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2. Effectiveness of Vortioxetine Treatment on Depression and Cognitive Functions in Patients with Alzheimer's Disease: A 12-Month, Retrospective, Observational Study.

Author

García-Alberca, José María, De La Guia, Paz, Gris, Esther, Mendoza, Silvia, Lopez De La Rica, María, Barbancho, Miguel Ángel, Lara, José Pablo, and Blanco-Reina, Encarnación

Subjects
*HAMILTON Depression Inventory, *ALZHEIMER'S patients, *ALZHEIMER'S disease, *MENTAL depression, *COGNITIVE ability
Abstract

This study aimed to assess the effectiveness of vortioxetine for improving depressive symptoms, cognitive performance, daily and global functioning in patients with Alzheimer's disease (AD) and major depressive disorder (MDD) in real-world clinical practice. We retrospectively identified 46 AD patients who had received treatment for 12 months with vortioxetine. Drug effects were evaluated at baseline, 4, 8, and 12 months. The primary endpoint was change from baseline in the Hamilton Depression Rating Scale (HDRS) and in the Cornell Scale for Depression in Dementia (CSDD) to month 12. Cognitive and daily and global functioning changes were also evaluated. Significant baseline-to-endpoint improvement in depressive symptom severity was observed (p < 0.0001). At month 12, the least-square mean (standard error) change score from baseline was −10.48 (±0.42) on the HDRS and −9.04 (±0.62) on the CSDD. Significant improvements in cognitive performance were observed for the Rey Auditory Verbal Learning Test, the Symbol Digit Modalities Test, the Letter Fluency Test, the Category Fluency Test, and the Trail Making Test-A. Patients also experienced significant improvements in daily and global functioning. Vortioxetine was safe and well tolerated. Patients with AD and MDD receiving vortioxetine showed meaningful improvements in depressive symptoms, cognitive performance, and daily and global functioning over the 12-month treatment period. [ABSTRACT FROM AUTHOR]

Published
2024
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3. Erratum to: Effect of Nordic Sensi® Chair on Behavioral and Psychological Symptoms of Dementia in Nursing Homes Residents: A Randomized Controlled Trial

Author

García-Alberca, José María, primary, de la Rosa, María Dolores, additional, Solo de Zaldívar, Paloma, additional, Ledesma, María, additional, Oltra, Estela, additional, Esther, Gris, additional, Ocejo, Olga, additional, Torrecilla, Javier, additional, Zafra, Carmen, additional, Sánchez-Fernández, Ana, additional, Mancilla, Tomás, additional, López-Romero, Mercedes, additional, Jerez, Raquel, additional, Santana, Nuria, additional, Lara, José Pablo, additional, Barbancho, Miguel Ángel, additional, and Blanco-Reina, Encarnación, additional

Published
2024
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4. Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

Author

Abdelnour, C., Aguilera, N., Alarcon, E., Alegret, M., Benaque, A., Boada, M., Buendia, M., Cañabate, P., Carracedo, A., Corbatón, A., de Rojas, I., Diego, S., Espinosa, A., Gailhajenet, A., García González, P., Gil, S., Guitart, M., González Pérez, A., Hernández, I., Ibarria, M., Lafuente, A., Macias, J., Maroñas, O., Martín, E., Martínez, M.T., Marquié, M., Mauleón, A., Monté-Rubio, G., Montrreal, L., Moreno-Grau, S., Moreno, M., Orellana, A., Ortega, G., Pancho, A., Pelejà, E., Pérez-Cordon, A., Pineda, J.A., Preckler, S., Quintela, I., Real, L.M., Rodríguez-Gómez, O., Rosende-Roca, M., Ruiz, A., Ruiz, S., Sáez, M.E., Sanabria, A., Santos-Santos, M.A., Serrano-Rios, M., Sotolongo-Grau, O., Tárraga, L., Valero, S., Vargas, L., Adarmes-Gómez, A.D., Alarcón-Martín, E., Álvarez, I., Álvarez, V., Amer-Ferrer, Goo, Antequera, M., Antúnez, C., Baquero, M., Bernal, M., Blesa, R., Buiza-Rueda, D., Bullido, M.J., Burguera, J.A., Calero, M., Carrillo, F., Carrión-Claro, M., Casajeros, M.J., Clarimón, J., Cruz-Gamero, J.M., de Pancorbo, M.M., del Ser, T., Diez-Fairen, M., Fortea, J., Franco, E., Frank-García, A., García-Alberca, J.M., Garcia Madrona, S., Garcia-Ribas, G., Gómez-Garre, P., Hevilla, S., Jesús, S., Espinosa, Labrador, Lage, C., Legaz, A., Lleó, A., López de Munáin, A., López-García, S., Macias, D., Manzanares, S., Marín, M., Marín-Muñoz, J., Marín, T., Martín Montes, A., Martínez, B., Martínez, C., Martínez, V., Martínez-Lage Álvarez, P., Medina, M., Mendioroz Iriarte, M., Menéndez-González, M., Mir, P., Molinuevo, J.L., Pastor, A.B., Pastor, P., Pérez Tur, J., Periñán-Tocino, T., Piñol Ripoll, G., Rábano, A., Real de Asúa, D., Rodrigo, S., Rodríguez-Rodríguez, E., Royo, J.L., A, Ruiz, Sanchez del Valle Díaz, R., Sánchez-Juan, P., Sastre, I., Vicente, M.P., Vivancos, L., 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, 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, and Ruiz, Agustín

Published
2019
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5. An Insertion Within SIRPβ1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response.

Author

García-Alberca, José María, de Rojas, Itziar, Sanchez-Mejias, Elisabeth, Garrido-Martín, Diego, Gonzalez-Palma, Laura, Jimenez, Sebastian, Pino-Angeles, Almudena, Cruz-Gamero, Jose Manuel, Mendoza, Silvia, Alarcón-Martín, Emilio, Muñoz-Castro, Clara, Real, Luis Miguel, Tena, Juan Jesus, Polvillo, Rocio, Govantes, Fernando, Lopez, Aroa, Royo-Aguado, Jose Luis, Navarro, Victoria, Gonzalez, Irene, and Ruiz, Maximiliano

Subjects
*ALZHEIMER'S disease, *MILD cognitive impairment, *COGNITION disorders, *MICROGLIA, *PHAGOCYTIC function tests, *WHITE matter (Nerve tissue)
Abstract

Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPβ1, a surface receptor that triggers amyloid-β(Aβ) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPβ1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPβ1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPβ1 protein isoform landscape compromising its ability to bind oligomeric Aβ and its affinity for TYROBP. SIRPβ1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aβ ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPβ1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPβ1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aβ. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPβ1 structural variant might be considered as a potential modulator of this causative pathway. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Effect of Nordic Sensi® Chair on Behavioral and Psychological Symptoms of Dementia in Nursing Homes Residents: A Randomized Controlled Trial

Author

García-Alberca, José María, primary, de la Rosa, María Dolores, additional, Solo de Zaldívar, Paloma, additional, Ledesma, María, additional, Oltra, Estela, additional, Gris, Esther, additional, Ocejo, Olga, additional, Torrecilla, Javier, additional, Zafra, Carmen, additional, Sánchez-Fernández, Ana, additional, Mancilla, Tomás, additional, López-Romero, Mercedes, additional, Jerez, Raquel, additional, Santana, Nuria, additional, Lara, José Pablo, additional, Barbancho, Miguel Ángel, additional, and Blanco-Reina, Encarnación, additional

Published
2023
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7. Effect of Nordic Sensi® Chair on Behavioral and Psychological Symptoms of Dementia in Nursing Homes Residents: A Randomized Controlled Trial.

