampal volume

Author

Sánchez-Benavides, Gonzalo, Suárez-Calvet, Marc, Milà-Alomà, Marta, Arenaza-Urquijo, Eider M., Grau-Rivera, Oriol, Operto, Grégory, Gispert, Juan Domingo, Vilor-Tejedor, Natalia, Sala-Vila, Aleix, Crous-Bou, Marta, González-de-Echávarri, José Maria, Minguillon, Carolina, Fauria, Karine, Simon, Maryline, Kollmorgen, Gwendlyn, Zetterberg, Henrik, Blennow, Kaj, and Molinuevo, José Luis

Published
2021
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14. Genome-wide associations for birth weight and correlations with adult disease

Author

Horikoshi, Momoko, Beaumont, Robin N, Day, Felix R, Warrington, Nicole M, Kooijman, Marjolein N, Fernandez-Tajes, Juan, Feenstra, Bjarke, van Zuydam, Natalie R, Gaulton, Kyle J, Grarup, Niels, Bradfield, Jonathan P, Strachan, David P, Li-Gao, Ruifang, Ahluwalia, Tarunveer S, Kreiner, Eskil, Rueedi, Rico, Lyytikäinen, Leo-Pekka, Cousminer, Diana L, Wu, Ying, Thiering, Elisabeth, Wang, Carol A, Have, Christian T, Hottenga, Jouke-Jan, Vilor-Tejedor, Natalia, Joshi, Peter K, Boh, Eileen Tai Hui, Ntalla, Ioanna, Pitkänen, Niina, Mahajan, Anubha, van Leeuwen, Elisabeth M, Joro, Raimo, Lagou, Vasiliki, Nodzenski, Michael, Diver, Louise A, Zondervan, Krina T, Bustamante, Mariona, Marques-Vidal, Pedro, Mercader, Josep M, Bennett, Amanda J, Rahmioglu, Nilufer, Nyholt, Dale R, Ma, Ronald CW, Tam, Claudia HT, Tam, Wing Hung, Ganesh, Santhi K, van Rooij, Frank JA, Jones, Samuel E, Loh, Po-Ru, Ruth, Katherine S, Tuke, Marcus A, Tyrrell, Jessica, Wood, Andrew R, Yaghootkar, Hanieh, Scholtens, Denise M, Paternoster, Lavinia, Prokopenko, Inga, Kovacs, Peter, Atalay, Mustafa, Willems, Sara M, Panoutsopoulou, Kalliope, Wang, Xu, Carstensen, Lisbeth, Geller, Frank, Schraut, Katharina E, Murcia, Mario, van Beijsterveldt, Catharina EM, Willemsen, Gonneke, Appel, Emil VR, Fonvig, Cilius E, Trier, Caecilie, Tiesler, Carla MT, Standl, Marie, Kutalik, Zoltán, Bonàs-Guarch, Sílvia, Hougaard, David M, Sánchez, Friman, Torrents, David, Waage, Johannes, Hollegaard, Mads V, de Haan, Hugoline G, Rosendaal, Frits R, Medina-Gomez, Carolina, Ring, Susan M, Hemani, Gibran, McMahon, George, Robertson, Neil R, Groves, Christopher J, Langenberg, Claudia, Luan, Jian’an, Scott, Robert A, Zhao, Jing Hua, Mentch, Frank D, MacKenzie, Scott M, Reynolds, Rebecca M, Lowe, William L, Tönjes, Anke, Stumvoll, Michael, Lindi, Virpi, Lakka, Timo A, and van Duijn, Cornelia M

Subjects
Nutrition, Perinatal Period - Conditions Originating in Perinatal Period, Human Genome, Genetics, Clinical Research, Preterm, Low Birth Weight and Health of the Newborn, Obesity, Prevention, Pediatric, Infant Mortality, 2.1 Biological and endogenous factors, Aetiology, Adult, Aging, Anthropometry, Birth Weight, Blood Pressure, Chromatin Assembly and Disassembly, Cohort Studies, Coronary Artery Disease, Datasets as Topic, Diabetes Mellitus, Type 2, Female, Fetus, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genomic Imprinting, Genotype, Glucose, Glycogen, Humans, Insulin, Male, Phenotype, Signal Transduction, CHARGE Consortium Hematology Working Group, Early Growth Genetics (EGG) Consortium, General Science & Technology
Abstract

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P

Published
2016

15. Differential associations between regional amyloid PET and Alzheimer’s disease polygenic risk scores

Author

Luckett, Emma S., primary, Collij, Lyduine E., additional, Lorenzini, Luigi, additional, Tesi, Niccoló, additional, Vilor‐Tejedor, Natalia, additional, García, David Vállez, additional, Alves, Isadora Lopes, additional, Shekari, Mahnaz, additional, Wink, Alle Meije, additional, Payoux, Pierre, additional, Dubois, Bruno, additional, Grau‐Rivera, Oriol, additional, Boada, Mercè, additional, Nordberg, Agneta K, additional, Scheltens, Philip, additional, Schöll, Michael, additional, Wolz, Robin, additional, Schmidt, Mark E, additional, Gismondi, Rossella, additional, Stephens, Andrew W., additional, Buckley, Christopher, additional, Frisoni, Giovanni B, additional, Hanseeuw, Bernard J, additional, Visser, Pieter Jelle, additional, Vandenberghe, Rik, additional, Farrar, Gill, additional, Gispert, Juan Domingo, additional, Ritchie, Craig W, additional, and Barkhof, Frederik, additional

Published
2023
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16. Plasma biomarkers rates of change across the preclinical stage of Alzheimer’s disease: a longitudinal study

Author

González Escalante, Armand, primary, Milà‐Alomà, Marta, additional, Ashton, Nicholas J., additional, Shekari, Mahnaz, additional, Salvadó, Gemma, additional, Ortiz‐Romero, Paula, additional, Montoliu‐Gaya, Laia, additional, Benedet, Andrea Lessa, additional, Karikari, Thomas K, additional, Rodriguez, Juan Lantero, additional, Vanmechelen, Eugeen, additional, Sánchez‐Benavides, Gonzalo, additional, Minguillon, Carolina, additional, Fauria, Karine, additional, Molinuevo, Jose Luis, additional, Zetterberg, Henrik, additional, del Campo, Marta, additional, Gispert, Juan Domingo, additional, Blennow, Kaj, additional, Vilor‐Tejedor, Natalia, additional, and Suarez‐Calvet, Marc, additional

Published
2023
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17. Association of human brain‐age with genetically predicted plasma levels of brain rejuvenating and aging factors identified in mice

Author

Anastasi, Federica, primary, Genius, Patricia, additional, Escalante, Armand González, additional, Rodríguez‐Fernández, Blanca, additional, Cumplido‐Mayoral, Irene, additional, Falcon, Carles, additional, Minguillon, Carolina, additional, del Campo, Marta, additional, Esteller, Manel, additional, Navarro, Arcadi, additional, Gispert, Juan Domingo, additional, Suárez‐Calvet, Marc, additional, and Vilor‐Tejedor, Natalia, additional

Published
2023
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18. Sex‐dependent effects on the association between air pollution and longitudinal changes in CSF and plasma biomarkers of Alzheimer’s disease