Author

García-Alberca, José María, de la Rosa, María Dolores, Solo de Zaldívar, Paloma, Ledesma, María, Oltra, Estela, Gris, Esther, Ocejo, Olga, Torrecilla, Javier, Zafra, Carmen, Sánchez-Fernández, Ana, Mancilla, Tomás, López-Romero, Mercedes, Jerez, Raquel, Santana, Nuria, Lara, José Pablo, Barbancho, Miguel Ángel, and Blanco-Reina, Encarnación

Subjects
*NURSING home patients, *RANDOMIZED controlled trials, *REMINISCENCE therapy, *ALZHEIMER'S disease, *VASCULAR dementia, *DEMENTIA, *CAREGIVERS
Abstract

Background: Behavioral and psychological symptoms of dementia (BPSD) are present in most people with dementia (PwD), including Alzheimer's disease. There is consensus that non-pharmacological therapies represent the first line of treatment to address BPSD. Objective: We explore the efficacy of the use of a rocking chair (Nordic Sensi® Chair, NSC) in the treatment of BPSD in nursing home residents with moderate and severe dementia. Methods: We carried out a 16-week randomized, single-blind, controlled, clinical trial with PwD admitted to nursing homes. Participants were assigned to a treatment group (n = 40) that received three times a week one session per day of 20 minutes in the NSC and a control group (n = 37). The Neuropsychiatric Inventory-Nursing Home (NPI-NH) was used as primary efficacy outcome. Occupational distress for the staff was evaluated using the NPI-NH Occupational Disruptiveness subscale (NPI-NH-OD). Statistical analyses were conducted by means of a Mixed Effects Model Analysis. Results: Treatment with the NSC was associated with a beneficial effect in most of BPSD, as reflected by differences between the treatment and control group on the NPI-NH total score (mean change score –18.87±5.56 versus –1.74±0.67, p = 0.004), agitation (mean change score –2.32±2.02 versus –0.78±1.44, p = 0.003) and irritability (mean change score –3.35±2.93 versus –1.42±1.31, p = 0.004). The NPI-NH-OD total score also improved the most in the treatment group (mean change score –9.67±7.67 versus –7.66±6.08, p = 0.003). Conclusions: The reduction in overall BPSD along with decreased caregiver occupational disruptiveness represent encouraging findings, adding to the potential of nonpharmacological interventions for nursing home residents living with dementia. [ABSTRACT FROM AUTHOR]

Published
2023
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9. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Author

European Research Council, Instituto de Salud Carlos III, Pérez-Tur, Jordi [0000-0002-9111-1712], European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR), Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, Rojas, Itziar de, Castillo, Atahualpa, Parveen, Kayenat, Kucukali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jurgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Molina Porcel, Laura, Duzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimón, Jordi, Moreno, Fermín, Pérez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis Miguel, Piñol-Ripoll, Gerard, García-Alberca, José María, Royo, José Luis, Rodríguez-Rodríguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, Mendonça, Alexandre de, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Francois, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stephanie, Grunblatt, Edna, Popp, Julius, Benussi, Luisa, Galimberti, Daniela, Arosio, Beatrice, Mecocci, Patrizia, Solfrizzi, Vincenzo, Parnetti, Lucilla, Squassina, Alessio, Tremolizzo, Lucio, Borroni, Barbara, Nacmias, Benedetta, Sorbi, Sandro, Caffarra, Paolo, Seripa, Davide, Rainero, Innocenzo, Daniele, Antonio, Masullo, Carlo, Spalletta, Gianfranco, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick, Magda, Tsolaki, Rossi, Giacomina, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustín, Ramírez, Alfredo, Lambert, Jean-Charles, Frikke-Schmidt, Ruth, European Research Council, Instituto de Salud Carlos III, Pérez-Tur, Jordi [0000-0002-9111-1712], European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR), Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, Rojas, Itziar de, Castillo, Atahualpa, Parveen, Kayenat, Kucukali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jurgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Molina Porcel, Laura, Duzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimón, Jordi, Moreno, Fermín, Pérez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis Miguel, Piñol-Ripoll, Gerard, García-Alberca, José María, Royo, José Luis, Rodríguez-Rodríguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, Mendonça, Alexandre de, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Francois, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stephanie, Grunblatt, Edna, Popp, Julius, Benussi, Luisa, Galimberti, Daniela, Arosio, Beatrice, Mecocci, Patrizia, Solfrizzi, Vincenzo, Parnetti, Lucilla, Squassina, Alessio, Tremolizzo, Lucio, Borroni, Barbara, Nacmias, Benedetta, Sorbi, Sandro, Caffarra, Paolo, Seripa, Davide, Rainero, Innocenzo, Daniele, Antonio, Masullo, Carlo, Spalletta, Gianfranco, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick, Magda, Tsolaki, Rossi, Giacomina, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustín, Ramírez, Alfredo, Lambert, Jean-Charles, and Frikke-Schmidt, Ruth

Abstract

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, setting, and participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main outcomes and measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK

Published
2023

10. Genetic Associations between Modifiable Risk Factors and Alzheimer Disease

Author

Danish Heart Foundation, Lundbeck Foundation, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, Rojas, Itziar de, Castillo, Atahualpa, Parveen, Kayenat, Kucukali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jurgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Molina Porcel, Laura, Duzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimón, Jordi, Moreno, Fermín, Pérez-Tur, Jordi, Bullido, Maria J, Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M, Pinol-Ripoll, Gerard, García-Alberca, José María, Royo, José Luis, Rodríguez-Rodríguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, Mendonça, Alexandre de, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, Van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Francois, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stephanie, Grunblatt, Edna, Popp, Julius, Benussi, Luisa, Galimberti, Daniela, Arosio, Beatrice, Mecocci, Patrizia, Solfrizzi, Vincenzo, Parnetti, Lucilla, Squassina, Alessio, Tremolizzo, Lucio, Borroni, Barbara, Nacmias, Benedetta, Sorbi, Sandro, Caffarra, Paolo, Seripa, Davide, Rainero, Innocenzo, Daniele, Antonio, Masullo, Carlo, Spalletta, Gianfranco, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick, Magda, Tsolaki, Rossi, Giacomina, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, Van der Flier, Wiesje, Ruiz, Agustin, Ramírez, Alfredo, Lambert, Jean-Charles, Frikke-Schmidt, Ruth, Danish Heart Foundation, Lundbeck Foundation, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, Rojas, Itziar de, Castillo, Atahualpa, Parveen, Kayenat, Kucukali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jurgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Molina Porcel, Laura, Duzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimón, Jordi, Moreno, Fermín, Pérez-Tur, Jordi, Bullido, Maria J, Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M, Pinol-Ripoll, Gerard, García-Alberca, José María, Royo, José Luis, Rodríguez-Rodríguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, Mendonça, Alexandre de, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, Van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Francois, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stephanie, Grunblatt, Edna, Popp, Julius, Benussi, Luisa, Galimberti, Daniela, Arosio, Beatrice, Mecocci, Patrizia, Solfrizzi, Vincenzo, Parnetti, Lucilla, Squassina, Alessio, Tremolizzo, Lucio, Borroni, Barbara, Nacmias, Benedetta, Sorbi, Sandro, Caffarra, Paolo, Seripa, Davide, Rainero, Innocenzo, Daniele, Antonio, Masullo, Carlo, Spalletta, Gianfranco, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick, Magda, Tsolaki, Rossi, Giacomina, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, Van der Flier, Wiesje, Ruiz, Agustin, Ramírez, Alfredo, Lambert, Jean-Charles, and Frikke-Schmidt, Ruth

Abstract

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK B

Published
2023

13. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Author

European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR), Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, Rojas, Itziar de, Castillo, Atahualpa, Parveen, Kayenat, Kucukali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jurgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Molina Porcel, Laura, Duzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimón, Jordi, Moreno, Fermín, Pérez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Pinol-Ripoll, Gerard, García-Alberca, José María, Royo, José Luis, Rodríguez-Rodríguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, Mendonça, Alexandre de, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Francois, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stephanie, Grunblatt, Edna, Popp, Julius, Benussi, Luisa, Galimberti, Daniela, Arosio, Beatrice, Mecocci, Patrizia, Solfrizzi, Vincenzo, Parnetti, Lucilla, Squassina, Alessio, Tremolizzo, Lucio, Borroni, Barbara, Nacmias, Benedetta, Sorbi, Sandro, Caffarra, Paolo, Seripa, Davide, Rainero, Innocenzo, Daniele, Antonio, Masullo, Carlo, Spalletta, Gianfranco, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick, Magda, Tsolaki, Rossi, Giacomina, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustin, Ramírez, Alfredo, Lambert, Jean-Charles, Frikke-Schmidt, Ruth, European Research Council, Instituto de Salud Carlos III, and Pérez-Tur, Jordi

Subjects
Aged, 80 and over, Male, Causality, epidemiology [Alzheimer Disease], Risk Factors, Cholesterol, HDL, Humans, ethyl 4-azidophenyl-1,4-dithiobutyrimidate, Female, genetics [Alzheimer Disease], ddc:610, Aged
Abstract

17 páginas, 3 figuras, 2 tablas. Material suplementario accesible en : https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2805006, Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, setting, and participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main outcomes and measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation., The work for this manuscript was further supported by the CoSTREAM project (www.costream.eu) and funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 667375. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)–Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER–‘Una manera de hacer Europa’).

Published
2023

14. Association of Rare APOE Missense Variants V236E and R251G with Risk of Alzheimer Disease

Author

Le Guen, Yann, Belloy, Michael E, Eger, Sarah J, Mir, Pablo, Moreno, Fermin, Pastor, Pau, Piñol-Ripoll, Gerard, Molina-Porcel, Laura, Pérez-Tur, Jordi, Rodríguez-Rodríguez, Eloy, Royo, Jose Luís, Sánchez-Valle, Raquel, Dichgans, Martin, Rasmussen, Katrine Laura, Rujescu, Dan, Thomassen, Jesper Qvist, Deleuze, Jean-François, He, Zihuai, Napolioni, Valerio, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick Gavin, van Duijn, Cornelia, Grenier-Boley, Benjamin, Tsolaki, Magda, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Rossi, Giacomina, Hiltunen, Mikko, Sims, Rebecca, van der Flier, Wiesje M, Ramirez, Alfredo, Andreassen, Ole A, de Rojas, Itziar, Frikke-Schmidt, Ruth, Williams, Julie, Ruiz, Agustín, Lambert, Jean-Charles, Greicius, Michael D, Members of the EADB, GR@ACE, DEGESCO, DemGene, GERAD, Groups, EADI, Arosio, Beatrice, Benussi, Luisa, Boland, Anne, Castillo-Morales, Atahualpa, Borroni, Barbara, Caffarra, Paolo, Daian, Delphine, Daniele, Antonio, Debette, Stéphanie, Dufouil, Carole, Düzel, Emrah, Galimberti, Daniela, Giedraitis, Vilmantas, Grimmer, Timo, Jansen, Iris, Graff, Caroline, Grünblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, Hort, Jakub, Jürgen, Deckert, Kuulasmaa, Teemu, van der Lugt, Aad, Nicolas, Aude, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonça, Alexandre, Moebus, Susanne, Nacmias, Benedetta, Nicolas, Gael, Olaso, Robert, Papenberg, Goran, Parnetti, Lucilla, Bellenguez, Céline, Pasquier, Florence, Peters, Oliver, Pijnenburg, Yolande A L, Popp, Julius, Rainero, Innocenzo, Ramakers, Inez, Riedel-Heller, Steffi, Scarmeas, Nikolaos, Scheltens, Philip, Scherbaum, Norbert, Dalmasso, Carolina, Schneider, Anja, Seripa, Davide, Soininen, Hilkka, Solfrizzi, Vincenzo, Spalletta, Gianfranco, Squassina, Alessio, van Swieten, John, Tegos, Thomas J, Tremolizzo, Lucio, Verhey, Frans, Küçükali, Fahri, Vyhnalek, Martin, Wiltfang, Jens, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Real, Luis M, Álvarez, Victoria, Bullido, María J, Clarimon, Jordi, García-Alberca, José María, Neurology, Amsterdam Neuroscience - Neurodegeneration, VU University medical center, APH - Personalized Medicine, APH - Methodology, National Institutes of Health (US), National Institute on Aging (US), European Research Council, Pérez-Tur, Jordi [0000-0002-9111-1712], RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Psychology 2, Psychiatrie & Neuropsychologie, MUMC+: MA Med Staf Spec Psychiatrie (9), Le Guen, Y, Belloy, M, Grenier-Boley, B, de Rojas, I, Castillo-Morales, A, Jansen, I, Nicolas, A, Bellenguez, C, Dalmasso, C, Küçükali, F, Eger, S, Rasmussen, K, Thomassen, J, Deleuze, J, He, Z, Napolioni, V, Amouyel, P, Jessen, F, Kehoe, P, van Duijn, C, Tsolaki, M, Sánchez-Juan, P, Sleegers, K, Ingelsson, M, Rossi, G, Hiltunen, M, Sims, R, van der Flier, W, Ramirez, A, Andreassen, O, Frikke-Schmidt, R, Williams, J, Ruiz, A, Lambert, J, Greicius, M, Arosio, B, Benussi, L, Boland, A, Borroni, B, Caffarra, P, Daian, D, Daniele, A, Debette, S, Dufouil, C, Düzel, E, Galimberti, D, Giedraitis, V, Grimmer, T, Graff, C, Grünblatt, E, Hanon, O, Hausner, L, Heilmann-Heimbach, S, Holstege, H, Hort, J, Jürgen, D, Kuulasmaa, T, van der Lugt, A, Masullo, C, Mecocci, P, Mehrabian, S, de Mendonça, A, Moebus, S, Nacmias, B, Nicolas, G, Olaso, R, Papenberg, G, Parnetti, L, Pasquier, F, Peters, O, Pijnenburg, Y, Popp, J, Rainero, I, Ramakers, I, Riedel-Heller, S, Scarmeas, N, Scheltens, P, Scherbaum, N, Schneider, A, Seripa, D, Soininen, H, Solfrizzi, V, Spalletta, G, Squassina, A, van Swieten, J, Tegos, T, Tremolizzo, L, Verhey, F, Vyhnalek, M, Wiltfang, J, Boada, M, García-González, P, Puerta, R, Real, L, Álvarez, V, Bullido, M, Clarimon, J, García-Alberca, J, Mir, P, Moreno, F, Pastor, P, Piñol-Ripoll, G, Molina-Porcel, L, Pérez-Tur, J, Rodríguez-Rodríguez, E, Royo, J, Sánchez-Valle, R, Dichgans, M, Rujescu, D, Epidemiology, Radiology & Nuclear Medicine, Graduate School, Medical Psychology, APH - Quality of Care, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), EADB Group, GR@ACE Groupp, DEGESCO Group, DemGene Group, GERAD Group, EADI Group, Repositório da Universidade de Lisboa, and Pérez-Tur, Jordi

Subjects
Male, Genotype, Apolipoprotein E2, epidemiology [Alzheimer Disease], Apolipoprotein E4, Medizin, genetics [Alzheimer Disease], APOLIPOPROTEIN-E, Apolipoproteins E, Settore BIO/13 - Biologia Applicata, Alzheimer Disease, genetics [Apolipoprotein E2], Humans, BEHAVIORAL DEFICITS, ddc:610, Age of Onset, PROGRESS, Alleles, genetics [Apolipoprotein E4], Alzheimer's disease, genetics, APOE, risk factor, A-BETA, Original Investigation, Settore MED/26 - NEUROLOGIA, ALLELE, genetics [Apolipoproteins E], [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, INFERENCE, Neurology (clinical), Human medicine
Abstract

34 páginas, 2 tablas, 2 figuras. 2 ficheros con material suplementario. Data used in preparation of this manuscript can be obtained upon application at: - dbGaP (https://www.ncbi.nlm.nih.gov/gap/advanced_search/) - NIAGADS and NIAGADS DSS (https://www.niagads.org/) - LONI (https://ida.loni.usc.edu/) - Synapse (https://adknowledgeportal.synapse.org/) - RADC Rush (https://www.radc.rush.edu/) - NACC (https://naccdata.org/) - UK Biobank (https://biobank.ndph.ox.ac.uk/showcase/), The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly., This work was supported by the National Institute of Health and National Institute of Aging grants AG060747 (MDG), AG066206 (ZH), AG066515 (ZH, MDG), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie (grant agreement No. 890650, YLG), the Alzheimer’s Association (AARF-20-683984, MEB), and the Iqbal Farrukh and Asad Jamal Fund, a grant from the EU Joint Programme – Neurodegenerative Disease Research (European Alzheimer DNA BioBank, EADB; JPND). Inserm UMR1167 is also funded by the Inserm, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine, and the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to Alzheimer’s disease). EADB thank the study participants, researchers, and staff for collecting and contributing to the data, the high-performance computing service at the University of Lille, and the staff at CEA-CNRGH for their help with sample preparation and genotyping, and technical assistance. Additional funders of individual investigators and institutions who contributed to data collection and genotyping are provided in the Supplemental Online Content.