Author

Vilor‐Tejedor, Natalia, primary, Escalante, Armand González, additional, Rodríguez‐Fernández, Blanca, additional, Genius, Patricia, additional, Milà‐Alomà, Marta, additional, Ortiz‐Romero, Paula, additional, Cirach, Marta, additional, Nieuwenhuijsen, Mark, additional, Sunyer, Jordi, additional, Minguillon, Carolina, additional, Fauria, Karine, additional, Kollmorgen, Gwendlyn, additional, Carboni, Margherita, additional, Molinuevo, Jose Luis, additional, Navarro, Arcadi, additional, Zetterberg, Henrik, additional, Blennow, Kaj, additional, Suarez‐Calvet, Marc, additional, and Gispert, Juan Domingo, additional

Published
2023
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21. Genetic predisposition to Alzheimer’s disease is differentially associated with joint volumetric variations in the disease continuum

Author

Genius, Patricia, primary, Calle, Maria Luz, additional, Cacciaglia, Raffaele, additional, Evans, Tavia E, additional, Falcon, Carles, additional, Minguillón, Carolina, additional, Adams, Hieab H.H., additional, Esteller, Manel, additional, Navarro, Arcadi, additional, Gispert, Juan Domingo, additional, and Vilor‐Tejedor, Natalia, additional

Published
2023
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23. Genetic characterization of the ALFA study: Uncovering genetic profiles in the Alzheimer's continuum.

Author

Vilor‐Tejedor, Natalia, Genius, Patricia, Rodríguez‐Fernández, Blanca, Minguillón, Carolina, Sadeghi, Iman, González‐Escalante, Armand, Crous‐Bou, Marta, Suárez‐Calvet, Marc, Grau‐Rivera, Oriol, Brugulat‐Serrat, Anna, Sánchez‐Benavides, Gonzalo, Esteller, Manel, Fauria, Karine, Molinuevo, José Luis, Navarro, Arcadi, and Gispert, Juan Domingo

Abstract

INTRODUCTION: In 2013, the ALzheimer's and FAmilies (ALFA) project was established to investigate pathophysiological changes in preclinical Alzheimer's disease (AD), and to foster research on early detection and preventive interventions. METHODS: We conducted a comprehensive genetic characterization of ALFA participants with respect to neurodegenerative/cerebrovascular diseases, AD biomarkers, brain endophenotypes, risk factors and aging biomarkers. We placed particular emphasis on amyloid/tau status and assessed gender differences. Multiple polygenic risk scores were computed to capture different aspects of genetic predisposition. We additionally compared AD risk in ALFA to that across the full disease spectrum from the Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: Results show that the ALFA project has been successful at establishing a cohort of cognitively unimpaired individuals at high genetic predisposition of AD. DISCUSSION: It is, therefore, well‐suited to study early pathophysiological changes in the preclinical AD continuum. Highlights: Prevalence of ε4 carriers in ALzheimer and FAmilies (ALFA) is higher than in the general European populationThe ALFA study is highly enriched in Alzheimer's disease (AD) genetic risk factors beyond APOEAD genetic profiles in ALFA are similar to clinical groups along the continuumALFA has succeeded in establishing a cohort of cognitively unimpaired individuals at high genetic AD riskALFA is well suited to study pathogenic events/early pathophysiological changes in AD [ABSTRACT FROM AUTHOR]

Published
2024
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26. Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer’s continuum when only subtle changes in Aβ pathology are detected

Author

Suárez‐Calvet, Marc, Karikari, Thomas K, Ashton, Nicholas J, Lantero Rodríguez, Juan, Milà‐Alomà, Marta, Gispert, Juan Domingo, Salvadó, Gemma, Minguillon, Carolina, Fauria, Karine, Shekari, Mahnaz, Grau‐Rivera, Oriol, Arenaza‐Urquijo, Eider M, Sala‐Vila, Aleix, Sánchez‐Benavides, Gonzalo, González‐de‐Echávarri, José Maria, Kollmorgen, Gwendlyn, Stoops, Erik, Vanmechelen, Eugeen, Zetterberg, Henrik, Blennow, Kaj, Molinuevo, José Luis, Beteta, Annabella, Cacciaglia, Raffaele, Cañas, Alba, Deulofeu, Carme, Cumplido, Irene, Dominguez, Ruth, Emilio, Maria, Falcon, Carles, Fuentes, Sherezade, Hernandez, Laura, Huesa, Gema, Huguet, Jordi, Marne, Paula, Menchón, Tania, Operto, Grégory, Polo, Albina, Pradas, Sandra, Soteras, Anna, Vilanova, Marc, and Vilor‐Tejedor, Natalia

Published
2020
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27. Sex differential effects on the joint contribution of air pollution and biological aging on cognitive performance in individuals at risk of Alzheimer's disease.

Author

Rodríguez‐Fernández, Blanca, Sánchez‐Benavides, Gonzalo, Minguillon, Carolina, Cirach, Marta, Nieuwenhuijsen, Mark, Sunyer, Jordi, Fauria, Karine, Molinuevo, Jose Luis, De Vivo, Immaculata, Navarro, Arcadi, Gispert, Juan Domingo, Sala‐Vila, Aleix, Crous‐Bou, Marta, and Vilor‐Tejedor, Natalia

Abstract

Background: Air pollution is associated with cognitive performance, risk for AD and may accelerate biological aging. Biological aging due to telomere shortening has been associated with cognitive impairment. However, few studies have looked at the link between air pollution, telomere length, and cognitive performance among sexes. In this study, we investigated the joint effect of sex, air pollution, and leukocyte telomere length (LTL), on cognitive performance in cognitively unimpaired (CU) individuals at risk of AD. Method: The study included 1,472 middle‐aged CU adults with increased risk of AD from the ALFA study [Table 1]. Residential exposure to air pollutants including nitrogen dioxide (NO2) and particulate matter (PM2.5, PM10) was estimated by land use regression models. LTL was determined by qPCR from DNA extracted from peripheral blood leukocytes. LTL was residualized against chronological age and sex (rLTL). A cognitive battery was administered to assess verbal memory, psychomotor speed, visual processing and executive function. Further, episodic memory (EM), executive function and Preclinical Alzheimer Cognitive Composite (PACC) composites were calculated by averaging normalized raw scores of the subtests. Models were corrected by chronological age, years of education and APOE‐ε4 status. Sex‐specific effects were investigated by adjusting interaction models. Result: There was no overall effect of neither rLTL nor air pollution on cognitive performance, but crossover interactions with sex were found. Exposure to higher levels of NO2 and PM2.5 were associated with worse EM only in men [Figure 1]. Three‐way interaction models revealed longer rLTL and lower levels of air pollution were associated with better performance on PACC (for PM2.5, PM10 and NO2) and EM (for PM10 and NO2) among men. In women, these associations were only observed at higher exposure levels of air pollution [Figure 2]. Conclusion: The results show that lower levels of air pollution allow for the protective effect of rLTL on cognitive performance only in men for whom air pollution had a stronger negative impact. In women, the results show different mechanisms through which air pollution and rLTL affect cognitive performance. Further analyses will be conducted to gain insight into the observed effects. [ABSTRACT FROM AUTHOR]

Published
2023
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28. A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts

Author

Middeldorp, Christel M., Hammerschlag, Anke R., Ouwens, Klaasjan G., Groen-Blokhuis, Maria M., St. Pourcain, Beate, Greven, Corina U., Pappa, Irene, Tiesler, Carla M.T., Ang, Wei, Nolte, Ilja M., Vilor-Tejedor, Natalia, Bacelis, Jonas, Ebejer, Jane L., Zhao, Huiying, Davies, Gareth E., Ehli, Erik A., Evans, David M., Fedko, Iryna O., Guxens, Mònica, Hottenga, Jouke-Jan, Hudziak, James J., Jugessur, Astanand, Kemp, John P., Krapohl, Eva, Martin, Nicholas G., Murcia, Mario, Myhre, Ronny, Ormel, Johan, Ring, Susan M., Standl, Marie, Stergiakouli, Evie, Stoltenberg, Camilla, Thiering, Elisabeth, Timpson, Nicholas J., Trzaskowski, Maciej, van der Most, Peter J., Wang, Carol, Nyholt, Dale R., Medland, Sarah E., Neale, Benjamin, Jacobsson, Bo, Sunyer, Jordi, Hartman, Catharina A., Whitehouse, Andrew J.O., Pennell, Craig E., Heinrich, Joachim, Plomin, Robert, Davey Smith, George, Tiemeier, Henning, Posthuma, Danielle, and Boomsma, Dorret I.