Published
2022

16. Supplemental Online Content. Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease

Author

Le Guen, Yann, Belloy, Michael E, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo-Morales, Atahualpa, Jansen, Iris, Nicolas, Aude, Bellenguez, Céline, Dalmasso, Carolina, Küçükali, Fahri, Eger, Sarah J, Jürgen, Deckert, Kuulasmaa, Teemu, van der Lugt, Aad, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonça, Alexandre, Moebus, Susanne, Nacmias, Benedetta, Nicolas, Gael, Olaso, Robert, Papenberg, Goran, Parnetti, Lucilla, Pasquier, Florence, Peters, Oliver, Pijnenburg, Yolande A L, Popp, Julius, Rainero, Innocenzo, Ramakers, Inez, Riedel-Heller, Steffi, Scarmeas, Nikolaos, Scheltens, Philip, Scherbaum, Norbert, Schneider, Anja, Seripa, Davide, Soininen, Hilkka, Solfrizzi, Vincenzo, Spalletta, Gianfranco, Squassina, Alessio, van Swieten, John, Tegos, Thomas J, Tremolizzo, Lucio, Verhey, Frans, Vyhnalek, Martin, Wiltfang, Jens, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Real, Luis Miguel, Álvarez, Victoria, Bullido, María J., Clarimón, Jordi, García-Alberca, José María, Mir, Pablo, Moreno, Fermín, Pastor, Pau, Piñol-Ripoll, Gerard, Molina-Porcel, Laura, Pérez-Tur, Jordi, Rodríguez Martínez, Eloy, Royo, José Luis, Sánchez-Valle, Raquel, Dichgans, Martin, Rujescu, Dan, Rasmussen, Katrine Laura, Thomassen, Jesper Qvist, Deleuze, Jean-François, He, Zihuai, Napolioni, Valerio, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick G., van Duijn, Cornelia, Tsolaki, Magda, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Rossi, Giacomina, Hiltunen, Mikko, Sims, Rebecca, van der Flier, Wiesje M., Ramírez, Alfredo, Andreassen, Ole A., Frikke-Schmidt, Ruth, Williams, Julie, Ruiz, Agustín, Lambert, Jean-Charles, Greicius, Michael D, Arosio, Beatrice, Benussi, Luisa, Boland, Anne, Borroni, Barbara, Caffarra, Paolo, Daian, Delphine, Daniele, Antonio, Debette, Stéphanie, Dufouil, Carole, Düzel, Emrah, Galimberti, Daniela, Giedraitis, Vilmantas, Grimmer, Timo, Graff, Caroline, Grünblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, Hort, Jakub, Le Guen, Yann, Belloy, Michael E, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo-Morales, Atahualpa, Jansen, Iris, Nicolas, Aude, Bellenguez, Céline, Dalmasso, Carolina, Küçükali, Fahri, Eger, Sarah J, Jürgen, Deckert, Kuulasmaa, Teemu, van der Lugt, Aad, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonça, Alexandre, Moebus, Susanne, Nacmias, Benedetta, Nicolas, Gael, Olaso, Robert, Papenberg, Goran, Parnetti, Lucilla, Pasquier, Florence, Peters, Oliver, Pijnenburg, Yolande A L, Popp, Julius, Rainero, Innocenzo, Ramakers, Inez, Riedel-Heller, Steffi, Scarmeas, Nikolaos, Scheltens, Philip, Scherbaum, Norbert, Schneider, Anja, Seripa, Davide, Soininen, Hilkka, Solfrizzi, Vincenzo, Spalletta, Gianfranco, Squassina, Alessio, van Swieten, John, Tegos, Thomas J, Tremolizzo, Lucio, Verhey, Frans, Vyhnalek, Martin, Wiltfang, Jens, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Real, Luis Miguel, Álvarez, Victoria, Bullido, María J., Clarimón, Jordi, García-Alberca, José María, Mir, Pablo, Moreno, Fermín, Pastor, Pau, Piñol-Ripoll, Gerard, Molina-Porcel, Laura, Pérez-Tur, Jordi, Rodríguez Martínez, Eloy, Royo, José Luis, Sánchez-Valle, Raquel, Dichgans, Martin, Rujescu, Dan, Rasmussen, Katrine Laura, Thomassen, Jesper Qvist, Deleuze, Jean-François, He, Zihuai, Napolioni, Valerio, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick G., van Duijn, Cornelia, Tsolaki, Magda, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Rossi, Giacomina, Hiltunen, Mikko, Sims, Rebecca, van der Flier, Wiesje M., Ramírez, Alfredo, Andreassen, Ole A., Frikke-Schmidt, Ruth, Williams, Julie, Ruiz, Agustín, Lambert, Jean-Charles, Greicius, Michael D, Arosio, Beatrice, Benussi, Luisa, Boland, Anne, Borroni, Barbara, Caffarra, Paolo, Daian, Delphine, Daniele, Antonio, Debette, Stéphanie, Dufouil, Carole, Düzel, Emrah, Galimberti, Daniela, Giedraitis, Vilmantas, Grimmer, Timo, Graff, Caroline, Grünblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, and Hort, Jakub

Abstract

Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging.

Published
2022

18. Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study

Author

Rojas, Itziar de, Hernández, Isabel, Montrreal, Laura, Quintela, Inés, Calero, Miguel, Royo, José Luis, Huerto Vilas, Raquel, González-Pérez, Antonio, Franco-Macías, Emilio, Macias, Juan, Menéndez-González, Manuel, Frank-García, Ana, Díez-Fairen, Mónica, Lage, Carmen, García-Madrona, Sebastián, Aguilera, Nuria, Garcia-González, Pablo, Puerta, Raquel, Sotolongo-Grau, Oscar, Alonso-Lana, Silvia, Rábano, Alberto, Arias Pastor, Alfonso, Pastor, Ana Belén, Corma-Gómez, Anaïs, Martin Montes, Ángel, Martínez Rodríguez, Carmen, Buiza-Rueda, Dolores, Periñán, María Teresa, Rodríguez-Rodríguez, Eloy, Álvarez, Ignacio, Rosas Allende, Irene, Pineda, Juan A., Bernal Sánchez-Arjona, María, Fernández-Fuertes, Marta, Mendoza, Silvia, Ser, Teodoro del, GR@ACE, DEGESCO Consortium, García-Ribas, Guillermo, Sanchez-Juan, Pascual, Pastor, Pau, Bullido, María Jesús, Álvarez, Victoria, Real, Luis M., Mir, Pablo, Piñol-Ripoll, Gerard, García-Alberca, José María, Medina, Miguel, Orellana, Adelina, Butler, Christopher R., Marquie, Marta, Sáez, María Eugenia, Carracedo, Ángel, Tárraga, Lluís, Boada, Mercè, Ruiz, Agustín, Instituto de Salud Carlos III, Unión Europea, Grifols (Spain), Fundación La Caixa, Fundació ACE, Centro de Investigación Biomédica en Red - CIBERNED (Enfermedades Neurodegenerativas), Fundación Reina Sofía, Grifols, La Caixa, Ace Alzheimer Center Barcelona, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), European Commission, Rojas, Itziar de [0000-0002-2148-381X], Calero, Miguel [0000-0001-5366-3324], Menéndez-González, Manuel [0000-0002-5218-0774], Díez-Fairen, Mónica [0000-0003-1882-0309], Rábano, Alberto [0000-0001-9320-6566], Rodríguez-Rodríguez, Eloy [0000-0001-7742-677X], Álvarez, Ignacio [0000-0002-8537-3935], Bullido, María Jesús [0000-0002-6477-1117], Álvarez, Victoria [0000-0002-1916-2523], Real, Luis M. [0000-0003-4932-7429], Medina, Miguel [0000-0002-7016-5340], Butler, Christopher R. [0000-0002-7502-9284], Sáez, María Eugenia [0000-0001-9299-2534], Carracedo, Ángel [0000-0003-1085-8986], Ruiz, Agustín [0000-0003-2633-2495], Universidad de Cantabria, Rojas, Itziar de, Calero, Miguel, Menéndez-González, Manuel, Díez-Fairen, Mónica, Rábano, Alberto, Rodríguez-Rodríguez, Eloy, Álvarez, Ignacio, Bullido, María Jesús, Álvarez, Victoria, Real, Luis M., Medina, Miguel, Butler, Christopher R., Sáez, María Eugenia, Carracedo, Ángel, Ruiz, Agustín, and UAM. Departamento de Biología Molecular

Subjects
SARS-CoV-2, COVID-19, GWAS, GR@ACE/DEGESCO, dementia, APOE, Medicine (miscellaneous), Biología y Biomedicina / Biología, Article, Medicine
Abstract

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis., We would like to thank patients and controls who participated in this project. The present work has been performed as part of the doctoral program of I. de Rojas at the Universitat de Barcelona (Barcelona, Spain) supported by national grant from the Instituto de Salud Carlos III FI20/00215. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria ‘La Caixa’, Fundació ACE, and CIBERNED. The Vallecas Project is supported by Queen Sofia Foundation and the Instituto de Salud Carlos III. The position held by SA-L is funded by Instituto de Salud Carlos III (Co-funded by European Social Fund “Investing in your future”) Sara Borrell Contract (CD19/00232). A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)–Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER–‘Una manera de hacer Europa’). Some control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.bancoadn.org, accessed date: 1 October 2021, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed following standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. This research has been conducted using the COVID-19 Host Genetic Initiative public resource obtained through the web site (https://www.covid19hg.org/results/, accessed date: 1 October 2021).

Published
2021

20. The Genetic Research in Alzheimer Disease (GERALD) Initiative Finds rs9320913 as a Neural eQTL of lincRNA AL589740.1

Author

Lopez-Gutierrez, Lidia, primary, García-Alberca, José María, additional, Mendoza, Silvia, additional, Gris, Esther, additional, De la Guía, María Paz, additional, Marin-Carmona, José Manuel, additional, Alarcón-Martín, Emilio, additional, Lobato, Almudena, additional, Cruz-Gamero, Jose Manuel, additional, Cura, Laura, additional, Ocejo, Olga, additional, Torrecilla, Javier, additional, Nieto, María Dolores, additional, Urbano, Concepción, additional, Pareja, Nuria, additional, Luque, Macarena, additional, García-Peralta, María, additional, Carrillejo, Rosario, additional, and Royo, José Luis, additional

Published
2021
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21. Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study

Author

Instituto de Salud Carlos III, Grifols, La Caixa, Ace Alzheimer Center Barcelona, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Fundación Reina Sofía, European Commission, Rojas, Itziar de [0000-0002-2148-381X], Calero, Miguel [0000-0001-5366-3324], Menéndez-González, Manuel [0000-0002-5218-0774], Díez-Fairen, Mónica [0000-0003-1882-0309], Rábano, Alberto [0000-0001-9320-6566], Rodríguez-Rodríguez, Eloy [0000-0001-7742-677X], Álvarez, Ignacio [0000-0002-8537-3935], Bullido, María Jesús [0000-0002-6477-1117], Álvarez, Victoria [0000-0002-1916-2523], Real, Luis M. [0000-0003-4932-7429], Medina, Miguel [0000-0002-7016-5340], Butler, Christopher R. [0000-0002-7502-9284], Sáez, María Eugenia [0000-0001-9299-2534], Carracedo, Ángel [0000-0003-1085-8986], Ruiz, Agustín [0000-0003-2633-2495], Rojas, Itziar de, Hernández, Isabel, Montrreal, Laura, Quintela, Inés, Calero, Miguel, Royo, José Luis, Huerto Vilas, Raquel, González-Pérez, Antonio, Franco-Macías, Emilio, Macías Sánchez, Juan, Menéndez-González, Manuel, Frank-García, Ana, Díez-Fairen, Mónica, Lage, Carmen, García-Madrona, Sebastián, Aguilera, Nuria, García-González, Pablo, Puerta, Raquel, Sotolongo-Grau, Oscar, Alonso-Lana, Silvia, Rábano, Alberto, Arias Pastor, Alfonso, Pastor, Ana Belén, Corma-Gómez, Anaïs, Martin Montes, Ángel, Martínez Rodríguez, Carmen, Buiza-Rueda, Dolores, Periñán, María Teresa, Rodríguez-Rodríguez, Eloy, Álvarez, Ignacio, Rosas Allende, Irene, Pineda, Juan A., Bernal Sánchez-Arjona, María, Fernández-Fuertes, Marta, Mendoza, Silvia, Ser, Teodoro del, GR@ACE, DEGESCO Consortium, García-Ribas, Guillermo, Sánchez-Juan, Pascual, Pastor, Pau, Bullido, María Jesús, Álvarez, Victoria, Real, Luis Miguel, Mir, Pablo, Piñol-Ripoll, Gerard, García-Alberca, José María, Medina, Miguel, Orellana, Adelina, Butler, Christopher R., Marquié, Marta, Sáez, María Eugenia, Carracedo, Ángel, Tárraga, Lluís, Boada, Mercè, Ruiz, Agustín, Instituto de Salud Carlos III, Grifols, La Caixa, Ace Alzheimer Center Barcelona, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Fundación Reina Sofía, European Commission, Rojas, Itziar de [0000-0002-2148-381X], Calero, Miguel [0000-0001-5366-3324], Menéndez-González, Manuel [0000-0002-5218-0774], Díez-Fairen, Mónica [0000-0003-1882-0309], Rábano, Alberto [0000-0001-9320-6566], Rodríguez-Rodríguez, Eloy [0000-0001-7742-677X], Álvarez, Ignacio [0000-0002-8537-3935], Bullido, María Jesús [0000-0002-6477-1117], Álvarez, Victoria [0000-0002-1916-2523], Real, Luis M. [0000-0003-4932-7429], Medina, Miguel [0000-0002-7016-5340], Butler, Christopher R. [0000-0002-7502-9284], Sáez, María Eugenia [0000-0001-9299-2534], Carracedo, Ángel [0000-0003-1085-8986], Ruiz, Agustín [0000-0003-2633-2495], Rojas, Itziar de, Hernández, Isabel, Montrreal, Laura, Quintela, Inés, Calero, Miguel, Royo, José Luis, Huerto Vilas, Raquel, González-Pérez, Antonio, Franco-Macías, Emilio, Macías Sánchez, Juan, Menéndez-González, Manuel, Frank-García, Ana, Díez-Fairen, Mónica, Lage, Carmen, García-Madrona, Sebastián, Aguilera, Nuria, García-González, Pablo, Puerta, Raquel, Sotolongo-Grau, Oscar, Alonso-Lana, Silvia, Rábano, Alberto, Arias Pastor, Alfonso, Pastor, Ana Belén, Corma-Gómez, Anaïs, Martin Montes, Ángel, Martínez Rodríguez, Carmen, Buiza-Rueda, Dolores, Periñán, María Teresa, Rodríguez-Rodríguez, Eloy, Álvarez, Ignacio, Rosas Allende, Irene, Pineda, Juan A., Bernal Sánchez-Arjona, María, Fernández-Fuertes, Marta, Mendoza, Silvia, Ser, Teodoro del, GR@ACE, DEGESCO Consortium, García-Ribas, Guillermo, Sánchez-Juan, Pascual, Pastor, Pau, Bullido, María Jesús, Álvarez, Victoria, Real, Luis Miguel, Mir, Pablo, Piñol-Ripoll, Gerard, García-Alberca, José María, Medina, Miguel, Orellana, Adelina, Butler, Christopher R., Marquié, Marta, Sáez, María Eugenia, Carracedo, Ángel, Tárraga, Lluís, Boada, Mercè, and Ruiz, Agustín

Abstract

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis.