Published
2016
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29. Polygenic determinants of White Matter Hyperintensities and sex‐specific genetic profiles in the Alzheimer’s continuum

Author

Genius, Patricia, primary, Rodríguez‐Fernández, Blanca, additional, Operto, Grégory, additional, Falcon, Carles, additional, Minguillón, Carolina, additional, Fauria, Karine, additional, Molinuevo, Jose Luis, additional, Esteller, Manel, additional, Guigó, Roderic, additional, Zetterberg, Henrik, additional, Blennow, Kaj, additional, Sudre, Carole H, additional, Suárez‐Calvet, Marc, additional, Navarro, Arcadi, additional, Gispert, Juan Domingo, additional, and Vilor‐Tejedor, Natalia, additional

Published
2022
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31. Understanding the role of biological aging on cognitive vulnerability among individuals at risk of Alzheimer's disease.

Author

Rodríguez‐Fernández, Blanca, Sánchez‐Benavides, Gonzalo, Minguillon, Carolina, Fauria, Karine, De Vivo, Immaculata, Navarro, Arcadi, Gispert, Juan Domingo, Molinuevo, Jose Luis, Sala‐Vila, Aleix, Vilor‐Tejedor, Natalia, and Crous‐Bou, Marta

Abstract

Background: Leukocyte telomere length (LTL) is an objective biomarker of biological aging and has been proposed to play a crucial role in AD progression by impairing cognitive resilience. However, a limited number of studies have evaluated the role of LTL in cognition, showing inconsistent results, particularly in the context of AD pathology. The main objective of this study was to evaluate the association between LTL and cognitive performance in middle‐aged cognitively unimpaired individuals at increased risk of AD. Method: The study included 1,532 participants from the ALFA cohort. LTL was determined by qPCR in peripheral blood leukocytes. LTL values were log‐transformed, normalized by computing z‐scores and residualized (rLTL) against age and sex using a linear regression model. A cognitive battery was administered to assess verbal memory, psychomotor speed, visual processing, and executive function. Episodic memory (EM), executive function, and global cognitive composites were calculated by averaging normalized raw scores of all subtests in each domain. Generalized linear models were implemented to assess the cross‐sectional association between rLTL and cognitive performance. Association analyses were performed separately in the accelerated aging group (rLTL < percentile 50th) and decelerated aging group (rLTL > percentile 50th). Stratified analyses by sex were conducted. Result: Individuals at accelerated aging had higher systolic blood pressure and a different distribution of familiar history of AD than those at decelerated aging [Table 1]. Longer rLTL was associated with better performance in the EM domain only among individuals within the accelerated aging group. Remarkably, only free recall measurements remained significant after correction for multiple comparisons. Conversely, longer rLTL was associated with worse psychomotor speed in the whole sample and among individuals in the decelerated group [Table 2]. Women mainly drove these results. Among men, longer rLTL had a beneficial effect on semantic fluency but a detrimental effect on cued recall among those at decelerated aging [Table 3]. Conclusion: rLTL has a differential effect on cognitive domains among cognitively unimpaired individuals at accelerated/decelerated biological aging. Moreover, results differed depending on sex and cognitive domain. Our results suggest a complex heterogeneity in biological aging mechanisms that appear to change in individuals at increased risk of AD. [ABSTRACT FROM AUTHOR]

Published
2023
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32. The influence of genetic predisposition to Alzheimer's disease in cognitive decline differs among sex in cognitively unimpaired individuals in the Alzheimer's continuum.

Author

Brugulat‐Serrat, Anna, Genius, Patricia, Rodríguez‐Fernández, Blanca, Sánchez‐Benavides, Gonzalo, López‐Martos, David, Grau‐Rivera, Oriol, Minguillon, Carolina, Fauria, Karine, Molinuevo, Jose Luis, Esteller, Manel, Navarro, Arcadi, Gispert, Juan Domingo, and Vilor‐Tejedor, Natalia

Abstract

Background: Evidence shows sex differences in cognitive performance in Alzheimer's disease (AD). However, studies exploring whether genetic predisposition to AD differs in cognition among sex are scarce. We aimed to evaluate whether the influence of AD genetic liability in cognition differs among sex in cognitively unimpaired (CU) individuals in the AD continuum. Method: We included 318 CU individuals from the ALFA+ cohort (Table 1). Cognitive change (∼3‐year follow‐up) was measured with a PACC and for individual cognitive domains. Polygenic scores estimating each participant's genetic predisposition to AD were calculated with (PRS‐AD) and without (PRS‐ADnoAPOE) considering the APOE region (threshold = 5×10‐6). Amyloid positivity (Aβ+) was defined as cerebrospinal fluid (CSF) Aβ42/40<0.0071. Generalized linear models stratified by sex and amyloid status were performed to assess the association between cognitive change and genetic predisposition to AD. Models were corrected by age, years of education, and time between visits. Models were additionally corrected by baseline Jack's cortical thickness AD signature as a marker of neurodegeneration. Result: In Aβ+ women (n = 65), a higher genetic predisposition to AD was associated with steeper memory (pPRS_AD = 0.04; pPRS_ADnoAPOE = 0.01) and executive function (pPRS_ADnoAPOE = 0.001) decline after correcting by brain AD signature. In Aβ+ men (n = 44), a higher genetic predisposition to AD was associated with worse follow‐up performance on attention (pPRS_AD = 0.05, pPRS_ADnoAPOE = 0.04), and results did not remain significant after correcting by brain AD signature (Figure 1). In Aβ‐, genetic predisposition to AD was also associated with executive function decline in women (n = 122) (pPRS_AD = 0.16, pPRS_ADnoAPOE = 0.02), while Aβ‐ men (n = 87) showed worse follow‐up performance on visual processing (pPRS_AD = 0.251, pPRS_ADnoAPOE = 0.001). Results remained significant after correcting by brain AD signature (Figure 2). Conclusion: Our results showed that genetic predisposition to AD is associated with changes in different cognitive domains in men and women. These findings will contribute to developing precision medicine approaches in AD encompassing sex‐sensitive strategies for prevention. [ABSTRACT FROM AUTHOR]

Published
2023
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33. A genome-wide association study of total child psychiatric problems scores