Published
2021

22. Common variants in Alzheimer's disease and risk stratification by polygenic risk scores

Author

Instituto de Salud Carlos III, Grifols, La Caixa, European Research Council, Pérez-Tur, Jordi [0000-0002-9111-1712], Rojas, Itziar de, Moreno-Grau, Sonia, Tesi, Niccolo, Grenier-Boley, Benjamin, Andrade, Victor, Jansen, Iris E., Pedersen, N. L., Stringa, N., Zettergren, Anna, Hernández, Isabel, Montrreal, Laura, Rossi, Giacomina, Tankard, R. M., Wiltfang, J., Giegling, Ina, Seidu, N. M., Dalmasso, Maria Carolina, Benussi, A., Boschi, Silvia, Sáez, María Eugenia, Binetti, Giuliano, Royo, José Luis, Pérez-Tur, Jordi, Spalletta, Gianfranco, Corbaton-Anchuelo, A., Froelich, L., Satizabal, Claudia L., Hagg, S., Ortega, G., Peters, Oliver, Vogelgsang, Jonathan, Serrano-Rios, M., Gil, S., Djurovic, Srdjan, Van Dongen, Jasper, Deramecourt, V., Kalaria, R. N., Wang, L. S., Goldhardt, O., Charbonnier, Camille, Farotti, Lucia, Kornhuber, Johannes, Andreassen, Ole A., Álvarez, Victoria, Herrmann, Martin J., Pasquier, Florence, Calero, Miguel, Holmes, Clive, Haapasalo, Annakaisa, Scherbaum, Norbert, Scheltens, Philip, Caffarra, P., Pineda, Juan A., Del Ser, Teodoro, Hort, Jakub, Espinosa, A., Bullido, María Jesús, Hampel, Harald, Medina, Miguel, Williams, Julie, Sims, Rebecca, Martinez-Larrad, M. T., Riederer, Peter, Esiri, M., Botne Sando, S., Grunblatt, E., Hoffmann, Per, Hiltunen, Mikko, Kern, Silke, Mendoza, Silvia, Kilander, Lena, Jessen, F., Ghidoni, R., Giedraitis, Vilmantas, Molina-Porcel, Laura, Sánchez-Juan, Pascual, Schmid, Matthias, van Duijn, Cornelia M., Antonell, A., Mir, Pablo, Moreno, F., Ferreira, Catarina B., Skrobot, Olivia, Sanchez-Valle, R., Chene, G., Duron, Emmanuelle, Martin Montes, Ángel, Ciccone, Simona, Piñol-Ripoll, Gerard, Ngandu, Tiia, Dardiotis, Efthimios, Scherer, Martin, Arosio, Beatrice, Meggy, A., Sotolongo-Grau, Oscar, Selbaek, Geir, Aarsland, D., Seshadri, Sudha, Bailly, Henri, Sánchez-García, Florentino, Roberto, Natalia, Armstrong, Nicola J., Farrer, Lindsay A., Popp, Julius, Riedel-Heller, Steffi, Fernández-Fuertes, Marta, Scamosci, Michela, Alcolea, Daniel, Rosas Allende, Irene, Marquié, Marta, Benussi, Luisa, Ewers, Michael, Antúnez, Carmen, van Broeckhoven, Christine, Masullo, C., Vyhnalek, Martin, Bossu, Paola, Appollonio, I., Mayeux, R., Lerch, Ondrej, Rábano, Alberto, Quenez, Olivier, Schneider, Anja, Wallon, David, Macías Sánchez, Juan, PGC-ALZ consortia, Yang, Q., Helisalmi, Seppo, Huisman, M., Lambert, Jean-Charles, Kehoe, Patrick G., Heneka, Michael T., DEGESCO consortium, Papenberg, Goran, Lowenmark, M., Frikke-Schmidt, Ruth, Fornage, Myriam, Kunkle, Brian W., Heilmann-Heimbach, Stefanie, Posthuma, Danielle, Tremolizzo, Lucio, Amouyel, Philippe, Franco-Macías, Emilio, Munoz-Fernandez, C., Sorbi, Sandro, Küçükali, Fahri, Dionigi Rossi, P., Huerto Vilas, Raquel, Spallazzi, Marco, Alarcón-Martín, Emilio, Maier, Wolfgang, de Mendonça, Alexandre, The GR@ACE study group, Benaque, Alba, EADB contributors, IGAP (ADGC, CHARGE, EADI, GERAD), van der Lee, Sven J., DeStefano, Anita, Lleó, Alberto, Kosmidis, Mary H., Rongve, A., Nicolas, Gael, Escott-Price, Valentina, Tybjaerg-Hansen, Anne, Chillotti, Caterina, Pastor, Pau, Buiza-Rueda, Dolores, Alegret, Montserrat, Lage, Carmen, Holmans, Peter A., Polak, Thomas, Pastor, Ana Belén, Nöthen, Markus M., García-Ribas, Guillermo, Pijnenburg, Yolande A L, Vidal, Jean-Sebastien, Squassina, Alessio, Kuulasmaa, Teemu, Pericak-Vance, M. A., Pisanu, Claudia, Fliessbach, Klaus, Grimmer, Timo, Galimberti, Daniela, Parnetti, L., López de Munain, Adolfo, Soininen, Hilkka, Carracedo, Ángel, Deckert, Jurgen, Karlsson, I. K., Buerger, Katharina, Clark, Christopher, Cecchetti, Roberta, Fostinelli, Silvia, Deniz-Naranjo, M. C., Engelborghs, S., Álvarez, Ignacio, Sakka, Paraskevi, Thomassen, Jesper Qvist, Ramirez, A., Holstege, Henne, Marshall, Rachel, Haines, Jonathan L., Hulsman, Marc, Kleineidam, Luca, Ferri, E., Pérez-Cordon, Alba, Menéndez-González, Manuel, van der Flier, Wiesje M., Rainero, Innocenzo, Rujescu, D., Wagner, Michael, Corma-Gómez, Anaïs, Lebouvier, T., Ruiz, Agustín, Vandenberghe, Rik, Weinhold, Leonie, Padovani, Alessandro, Diehl-Schmid, Janine, Mead, Simon, Fenoglio, Chiara, Conti, Elisa, Díez-Fairen, Mónica, Fischer, Peter, Abdelnour, Carla, Giaccone, G., González-Pérez, Antonio, Hartmann, Annette M., Hadjigeorgiou, Georgios, Zulaica, M., Sleegers, Kristel, Martínez Rodríguez, Carmen, García-González, Pablo, Rubino, Elisa, Bis, Joshua C., Orellana, Adelina, Zetterberg, Henrik, Schellenberg, Gerard D., Borroni, Barbara, Sanabria, Angela, Fortea, J., Reynolds, C. A., Gelpi, E., Bernal Sánchez-Arjona, María, Boerwinkle, Eric, Mather, K. A., Jian, X., Saltvedt, Ingvild, Frank-García, Ana, Rosende-Roca, Maitee, Kinhult Stahlbom, Anne, Hanon, Olivier, Skoog, Ingmar, Kivipelto, Miia, Lehtisalo, Jenni, García-Alberca, José María, Dufouil, Carole, Bellenguez, Celine, Ingelsson, Martin, Nacmias, B., Spottke, Annika, Ullgren, Abbe, Hausner, Lucrezia, Arias Pastor, Alfonso, Tsolaki, Magda, Seripa, Davide, Naj, A. C., Clarimón, Jordi, Nordestgaard, Borge G., Valero, Sergi, van Schoor, N. M., Scarpini, E., Graff, Caroline, Boada, Mercè, Tagliavini, F., Scarmeas, N., García-Madrona, Sebastián, Yannakoulia, Mary, Banaj, Nerisa, Blennow, Kaj, Duzel, Emrah, Tárraga, Lluís, Lemstra, A. W., Morgan, K., Kok, A. A. L., Bessi, Valentina, Baquero, Miquel, Rodríguez-Rodríguez, Eloy, Cervera-Carles, Laura, Archetti, Silvana, Grande, Giulia, Dichgans, Martin, Arcaro, Marina, Blesa, Rafael, Real, Luis Miguel, Ikram, M. Arfan, Mangialasche, Francesca, Quintela, Inés, Instituto de Salud Carlos III, Grifols, La Caixa, European Research Council, Pérez-Tur, Jordi [0000-0002-9111-1712], Rojas, Itziar de, Moreno-Grau, Sonia, Tesi, Niccolo, Grenier-Boley, Benjamin, Andrade, Victor, Jansen, Iris E., Pedersen, N. L., Stringa, N., Zettergren, Anna, Hernández, Isabel, Montrreal, Laura, Rossi, Giacomina, Tankard, R. M., Wiltfang, J., Giegling, Ina, Seidu, N. M., Dalmasso, Maria Carolina, Benussi, A., Boschi, Silvia, Sáez, María Eugenia, Binetti, Giuliano, Royo, José Luis, Pérez-Tur, Jordi, Spalletta, Gianfranco, Corbaton-Anchuelo, A., Froelich, L., Satizabal, Claudia L., Hagg, S., Ortega, G., Peters, Oliver, Vogelgsang, Jonathan, Serrano-Rios, M., Gil, S., Djurovic, Srdjan, Van Dongen, Jasper, Deramecourt, V., Kalaria, R. N., Wang, L. S., Goldhardt, O., Charbonnier, Camille, Farotti, Lucia, Kornhuber, Johannes, Andreassen, Ole A., Álvarez, Victoria, Herrmann, Martin J., Pasquier, Florence, Calero, Miguel, Holmes, Clive, Haapasalo, Annakaisa, Scherbaum, Norbert, Scheltens, Philip, Caffarra, P., Pineda, Juan A., Del Ser, Teodoro, Hort, Jakub, Espinosa, A., Bullido, María Jesús, Hampel, Harald, Medina, Miguel, Williams, Julie, Sims, Rebecca, Martinez-Larrad, M. T., Riederer, Peter, Esiri, M., Botne Sando, S., Grunblatt, E., Hoffmann, Per, Hiltunen, Mikko, Kern, Silke, Mendoza, Silvia, Kilander, Lena, Jessen, F., Ghidoni, R., Giedraitis, Vilmantas, Molina-Porcel, Laura, Sánchez-Juan, Pascual, Schmid, Matthias, van Duijn, Cornelia M., Antonell, A., Mir, Pablo, Moreno, F., Ferreira, Catarina B., Skrobot, Olivia, Sanchez-Valle, R., Chene, G., Duron, Emmanuelle, Martin Montes, Ángel, Ciccone, Simona, Piñol-Ripoll, Gerard, Ngandu, Tiia, Dardiotis, Efthimios, Scherer, Martin, Arosio, Beatrice, Meggy, A., Sotolongo-Grau, Oscar, Selbaek, Geir, Aarsland, D., Seshadri, Sudha, Bailly, Henri, Sánchez-García, Florentino, Roberto, Natalia, Armstrong, Nicola J., Farrer, Lindsay A., Popp, Julius, Riedel-Heller, Steffi, Fernández-Fuertes, Marta, Scamosci, Michela, Alcolea, Daniel, Rosas Allende, Irene, Marquié, Marta, Benussi, Luisa, Ewers, Michael, Antúnez, Carmen, van Broeckhoven, Christine, Masullo, C., Vyhnalek, Martin, Bossu, Paola, Appollonio, I., Mayeux, R., Lerch, Ondrej, Rábano, Alberto, Quenez, Olivier, Schneider, Anja, Wallon, David, Macías Sánchez, Juan, PGC-ALZ consortia, Yang, Q., Helisalmi, Seppo, Huisman, M., Lambert, Jean-Charles, Kehoe, Patrick G., Heneka, Michael T., DEGESCO consortium, Papenberg, Goran, Lowenmark, M., Frikke-Schmidt, Ruth, Fornage, Myriam, Kunkle, Brian W., Heilmann-Heimbach, Stefanie, Posthuma, Danielle, Tremolizzo, Lucio, Amouyel, Philippe, Franco-Macías, Emilio, Munoz-Fernandez, C., Sorbi, Sandro, Küçükali, Fahri, Dionigi Rossi, P., Huerto Vilas, Raquel, Spallazzi, Marco, Alarcón-Martín, Emilio, Maier, Wolfgang, de Mendonça, Alexandre, The GR@ACE study group, Benaque, Alba, EADB contributors, IGAP (ADGC, CHARGE, EADI, GERAD), van der Lee, Sven J., DeStefano, Anita, Lleó, Alberto, Kosmidis, Mary H., Rongve, A., Nicolas, Gael, Escott-Price, Valentina, Tybjaerg-Hansen, Anne, Chillotti, Caterina, Pastor, Pau, Buiza-Rueda, Dolores, Alegret, Montserrat, Lage, Carmen, Holmans, Peter A., Polak, Thomas, Pastor, Ana Belén, Nöthen, Markus M., García-Ribas, Guillermo, Pijnenburg, Yolande A L, Vidal, Jean-Sebastien, Squassina, Alessio, Kuulasmaa, Teemu, Pericak-Vance, M. A., Pisanu, Claudia, Fliessbach, Klaus, Grimmer, Timo, Galimberti, Daniela, Parnetti, L., López de Munain, Adolfo, Soininen, Hilkka, Carracedo, Ángel, Deckert, Jurgen, Karlsson, I. K., Buerger, Katharina, Clark, Christopher, Cecchetti, Roberta, Fostinelli, Silvia, Deniz-Naranjo, M. C., Engelborghs, S., Álvarez, Ignacio, Sakka, Paraskevi, Thomassen, Jesper Qvist, Ramirez, A., Holstege, Henne, Marshall, Rachel, Haines, Jonathan L., Hulsman, Marc, Kleineidam, Luca, Ferri, E., Pérez-Cordon, Alba, Menéndez-González, Manuel, van der Flier, Wiesje M., Rainero, Innocenzo, Rujescu, D., Wagner, Michael, Corma-Gómez, Anaïs, Lebouvier, T., Ruiz, Agustín, Vandenberghe, Rik, Weinhold, Leonie, Padovani, Alessandro, Diehl-Schmid, Janine, Mead, Simon, Fenoglio, Chiara, Conti, Elisa, Díez-Fairen, Mónica, Fischer, Peter, Abdelnour, Carla, Giaccone, G., González-Pérez, Antonio, Hartmann, Annette M., Hadjigeorgiou, Georgios, Zulaica, M., Sleegers, Kristel, Martínez Rodríguez, Carmen, García-González, Pablo, Rubino, Elisa, Bis, Joshua C., Orellana, Adelina, Zetterberg, Henrik, Schellenberg, Gerard D., Borroni, Barbara, Sanabria, Angela, Fortea, J., Reynolds, C. A., Gelpi, E., Bernal Sánchez-Arjona, María, Boerwinkle, Eric, Mather, K. A., Jian, X., Saltvedt, Ingvild, Frank-García, Ana, Rosende-Roca, Maitee, Kinhult Stahlbom, Anne, Hanon, Olivier, Skoog, Ingmar, Kivipelto, Miia, Lehtisalo, Jenni, García-Alberca, José María, Dufouil, Carole, Bellenguez, Celine, Ingelsson, Martin, Nacmias, B., Spottke, Annika, Ullgren, Abbe, Hausner, Lucrezia, Arias Pastor, Alfonso, Tsolaki, Magda, Seripa, Davide, Naj, A. C., Clarimón, Jordi, Nordestgaard, Borge G., Valero, Sergi, van Schoor, N. M., Scarpini, E., Graff, Caroline, Boada, Mercè, Tagliavini, F., Scarmeas, N., García-Madrona, Sebastián, Yannakoulia, Mary, Banaj, Nerisa, Blennow, Kaj, Duzel, Emrah, Tárraga, Lluís, Lemstra, A. W., Morgan, K., Kok, A. A. L., Bessi, Valentina, Baquero, Miquel, Rodríguez-Rodríguez, Eloy, Cervera-Carles, Laura, Archetti, Silvana, Grande, Giulia, Dichgans, Martin, Arcaro, Marina, Blesa, Rafael, Real, Luis Miguel, Ikram, M. Arfan, Mangialasche, Francesca, and Quintela, Inés