Author

Neumann, Alexander, primary, Nolte, Ilja M., additional, Pappa, Irene, additional, Ahluwalia, Tarunveer S., additional, Pettersson, Erik, additional, Rodriguez, Alina, additional, Whitehouse, Andrew, additional, van Beijsterveldt, Catharina E. M., additional, Benyamin, Beben, additional, Hammerschlag, Anke R., additional, Helmer, Quinta, additional, Karhunen, Ville, additional, Krapohl, Eva, additional, Lu, Yi, additional, van der Most, Peter J., additional, Palviainen, Teemu, additional, St Pourcain, Beate, additional, Seppälä, Ilkka, additional, Suarez, Anna, additional, Vilor-Tejedor, Natalia, additional, Tiesler, Carla M. T., additional, Wang, Carol, additional, Wills, Amanda, additional, Zhou, Ang, additional, Alemany, Silvia, additional, Bisgaard, Hans, additional, Bønnelykke, Klaus, additional, Davies, Gareth E., additional, Hakulinen, Christian, additional, Henders, Anjali K., additional, Hyppönen, Elina, additional, Stokholm, Jakob, additional, Bartels, Meike, additional, Hottenga, Jouke-Jan, additional, Heinrich, Joachim, additional, Hewitt, John, additional, Keltikangas-Järvinen, Liisa, additional, Korhonen, Tellervo, additional, Kaprio, Jaakko, additional, Lahti, Jari, additional, Lahti-Pulkkinen, Marius, additional, Lehtimäki, Terho, additional, Middeldorp, Christel M., additional, Najman, Jackob M., additional, Pennell, Craig, additional, Power, Chris, additional, Oldehinkel, Albertine J., additional, Plomin, Robert, additional, Räikkönen, Katri, additional, Raitakari, Olli T., additional, Rimfeld, Kaili, additional, Sass, Lærke, additional, Snieder, Harold, additional, Standl, Marie, additional, Sunyer, Jordi, additional, Williams, Gail M., additional, Bakermans-Kranenburg, Marian J., additional, Boomsma, Dorret I., additional, van IJzendoorn, Marinus H., additional, Hartman, Catharina A., additional, and Tiemeier, Henning, additional

Published
2022
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34. CSF Synaptic Biomarkers in the Preclinical Stage of Alzheimer Disease and Their Association With MRI and PET

Author

Milà-Alomà, Marta, Brinkmalm, Ann, Ashton, Nicholas J., Kvartsberg, Hlin, Shekari, Mahnaz, Operto, Grégory, Salvadó, Gemma, Falcon, Carles, Gispert, Juan Domingo, Vilor-Tejedor, Natalia, Arenaza-Urquijo, Eider M., Grau-Rivera, Oriol, Sala-Vila, Aleix, Sanchez-Benavides, Gonzalo, González-de-Echávarri, José María, Minguillon, Carolina, Fauria, Karine, Niñerola-Baizán, Aida, Perissinotti, Andrés, Kollmorgen, Gwendlyn, Suridjan, Ivonne, Zetterberg, Henrik, Molinuevo, José Luis, Blennow, Kaj, and Suárez-Calvet, Marc

Subjects
Amyloid beta-Peptides, tau Proteins, Middle Aged, Magnetic Resonance Imaging, Cross-Sectional Studies, Alzheimer Disease, Positron-Emission Tomography, Humans, Female, Biomarkers, Research Article
Abstract

Background and Objectives To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer continuum and associated with Alzheimer disease (AD) risk factors, primary pathology, and neurodegeneration markers. Methods This cross-sectional study was performed in the Alzheimer's and Families (ALFA+) cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and growth-associated protein-43 (GAP-43) were measured with immunoassays, and synaptosomal-associated protein-25 (SNAP-25) and synaptotagmin-1 were measured with immunoprecipitation mass spectrometry. AD CSF biomarkers β-amyloid (Aβ)42/40, phosphorylated tau (p-tau), and total tau and the neurodegeneration biomarker neurofilament light chain (NfL) were also measured. Participants underwent structural MRI and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers. Results All CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE ε4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ42/40 and Aβ PET Centiloid values), and it is important to note that the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism but lower cortical thickness in AD-related brain regions. Discussion CSF synaptic biomarkers increase in the early preclinical stages of the Alzheimer continuum even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, APOE ε4, and markers of neurodegeneration. Trial Registration Information ClinicalTrials.gov Identifier NCT02485730.

Published
2021

35. Additional file 1 of Genetically predicted telomere length and Alzheimer’s disease endophenotypes: a Mendelian randomization study

Author

Rodríguez-Fernández, Blanca, Vilor-Tejedor, Natalia, Arenaza-Urquijo, Eider M., Sánchez-Benavides, Gonzalo, Suárez-Calvet, Marc, Operto, Grégory, Minguillón, Carolina, Fauria, Karine, Kollmorgen, Gwendlyn, Suridjan, Ivonne, Castro de Moura, Manuel, Piñeyro, David, Esteller, Manel, Blennow, Kaj, Zetterberg, Henrik, De Vivo, Immaculata, Molinuevo, José Luis, Navarro, Arcadi, Gispert, Juan Domingo, Sala-Vila, Aleix, Crous-Bou, Marta, Rodríguez-Fernández, Blanca, Vilor-Tejedor, Natalia, Arenaza-Urquijo, Eider M., Sánchez-Benavides, Gonzalo, Suárez-Calvet, Marc, Operto, Grégory, Minguillón, Carolina, Fauria, Karine, Kollmorgen, Gwendlyn, Suridjan, Ivonne, Castro de Moura, Manuel, Piñeyro, David, Esteller, Manel, Blennow, Kaj, Zetterberg, Henrik, De Vivo, Immaculata, Molinuevo, José Luis, Navarro, Arcadi, Gispert, Juan Domingo, Sala-Vila, Aleix, and Crous-Bou, Marta

Abstract

Additional file 1: Supplementary Table 1. Characteristics of Single Nucleotide Polymorphisms (SNPs) associated with longer telomere length. The effect allele refers to the allele that is associated with longer telomere length. Chromosomal position of the SNPs (genome assembly GRCh37 (hg19)) according to the public archive for genetic variation within and across different species developed and hosted by the National Center for Biotechnology Information (NCBI) in collaboration with the National Human Genome Research Institute (NHGRI) (dbSNP).

Published
2022

36. Additional file 3 of Genetically predicted telomere length and Alzheimer’s disease endophenotypes: a Mendelian randomization study

Author

Rodríguez-Fernández, Blanca, Vilor-Tejedor, Natalia, Arenaza-Urquijo, Eider M., Sánchez-Benavides, Gonzalo, Suárez-Calvet, Marc, Operto, Grégory, Minguillón, Carolina, Fauria, Karine, Kollmorgen, Gwendlyn, Suridjan, Ivonne, Castro de Moura, Manuel, Piñeyro, David, Esteller, Manel, Blennow, Kaj, Zetterberg, Henrik, De Vivo, Immaculata, Molinuevo, José Luis, Navarro, Arcadi, Gispert, Juan Domingo, Sala-Vila, Aleix, Crous-Bou, Marta, Rodríguez-Fernández, Blanca, Vilor-Tejedor, Natalia, Arenaza-Urquijo, Eider M., Sánchez-Benavides, Gonzalo, Suárez-Calvet, Marc, Operto, Grégory, Minguillón, Carolina, Fauria, Karine, Kollmorgen, Gwendlyn, Suridjan, Ivonne, Castro de Moura, Manuel, Piñeyro, David, Esteller, Manel, Blennow, Kaj, Zetterberg, Henrik, De Vivo, Immaculata, Molinuevo, José Luis, Navarro, Arcadi, Gispert, Juan Domingo, Sala-Vila, Aleix, and Crous-Bou, Marta

Abstract

Additional file 3: Supplementary Table 1. Characteristics of the study participants with information for cognition outcomes. Mean and SD are shown for continuous variables. Supplementary Table 2. Characteristics of the study participants with information for neuroimaging outcomes. Mean and SD are shown for continuous variables. Supplementary Table 3. Characteristics of the study participants with information for CSF biomarkers. Mean and SD are shown for continuous variables.