Abstract

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.

Published
2021

26. Erratum to: Effect of Nordic Sensi® Chair on Behavioral and Psychological Symptoms of Dementia in Nursing Homes Residents: A Randomized Controlled Trial.

Author

García-Alberca, José María, de la Rosa, María Dolores, Solo de Zaldívar, Paloma, Ledesma, María, Oltra, Estela, Esther, Gris, Ocejo, Olga, Torrecilla, Javier, Zafra, Carmen, Sánchez-Fernández, Ana, Mancilla, Tomás, López-Romero, Mercedes, Jerez, Raquel, Santana, Nuria, Lara, José Pablo, Barbancho, Miguel Ángel, and Blanco-Reina, Encarnación

Subjects
*NURSING home residents, *RANDOMIZED controlled trials, *DEMENTIA, *VASCULAR dementia, *ALZHEIMER'S disease, *SYMPTOMS, *REMINISCENCE therapy
Abstract

This document is a correction notice for an article titled "Effect of Nordic Sensi® Chair on Behavioral and Psychological Symptoms of Dementia in Nursing Homes Residents: A Randomized Controlled Trial" published in the Journal of Alzheimer's Disease. The correction addresses errors and omissions in the Acknowledgment and Funding sections of the article. The authors express gratitude to Wellness Nordic A/S for providing the NSC for the study and acknowledge the participation of patients and caregivers. The funding for the research was supported in part by Arjo Huntleigh AB, Malmö, Sweden, with no involvement in the study design or data analysis. The authors of the article are listed at the end. [Extracted from the article]

Published
2024
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28. Medial temporal lobe atrophy is independently associated with behavioural and psychological symptoms in Alzheimer's disease.

Author

García‐Alberca, José María, Florido, Mercedes, Cáceres, Marta, Sánchez‐Toro, Alicia, Lara, José Pablo, and García‐Casares, Natalia

Subjects
*ALZHEIMER'S disease, *LONGITUDINAL method, *MAGNETIC resonance imaging, *QUESTIONNAIRES, *TEMPORAL lobe, *LOGISTIC regression analysis, *BEHAVIOR disorders, *CROSS-sectional method, *ATROPHY, *DESCRIPTIVE statistics, *CONFOUNDING variables, *WHITE matter (Nerve tissue), *ODDS ratio, *SYMPTOMS, *PSYCHOLOGY
Abstract

Aim: Evidence describing the contribution of cerebral white matter disease and medial temporal atrophy (MTA) to behavioural and psychological symptoms of dementia (BPSD) has been conflicting. The aim of this study was to assess the relationship of white matter hyperintensities (WMH) and MTA observed on magnetic resonance imaging with BPSD among patients with Alzheimer's disease. Methods: In a cross‐sectional study of a prospective cohort of patients attending a memory clinic, 46 patients with probable Alzheimer's disease (mean age: 72.38 ± 7.05 years) were studied. Sociodemographic, cognitive, and BPSD data were collected. BPSD were assessed using the Neuropsychiatric Inventory. Magnetic resonance imaging, WMH, and MTA were rated using the Scheltens scales for the assessment of signal hyperintensities and atrophy of medial temporal lobes. For multivariate analysis, two binary logistic regression analyses were carried out, with presence or absence of each BPSD as the dependent variable and with WMH or MTA as the predictor variable. Results of the logistic regression were analyzed to see if the significance of the WMH or MTA score was maintained in a model that factored in other possible confounding variables identified in univariate analysis. Results: The results of binary logistic regression analysis showed that in models that accounted for confounding variables, increased total MTA was significantly associated with apathy (odds ratio = 1.605, adjusted P = 0.042) and disinhibition (odds ratio = 0.607, adjusted P = 0.042). WMH measures did not significantly predict any BPSD item. Conclusions: These findings indicate that MTA potentially contributes to the aetiology of BPSD, and they provide evidence to support the hypothesis that Alzheimer's disease pathology itself can contribute to BPSD. [ABSTRACT FROM AUTHOR]

Published
2019
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36. Cognitive-behavioural treatment for depression in Alzheimer's disease patients: a case study.

Author

García‐Alberca, José María

Subjects
*MENTAL depression, *THERAPEUTICS, *ALZHEIMER'S disease, *COGNITION disorders, *COGNITIVE therapy, *SERVICES for caregivers, *MEMORY disorders, *BURDEN of care
Abstract

The article presents a case study of a 75-year-old married man diagnosed with Alzheimer's disease (AD). Topics discussed include treatment of depression of AD's patients through cognitive-behavioral interventions, decrease in sadness, caregiver distress and caregiver burden after treatment and an increase in pleasant activities.

Published
2017
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37. Real-world assessment of caregiver preference and compliance to treatment with twice-weekly versus daily rivastigmine patches in Alzheimer's disease.