Published
2022

37. Additional file 4 of Genetically predicted telomere length and Alzheimer’s disease endophenotypes: a Mendelian randomization study

Author

Rodríguez-Fernández, Blanca, Vilor-Tejedor, Natalia, Arenaza-Urquijo, Eider M., Sánchez-Benavides, Gonzalo, Suárez-Calvet, Marc, Operto, Grégory, Minguillón, Carolina, Fauria, Karine, Kollmorgen, Gwendlyn, Suridjan, Ivonne, Castro de Moura, Manuel, Piñeyro, David, Esteller, Manel, Blennow, Kaj, Zetterberg, Henrik, De Vivo, Immaculata, Molinuevo, José Luis, Navarro, Arcadi, Gispert, Juan Domingo, Sala-Vila, Aleix, Crous-Bou, Marta, Rodríguez-Fernández, Blanca, Vilor-Tejedor, Natalia, Arenaza-Urquijo, Eider M., Sánchez-Benavides, Gonzalo, Suárez-Calvet, Marc, Operto, Grégory, Minguillón, Carolina, Fauria, Karine, Kollmorgen, Gwendlyn, Suridjan, Ivonne, Castro de Moura, Manuel, Piñeyro, David, Esteller, Manel, Blennow, Kaj, Zetterberg, Henrik, De Vivo, Immaculata, Molinuevo, José Luis, Navarro, Arcadi, Gispert, Juan Domingo, Sala-Vila, Aleix, and Crous-Bou, Marta

Abstract

Additional file 4: Supplementary Table 1. Results of the effect of genetically predicted longer telomere length on AD endophenotypes in the entire sample. Supplementary Table 2. Results of the effect of genetically predicted longer telomere length on AD endophenotypes among APOE-ɛ4 carriers. Supplementary Table 3. Results of the effect of genetically predicted longer telomere length on AD endophenotypes among APOE-ɛ4 non-carriers. Supplementary Table 4. Results of the effect of genetically predicted longer telomere length on AD endophenotypes among individuals at high genetic predisposition to Alzheimer's disease. Supplementary Table 5. Results of the effect of genetically predicted longer telomere length on AD endophenotypes among individuals at low genetic predisposition to Alzheimer's disease.

Published
2022

38. Additional file 2 of Genetically predicted telomere length and Alzheimer’s disease endophenotypes: a Mendelian randomization study

Author

Rodríguez-Fernández, Blanca, Vilor-Tejedor, Natalia, Arenaza-Urquijo, Eider M., Sánchez-Benavides, Gonzalo, Suárez-Calvet, Marc, Operto, Grégory, Minguillón, Carolina, Fauria, Karine, Kollmorgen, Gwendlyn, Suridjan, Ivonne, Castro de Moura, Manuel, Piñeyro, David, Esteller, Manel, Blennow, Kaj, Zetterberg, Henrik, De Vivo, Immaculata, Molinuevo, José Luis, Navarro, Arcadi, Gispert, Juan Domingo, Sala-Vila, Aleix, Crous-Bou, Marta, Rodríguez-Fernández, Blanca, Vilor-Tejedor, Natalia, Arenaza-Urquijo, Eider M., Sánchez-Benavides, Gonzalo, Suárez-Calvet, Marc, Operto, Grégory, Minguillón, Carolina, Fauria, Karine, Kollmorgen, Gwendlyn, Suridjan, Ivonne, Castro de Moura, Manuel, Piñeyro, David, Esteller, Manel, Blennow, Kaj, Zetterberg, Henrik, De Vivo, Immaculata, Molinuevo, José Luis, Navarro, Arcadi, Gispert, Juan Domingo, Sala-Vila, Aleix, and Crous-Bou, Marta

Abstract

Additional file 2: Supplementary Table 1. Linear regression estimates for cognition outcomes in the entire sample. All models are adjusted for covariates: age, sex, education, and APOE status. Supplementary Table 2. Linear regression estimates for neuroimaging outcomes (i.e., Alzheimer’s disease and aging signatures) outcome in the entire sample. All models are adjusted for covariates: age, sex, education, and APOE status. Supplementary Table 3. Linear regression estimates for CSF biomarkers outcomes in the entire sample. All models are adjusted for covariates: age, sex, education, and APOE status. Supplementary Table 4. Linear regression estimates for cognition outcomes in APOE-ɛ4 carriers. All models are adjusted for covariates: age, sex, and education. Supplementary Table 5. Linear regression estimates for neuroimaging outcomes (i.e., Alzheimer’s disease and aging signatures) in APOE-ɛ4 carriers. All models are adjusted for covariates: age, sex, and education. Supplementary Table 6. Linear regression estimates for CSF biomarkers outcomes in APOE-ɛ4 carriers. All models are adjusted for covariates: age, sex, and education. Supplementary Table 7. Linear regression estimates for cognition outcomes in APOE-ɛ4 non-carriers. All models are adjusted for covariates: age, sex, and education. Supplementary Table 8. Linear regression estimates for neuroimaging outcomes (i.e., Alzheimer’s disease and aging signatures) in APOE-ɛ4 non-carriers. All models are adjusted for covariates: age, sex, and education. Supplementary Table 9. Linear regression estimates for CSF biomarkers outcomes in APOE-ɛ4 carriers. All models are adjusted for covariates: age, sex, and education. Supplementary Table 10. Linear regression estimates for cognition outcomes among individuals at high genetic predisposition to AD. All models are adjusted for covariates: age, sex, and education. Supplementary Table 11. Linear regression estimates for neuroimaging outcomes (i.e., Alzheimer’s disease and aging s

Published
2022

39. Cross-sectional and longitudinal association of sleep and Alzheimer biomarkers in cognitively unimpaired adults

Author

Blackman, Jonathan, Stankeviciute, Laura, Arenaza-Urquijo, Eider M., Suárez-Calvet, Marc, Sánchez-Benavides, Gonzalo, Vilor-Tejedor, Natalia, Iranzo, Alejandro, Molinuevo, Jose Luis, Gispert, Juan Domingo, Coulthard, Elizabeth, Grau-Rivera, Oriol, Blackman, Jonathan, Stankeviciute, Laura, Arenaza-Urquijo, Eider M., Suárez-Calvet, Marc, Sánchez-Benavides, Gonzalo, Vilor-Tejedor, Natalia, Iranzo, Alejandro, Molinuevo, Jose Luis, Gispert, Juan Domingo, Coulthard, Elizabeth, and Grau-Rivera, Oriol