Author

García-Alberca JM, De La Guía P, Gris E, Mendoza S, López De La Rica M, López-Trigo JA, López-Mongil R, García-López T, López-García R, Rodríguez Del Rey T, Gay-Puente J, García-Castro J, Casales F, Morato X, Boada M, González-Velasco G, Marín-Carmona JM, Páez NI, León M, Carrillejo R, Rius F, Barbancho MÁ, Lara JP, and Blanco-Reina E

Abstract

Background: Adherence is critical in patients with Alzheimer's disease (AD) in order to achieve optimal benefit from therapy. However, patient compliance with the treatment remains a challenge., Objective: To evaluate, in a real-world clinical setting, caregiver preference and treatment compliance with twice-weekly versus daily transdermal rivastigmine patch in mild-to-moderate AD., Methods: 92 patients who had been treated with daily rivastigmine patch for at least six months prior to switching to twice-weekly patch were evaluated. The change in therapeutic regimen was decided by the treating physician in accordance with standard practice. Caregivers' satisfaction with daily rivastigmine patch was assessed at study entry. Caregiver's preference and satisfaction with twice-weekly patch as well as patient compliance were evaluated at weeks 12 and 24 using the Alzheimer's Disease Caregiver Preference Questionnaire., Results: A significantly higher proportion of caregivers expressed a preference for the twice-weekly patch over the daily patch ( p  < 0.001), and this preference was found to be associated with ease of use ( p  < 0.001), ease of following the schedule ( p  < 0.001), and ease of compliance ( p  < 0.001). Furthermore, caregivers were more satisfied with the twice-weekly patch ( p  < 0.0001). At 24 weeks, patient compliance was significantly better with the twice-weekly patch than with the daily patch ( p  = 0.002). Caregiver burden significantly improved at the end of the treatment ( p  = 0.003). No serious adverse events were reported., Conclusions: The twice-weekly rivastigmine patch offers a convenient and straightforward dosing regimen for caregivers, with potential to enhance adherence with treatment in AD patients without causing serious adverse events., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Published
2024
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38. Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.

Author

Le Guen Y, Luo G, Ambati A, Damotte V, Jansen I, Yu E, Nicolas A, de Rojas I, Peixoto Leal T, Miyashita A, Bellenguez C, Lian MM, Parveen K, Morizono T, Park H, Grenier-Boley B, Naito T, Küçükali F, Talyansky SD, Yogeshwar SM, Sempere V, Satake W, Alvarez V, Arosio B, Belloy ME, Benussi L, Boland A, Borroni B, Bullido MJ, Caffarra P, Clarimon J, Daniele A, Darling D, Debette S, Deleuze JF, Dichgans M, Dufouil C, During E, Düzel E, Galimberti D, Garcia-Ribas G, García-Alberca JM, García-González P, Giedraitis V, Goldhardt O, Graff C, Grünblatt E, Hanon O, Hausner L, Heilmann-Heimbach S, Holstege H, Hort J, Jung YJ, Jürgen D, Kern S, Kuulasmaa T, Lee KH, Lin L, Masullo C, Mecocci P, Mehrabian S, de Mendonça A, Boada M, Mir P, Moebus S, Moreno F, Nacmias B, Nicolas G, Niida S, Nordestgaard BG, Papenberg G, Papma J, Parnetti L, Pasquier F, Pastor P, Peters O, Pijnenburg YAL, Piñol-Ripoll G, Popp J, Porcel LM, Puerta R, Pérez-Tur J, Rainero I, Ramakers I, Real LM, Riedel-Heller S, Rodriguez-Rodriguez E, Ross OA, Royo LJ, Rujescu D, Scarmeas N, Scheltens P, Scherbaum N, Schneider A, Seripa D, Skoog I, Solfrizzi V, Spalletta G, Squassina A, van Swieten J, Sánchez-Valle R, Tan EK, Tegos T, Teunissen C, Thomassen JQ, Tremolizzo L, Vyhnalek M, Verhey F, Waern M, Wiltfang J, Zhang J, Zetterberg H, Blennow K, He Z, Williams J, Amouyel P, Jessen F, Kehoe PG, Andreassen OA, Van Duin C, Tsolaki M, Sánchez-Juan P, Frikke-Schmidt R, Sleegers K, Toda T, Zettergren A, Ingelsson M, Okada Y, Rossi G, Hiltunen M, Gim J, Ozaki K, Sims R, Foo JN, van der Flier W, Ikeuchi T, Ramirez A, Mata I, Ruiz A, Gan-Or Z, Lambert JC, Greicius MD, and Mignot E

Subjects
Humans, Histocompatibility Antigens, HLA Antigens, Alzheimer Disease genetics, HLA-DRB1 Chains genetics, Parkinson Disease genetics
Abstract

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Published
2023
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39. Combined treatment with Ginkgo biloba extract EGb 761 plus acetylcholinesterase inhibitors improved cognitive function and neuropsychiatric symptoms in patients with mild cognitive impairment.

Author

García-Alberca JM, Gris E, and Mendoza S

Abstract

Introduction: Mild cognitive impairment (MCI) is a neurocognitive state between normal aging and dementia. There is currently no approved treatment for MCI, with acetylcholinesterase inhibitors (AChEI) being the commonly prescribed drugs. The Ginkgo biloba extract EGb 761 is an herbal remedy used for cognitive disorders, including dementia. This study aims to explore the potential synergistic effect of combination therapy with EGb 761 plus AChEI in patients with amnestic MCI in a real-life setting., Methods: We retrospectively identified 133 patients with amnestic MCI who were attending a memory clinic. Patients had received treatment with any of the following drugs: G. biloba extract EGb 761, donepezil, galantamine, or rivastigmine at their standard doses. Subjects were divided into three treatment groups: EGb 761, AChEI, and EGb 761+AChEI. Patients were assessed by Mini-Mental State Examination (MMSE), Rey Auditory Verbal Learning Test (RAVLT), Symbol Digit Modalities Test, Boston Naming Test, Trail Making Test (TMT Parts A and B), Letter and Category Fluency Test (LFT, CFT), Neuropsychiatric Inventory (NPI), and Interview for Deterioration in Daily Living. Mixed-effects model analysis was carried out to evaluate changes in cognitive, functional, and behavioral outcomes over a 12-month follow-up., Results: After 12 months, EGb 761+AChEI showed significant improvement in MMSE, RAVLT, CFT, TMT A-B, and NPI compared to AChEI and in MMSE and RAVLT compared to EGb 761. At 12 months, EGb 761 was superior to AChEI on the CFT, TMT A-B, and NPI., Discussion: Our findings suggest that combined therapy with EGb 761 plus AChEI may provide added cognitive and functional benefits in patients with MCI and provides additional real-world evidence for the combined use of EGb 761 and anti-dementia drugs in patients with MCI. This study can serve as a model for the design of clinical trials that help to support the combined use of EGb 761 and anti-dementia drugs in patients with MCI., Competing Interests: The authors report that they have no conflict of interest to disclose. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Published
2022
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40. Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease.

Author

Le Guen Y, Belloy ME, Grenier-Boley B, de Rojas I, Castillo-Morales A, Jansen I, Nicolas A, Bellenguez C, Dalmasso C, Küçükali F, Eger SJ, Rasmussen KL, Thomassen JQ, Deleuze JF, He Z, Napolioni V, Amouyel P, Jessen F, Kehoe PG, van Duijn C, Tsolaki M, Sánchez-Juan P, Sleegers K, Ingelsson M, Rossi G, Hiltunen M, Sims R, van der Flier WM, Ramirez A, Andreassen OA, Frikke-Schmidt R, Williams J, Ruiz A, Lambert JC, Greicius MD, Arosio B, Benussi L, Boland A, Borroni B, Caffarra P, Daian D, Daniele A, Debette S, Dufouil C, Düzel E, Galimberti D, Giedraitis V, Grimmer T, Graff C, Grünblatt E, Hanon O, Hausner L, Heilmann-Heimbach S, Holstege H, Hort J, Jürgen D, Kuulasmaa T, van der Lugt A, Masullo C, Mecocci P, Mehrabian S, de Mendonça A, Moebus S, Nacmias B, Nicolas G, Olaso R, Papenberg G, Parnetti L, Pasquier F, Peters O, Pijnenburg YAL, Popp J, Rainero I, Ramakers I, Riedel-Heller S, Scarmeas N, Scheltens P, Scherbaum N, Schneider A, Seripa D, Soininen H, Solfrizzi V, Spalletta G, Squassina A, van Swieten J, Tegos TJ, Tremolizzo L, Verhey F, Vyhnalek M, Wiltfang J, Boada M, García-González P, Puerta R, Real LM, Álvarez V, Bullido MJ, Clarimon J, García-Alberca JM, Mir P, Moreno F, Pastor P, Piñol-Ripoll G, Molina-Porcel L, Pérez-Tur J, Rodríguez-Rodríguez E, Royo JL, Sánchez-Valle R, Dichgans M, and Rujescu D

Subjects
Age of Onset, Alleles, Apolipoprotein E2 genetics, Apolipoprotein E4 genetics, Apolipoproteins E genetics, Female, Genotype, Humans, Male, Alzheimer Disease epidemiology, Alzheimer Disease genetics
Abstract

Importance: The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly., Objective: To determine whether rare missense variants on APOE are associated with AD risk., Design, Setting, and Participants: Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021., Main Outcomes and Measures: In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression., Results: A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers., Conclusions and Relevance: In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.

Published
2022
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