Abstract

Sleep abnormalities are prevalent in Alzheimer's disease, with sleep quality already impaired at its preclinical stage. Epidemiological and experimental data point to sleep abnormalities contributing to the risk of Alzheimer's disease. However, previous studies are limited by either a lack of Alzheimer's disease biomarkers, reduced sample size or cross-sectional design. Understanding if, when, and how poor sleep contributes to Alzheimer's disease progression is important so that therapies can be targeted to the right phase of the disease. Using the largest cohort to date, the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study, we test the hypotheses that poor sleep is associated with core Alzheimer's disease CSF biomarkers cross-sectionally and predicts future increments of Alzheimer's disease pathology in people without identifiable symptoms of Alzheimer's disease at baseline. This study included 1168 adults aged over 50 years with CSF core Alzheimer's disease biomarkers (total tau, phosphorylated tau and amyloid-beta), cognitive performance, and sleep quality (Pittsburgh sleep quality index questionnaire) data. We used multivariate linear regressions to analyse associations between core Alzheimer's disease biomarkers and the following Pittsburgh sleep quality index measures: total score of sleep quality, binarized score (poor sleep categorized as Pittsburgh sleep quality index > 5), sleep latency, duration, efficiency and disturbance. On a subsample of 332 participants with CSF taken at baseline and after an average period of 1.5 years, we assessed the effect of baseline sleep quality on change in Alzheimer's disease biomarkers over time. Cross-sectional analyses revealed that poor sleep quality (Pittsburgh sleep quality index total > 5) was significantly associated with higher CSF t-tau; shorter sleep duration (<7 h) was associated with higher CSF p-tau and t-tau; and a higher degree of sleep disturbance (1-9 versus 0 and >9 vers

Published
2022

40. Brain transcriptomic profiling reveals common alterations across neurodegenerative and psychiatric disorders

Author

European School of Molecular Medicine, Ministerio de Ciencia e Innovación (España), Ministerio de Educación, Cultura y Deporte (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, Fundación la Caixa, Sadeghi, Iman, Gispert, Juan Domingo, Palumbo, Emilio, Muñoz-Aguirre, Manuel, Wucher, Valentin, D’Argenio, Valeria, Santpere, Gabriel, Navarro, Arcadi, Guigó, Roderic, Vilor-Tejedor, Natalia, European School of Molecular Medicine, Ministerio de Ciencia e Innovación (España), Ministerio de Educación, Cultura y Deporte (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, Fundación la Caixa, Sadeghi, Iman, Gispert, Juan Domingo, Palumbo, Emilio, Muñoz-Aguirre, Manuel, Wucher, Valentin, D’Argenio, Valeria, Santpere, Gabriel, Navarro, Arcadi, Guigó, Roderic, and Vilor-Tejedor, Natalia

Abstract

Neurodegenerative and neuropsychiatric disorders (ND-NPs) are multifactorial, polygenic and complex behavioral phenotypes caused by brain abnormalities. Large-scale collaborative efforts have tried to identify the genetic architecture of these conditions. However, the specific and shared underlying molecular pathobiology of brain illnesses is not clear. Here, we examine transcriptome-wide characterization of eight conditions, using a total of 2,633 post-mortem brain samples from patients with Alzheimer’s disease (AD), Parkinson’s disease (PD), Progressive Supranuclear Palsy (PSP), Pathological Aging (PA), Autism Spectrum Disorder (ASD), Schizophrenia (Scz), Major Depressive Disorder (MDD), and Bipolar Disorder (BP)–in comparison with 2,078 brain samples from matched control subjects. Similar transcriptome alterations were observed between NDs and NPs with the top correlations obtained between Scz-BP, ASD-PD, AD-PD, and Scz-ASD. Region-specific comparisons also revealed shared transcriptome alterations in frontal and temporal lobes across NPs and NDs. Co-expression network analysis identified coordinated dysregulations of cell-type-specific modules across NDs and NPs. This study provides a transcriptomic framework to understand the molecular alterations of NPs and NDs through their shared- and specific gene expression in the brain.

Published
2022

41. A genome-wide association study of total child psychiatric problems scores

Author

Neumann, Alexander, Nolte, Ilja M, Pappa, Irene, Ahluwalia, Tarunveer S., Pettersson, Erik, Rodriguez, Alina, Whitehouse, Andrew, van Beijsterveldt, Catharina E. M., Benyamin, Beben, Hammerschlag, Anke R., Helmer, Quinta, Karhunen, Ville, Krapohl, Eva, Lu, Yi, van der Most, Peter J., Palviainen, Teemu, Pourcain, Beate St, Seppälä, Ilkka, Suarez, Anna, Vilor-Tejedor, Natalia, Tiesler, Carla M. T., Wang, Carol, Wills, Amanda, Zhou, Ang, Alemany, Silvia, Bisgaard, Hans, Bønnelykke, Klaus, Davies, Gareth E., Hakulinen, Christian, Henders, Anjali K., Hyppönen, Elina, Stokholm, Jakob, Bartels, Meike, Hottenga, Jouke-Jan, Heinrich, Joachim, Hewitt, John, Keltikangas-Järvinen, Liisa, Korhonen, Tellervo, Kaprio, Jaakko, Lahti, Jari, Lahti-Pulkkinen, Marius, Lehtimäki, Terho, Middeldorp, Christel M., Najman, Jackob M., Pennell, Craig, Power, Chris, Oldehinkel, Albertine J., Plomin, Robert, Räikkönen, Katri, Raitakari, Olli T., Rimfeld, Kaili, Sass, Lærke, Snieder, Harold, Standl, Marie, Sunyer, Jordi, Williams, Gail M., Bakermans-Kranenburg, Marian J., Boomsma, Dorret I., van IJzendoorn, Marinus H., Hartman, Catharina A., Tiemeier, Henning, Neumann, Alexander, Nolte, Ilja M, Pappa, Irene, Ahluwalia, Tarunveer S., Pettersson, Erik, Rodriguez, Alina, Whitehouse, Andrew, van Beijsterveldt, Catharina E. M., Benyamin, Beben, Hammerschlag, Anke R., Helmer, Quinta, Karhunen, Ville, Krapohl, Eva, Lu, Yi, van der Most, Peter J., Palviainen, Teemu, Pourcain, Beate St, Seppälä, Ilkka, Suarez, Anna, Vilor-Tejedor, Natalia, Tiesler, Carla M. T., Wang, Carol, Wills, Amanda, Zhou, Ang, Alemany, Silvia, Bisgaard, Hans, Bønnelykke, Klaus, Davies, Gareth E., Hakulinen, Christian, Henders, Anjali K., Hyppönen, Elina, Stokholm, Jakob, Bartels, Meike, Hottenga, Jouke-Jan, Heinrich, Joachim, Hewitt, John, Keltikangas-Järvinen, Liisa, Korhonen, Tellervo, Kaprio, Jaakko, Lahti, Jari, Lahti-Pulkkinen, Marius, Lehtimäki, Terho, Middeldorp, Christel M., Najman, Jackob M., Pennell, Craig, Power, Chris, Oldehinkel, Albertine J., Plomin, Robert, Räikkönen, Katri, Raitakari, Olli T., Rimfeld, Kaili, Sass, Lærke, Snieder, Harold, Standl, Marie, Sunyer, Jordi, Williams, Gail M., Bakermans-Kranenburg, Marian J., Boomsma, Dorret I., van IJzendoorn, Marinus H., Hartman, Catharina A., and Tiemeier, Henning

Abstract

Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG < 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG > 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.

Published
2022

42. Associations between air pollution and biomarkers of Alzheimer’s disease in cognitively unimpaired individuals

Author

Alemany, Silvia, primary, Crous-Bou, Marta, additional, Vilor-Tejedor, Natalia, additional, Milà-Alomà, Marta, additional, Suárez-Calvet, Marc, additional, Salvadó, Gemma, additional, Cirach, Marta, additional, Arenaza-Urquijo, Eider M., additional, Sanchez-Benavides, Gonzalo, additional, Grau-Rivera, Oriol, additional, Minguillon, Carolina, additional, Fauria, Karine, additional, Kollmorgen, Gwendlyn, additional, Domingo Gispert, Juan, additional, Gascón, Mireia, additional, Nieuwenhuijsen, Mark, additional, Zetterberg, Henrik, additional, Blennow, Kaj, additional, Sunyer, Jordi, additional, and Luis Molinuevo, José, additional

Published
2021
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45. Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum

Author

Benedet, Andréa L., Milà-Alomà, Marta, Vrillon, Agathe, Ashton, Nicholas J., Pascoal, Tharick A., Lussier, Firoza, Karikari, Thomas K., Hourregue, Claire, Cognat, Emmanuel, Dumurgier, Julien, Stevenson, Jenna, Rahmouni, Nesrine, Pallen, Vanessa, Poltronetti, Nina M., Salvadó, Gemma, Shekari, Mahnaz, Operto, Gregory, Gispert, Juan Domingo, Minguillon, Carolina, Fauria, Karine, Kollmorgen, Gwendlyn, Suridjan, Ivonne, Zimmer, Eduardo R., Zetterberg, Henrik, Molinuevo, José Luis, Paquet, Claire, Rosa-Neto, Pedro, Blennow, Kaj, Suárez-Calvet, Marc, Beteta, Annabella, Cacciaglia, Raffaele, Cañas, Alba, Deulofeu, Carme, Cumplido, Irene, Dominguez, Ruth, Emilio, Maria, Falcon, Carles, Fuentes, Sherezade, Hernandez, Laura, Huesa, Gema, Huguet, Jordi, Marne, Paula, Menchón, Tania, Operto, Grégory, Polo, Albina, Pradas, Sandra, Soteras, Anna, Vilanova, Marc, Vilor-Tejedor, Natalia, Gaubert, Sinead, Lilamand, Matthieu, Hugon, Jacques, Indart, Sandrine, Fayel, Alexandra, Gmiz, Malika, Francisque, Hélène, Meauzoone, Aurélie, Martinet, Matthieu, Tence, Gabrielle, Chamoun, Mira, Therriault, Joseph, Tissot, Cécile, Bezgin, Gleb, Gauthier, Serge, Gagnon, Guilaine, and Stevensson, Alyssa

Subjects
medicine.medical_specialty, macromolecular substances, Cohort Studies, Cerebrospinal fluid, Alzheimer Disease, Internal medicine, Glial Fibrillary Acidic Protein, medicine, Dementia, Humans, Online First, Demència, Aged, Original Investigation, Aged, 80 and over, Glial fibrillary acidic protein, biology, business.industry, Research, Area under the curve, Plasma sanguini, Middle Aged, medicine.disease, Astrogliosis, Alzheimer, Malaltia d', Endocrinology, Cross-Sectional Studies, nervous system, Concomitant, Marcadors bioquímics, biology.protein, Biomarker (medicine), Neurology (clinical), Alzheimer's disease, business, Biomarkers, Comments
Abstract

Key Points Question What are the levels of plasma glial fibrillary acidic protein (GFAP) throughout the Alzheimer disease (AD) continuum, and how do they compare with the levels of cerebrospinal fluid (CSF) GFAP? Findings In this cross-sectional study, plasma GFAP levels were elevated in the preclinical and symptomatic stages of AD, with levels higher than those of CSF GFAP. Plasma GFAP had a higher accuracy than CSF GFAP to discriminate between amyloid-β (Aβ)–positive and Aβ-negative individuals, also at the preclinical stage. Meaning This study suggests that plasma GFAP is a sensitive biomarker that significantly outperforms CSF GFAP in indicating Aβ pathology in the early stages of AD., Importance Glial fibrillary acidic protein (GFAP) is a marker of reactive astrogliosis that increases in the cerebrospinal fluid (CSF) and blood of individuals with Alzheimer disease (AD). However, it is not known whether there are differences in blood GFAP levels across the entire AD continuum and whether its performance is similar to that of CSF GFAP. Objective To evaluate plasma GFAP levels throughout the entire AD continuum, from preclinical AD to AD dementia, compared with CSF GFAP. Design, Setting, and Participants This observational, cross-sectional study collected data from July 29, 2014, to January 31, 2020, from 3 centers. The Translational Biomarkers in Aging and Dementia (TRIAD) cohort (Montreal, Canada) included individuals in the entire AD continuum. Results were confirmed in the Alzheimer’s and Families (ALFA+) study (Barcelona, Spain), which included individuals with preclinical AD, and the BioCogBank Paris Lariboisière cohort (Paris, France), which included individuals with symptomatic AD. Main Outcomes and Measures Plasma and CSF GFAP levels measured with a Simoa assay were the main outcome. Other measurements included levels of CSF amyloid-β 42/40 (Aβ42/40), phosphorylated tau181 (p-tau181), neurofilament light (NfL), Chitinase-3-like protein 1 (YKL40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and levels of plasma p-tau181 and NfL. Results of amyloid positron emission tomography (PET) were available in TRIAD and ALFA+, and results of tau PET were available in TRIAD. Results A total of 300 TRIAD participants (177 women [59.0%]; mean [SD] age, 64.6 [17.6] years), 384 ALFA+ participants (234 women [60.9%]; mean [SD] age, 61.1 [4.7] years), and 187 BioCogBank Paris Lariboisière participants (116 women [62.0%]; mean [SD] age, 69.9 [9.2] years) were included. Plasma GFAP levels were significantly higher in individuals with preclinical AD in comparison with cognitively unimpaired (CU) Aβ-negative individuals (TRIAD: Aβ-negative mean [SD], 185.1 [93.5] pg/mL, Aβ-positive mean [SD], 285.0 [142.6] pg/mL; ALFA+: Aβ-negative mean [SD], 121.9 [42.4] pg/mL, Aβ-positive mean [SD], 169.9 [78.5] pg/mL). Plasma GFAP levels were also higher among individuals in symptomatic stages of the AD continuum (TRIAD: CU Aβ-positive mean [SD], 285.0 [142.6] pg/mL, mild cognitive impairment [MCI] Aβ-positive mean [SD], 332.5 [153.6] pg/mL; AD mean [SD], 388.1 [152.8] pg/mL vs CU Aβ-negative mean [SD], 185.1 [93.5] pg/mL; Paris: MCI Aβ-positive, mean [SD], 368.6 [158.5] pg/mL; AD dementia, mean [SD], 376.4 [179.6] pg/mL vs CU Aβ-negative mean [SD], 161.2 [67.1] pg/mL). Plasma GFAP magnitude changes were consistently higher than those of CSF GFAP. Plasma GFAP more accurately discriminated Aβ-positive from Aβ-negative individuals than CSF GFAP (area under the curve for plasma GFAP, 0.69-0.86; area under the curve for CSF GFAP, 0.59-0.76). Moreover, plasma GFAP levels were positively associated with tau pathology only among individuals with concomitant Aβ pathology. Conclusions and Relevance This study suggests that plasma GFAP is a sensitive biomarker for detecting and tracking reactive astrogliosis and Aβ pathology even among individuals in the early stages of AD., This cross-sectional cohort study evaluates plasma glial fibrillary acidic protein levels throughout the entire Alzheimer disease continuum, from preclinical Alzheimer disease to Alzheimer disease dementia, compared with cerebrospinal fluid glial fibrillary acidic protein.

Published
2021

46. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

Author

Felix, Janine F., Bradfield, Jonathan P., Monnereau, Claire, van der Valk, Ralf J.P., Stergiakouli, Evie, Chesi, Alessandra, Gaillard, Romy, Feenstra, Bjarke, Thiering, Elisabeth, Kreiner-Møller, Eskil, Mahajan, Anubha, Pitkänen, Niina, Joro, Raimo, Cavadino, Alana, Huikari, Ville, Franks, Steve, Groen-Blokhuis, Maria M., Cousminer, Diana L., Marsh, Julie A., Lehtimäki, Terho, Curtin, John A., Vioque, Jesus, Ahluwalia, Tarunveer S., Myhre, Ronny, Price, Thomas S., Vilor-Tejedor, Natalia, Yengo, Loïc, Grarup, Niels, Ntalla, Ioanna, Ang, Wei, Atalay, Mustafa, Bisgaard, Hans, Blakemore, Alexandra I., Bonnefond, Amelie, Carstensen, Lisbeth, Eriksson, Johan, Flexeder, Claudia, Franke, Lude, Geller, Frank, Geserick, Mandy, Hartikainen, Anna-Liisa, Haworth, Claire M.A., Hirschhorn, Joel N., Hofman, Albert, Holm, Jens-Christian, Horikoshi, Momoko, Hottenga, Jouke Jan, Huang, Jinyan, Kadarmideen, Haja N., Kähönen, Mika, Kiess, Wieland, Lakka, Hanna-Maaria, Lakka, Timo A., Lewin, Alexandra M., Liang, Liming, Lyytikäinen, Leo-Pekka, Ma, Baoshan, Magnus, Per, McCormack, Shana E., McMahon, George, Mentch, Frank D., Middeldorp, Christel M., Murray, Clare S., Pahkala, Katja, Pers, Tune H., Pfäffle, Roland, Postma, Dirkje S., Power, Christine, Simpson, Angela, Sengpiel, Verena, Tiesler, Carla M. T., Torrent, Maties, Uitterlinden, André G., van Meurs, Joyce B., Vinding, Rebecca, Waage, Johannes, Wardle, Jane, Zeggini, Eleftheria, Zemel, Babette S., Dedoussis, George V., Pedersen, Oluf, Froguel, Philippe, Sunyer, Jordi, Plomin, Robert, Jacobsson, Bo, Hansen, Torben, Gonzalez, Juan R., Custovic, Adnan, Raitakari, Olli T., Pennell, Craig E., Widén, Elisabeth, Boomsma, Dorret I., Koppelman, Gerard H., Sebert, Sylvain, Järvelin, Marjo-Riitta, Hyppönen, Elina, McCarthy, Mark I., Lindi, Virpi, Harri, Niinikoski, Körner, Antje, Bønnelykke, Klaus, Heinrich, Joachim, Melbye, Mads, Rivadeneira, Fernando, Hakonarson, Hakon, Ring, Susan M., Smith, George Davey, Sørensen, Thorkild I.A., Timpson, Nicholas J., Grant, Struan F.A., Jaddoe, Vincent W.V., Kalkwarf, Heidi J., Lappe, Joan M., Gilsanz, Vicente, Oberfield, Sharon E., Shepherd, John A., Kelly, Andrea, and Zemel, Babette S.

Published
2016
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47. Genetic Influences on Hippocampal Subfields

Author

Vilor-Tejedor, Natalia, primary, Evans, Tavia E., additional, Adams, Hieab H., additional, González-de-Echávarri, José María, additional, Molinuevo, José Luis, additional, Guigo, Roderic, additional, Gispert, Juan Domingo, additional, and Operto, Grégory, additional

Published
2021
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48. Additional file 1 of Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer’s continuum

Author

Vilor-Tejedor, Natalia, Ciampa, Iacopo, Operto, Grégory, Falcón, Carles, Suárez-Calvet, Marc, Crous-Bou, Marta, Shekari, Mahnaz, Arenaza-Urquijo, Eider M., Milà-Alomà, Marta, Grau-Rivera, Oriol, Minguillon, Carolina, Kollmorgen, Gwendlyn, Zetterberg, Henrik, Blennow, Kaj, Guigo, Roderic, Molinuevo, José Luis, and Gispert, Juan Domingo

Abstract

Additional file 1: Figure S1. Association models between Alzheimer’s Disease CSF biomarkers and enlargement of Perivascular Spaces.

Published
2021
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49. Additional file 1 of Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile

Author

Milà-Alomà, Marta, Shekari, Mahnaz, Salvadó, Gemma, Gispert, Juan Domingo, Arenaza-Urquijo, Eider M., Operto, Grégory, Falcon, Carles, Vilor-Tejedor, Natalia, Grau-Rivera, Oriol, Sala-Vila, Aleix, Sánchez-Benavides, Gonzalo, González-de-Echávarri, José Maria, Minguillon, Carolina, Fauria, Karine, Niñerola-Baizán, Aida, Perissinotti, Andrés, Simon, Maryline, Kollmorgen, Gwendlyn, Zetterberg, Henrik, Blennow, Kaj, Suárez-Calvet, Marc, and Molinuevo, José Luis

Abstract

Additional file 1: Table S1. Confusion table of group prevalence for each low burden definition. Table S2. CSF biomarker levels by Aβ group including CSF biomarkers extreme values. Table S3. Structural MRI measurements by Aβ group. Table S4. FDG PET measurements by Aβ group. Fig. S1. Comparison of all CSF biomarkers between Aβ groups.

Published
2021
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50. Single-cell Transcriptional Changes in Neurodegenerative Diseases

Author

Ahmadi, Amirhossein, Gispert, Juan Domingo, Navarro, Arcadi, Vilor-Tejedor, Natalia, Sadeghi, Iman, Ministerio de Ciencia, Innovación y Universidades (España), La Caixa, and Generalitat de Catalunya

Subjects
Single-cell RNA sequencing, Multiple sclerosis, Huntington, Parkinson, Neurodegenerative disease, Alzheimer's
Abstract

In recent decades, our understanding of the molecular changes involved in neurodegenerative diseases has been transformed. Single-cell RNA sequencing and single-nucleus RNA sequencing technologies have been applied to provide cellular and molecular details of the brain at the single-cell level. This has expanded our knowledge of the central nervous system and provided insights into the molecular vulnerability of brain cell types and underlying mechanisms in neurodegenerative diseases. In this review, we highlight the recent advances and findings related to neurodegenerative diseases using these cutting-edge technologies. At the time of writing this review, N.V.T is funded by a postdoctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministerio de Ciencia, Innovación y Universidades – Spanish State Research Agency. Her research is also supported by the “la Caixa'' Foundation (LCF/PR/GN17/10300004) and the Health Department of the Catalan Government (Health Research and Innovation Strategic Plan (PERIS) 2016–2020 grant #SLT002/16/00201). J.D.G is supported by the Spanish Ministry of Science and Innovation (RYC-2013-13054). All CRG authors acknowledge the support of the Spanish Ministry of Science, Innovation, and Universities to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya.

Published
2021

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