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1. Neutrophil Reactivity Intensity and misclassification of immature granulocytes.

Author

Wiwe, Elias Frost, Kofoed, Isabella Katarina, Dufréchou, Muriel Julie Falk, Philipsen, Jens Peter, Lemvig, Birthe, Rasmussen, Katrine Laura, Smith, Julie, and Hillig, Thore

Subjects
PREDICTIVE tests, INFECTION control, AUTOANALYZERS, NEUTROPHILS, FLUORESCENT antibody technique, EXPERIMENTAL design, MEDICAL screening, COLLECTION & preservation of biological specimens, GRANULOCYTES, BIOMARKERS, SENSITIVITY & specificity (Statistics)
Abstract

Introduction: Immature granulocyte percentage (IG%) is an important biomarker for infection control. We observed spurious cases where the IG% was dramatically underestimated on the automated Sysmex XN‐series hehmatology analyzer compared with manual differential. These cases were associated with high values of "Neutrophil Reactivity Intensity" (NEUT‐RI), which should reflect the metabolic activity of the neutrophils. Methods: We conducted a three‐stage study to evaluate whether NEUT‐RI could be utilized to screen for misclassified IG% results defined as the manual differential estimating a 10 percentage points higher IG% compared with the automated Sysmex differential. First, 124 patient samples were selected for 800‐cell manual smear analysis based on their NEUT‐RI values and compared with the automatic Sysmex IG% results. Next, 11 098 routine 110‐cell manual smear analyses were compared with the corresponding Sysmex IG% results. Finally, during a 19‐day period 160 additional patient samples underwent smear based on NEUT‐RI values ≥56 fluorescence intensity (FI) to screen for misclassified results beyond our current smear practice. Results: NEUT‐RI ≥56 predicted IG% misclassification with 91% sensitivity and 88% specificity, but primarily when the internal Sysmex flag "Abnormal WBC Scattergram" was present. 90.1% of misclassified results were identified by this flag. Beyond our existing smear rules including this flag, NEUT‐RI ≥56 FI had a positive predictive value below 1%. Conclusion: Both NEUT‐RI and the internal Sysmex flag "Abnormal WBC Scattergram" work well to identify cases of IG% misclassification. However, in our setting NEUT‐RI ≥56 FI had no meaningful additional predictive capacity to identify misclassifications beyond our current smear rules. [ABSTRACT FROM AUTHOR]

Published
2024
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3. Transferability of a European-derived Alzheimer’s Disease Genetic Risk Score across Multi-Ancestry Populations

Author

Nicolas, Aude, primary, Grenier-Boley, Benjamin, additional, Sherva, Richard, additional, Kim, Yoontae, additional, Kikuchi, Masataka, additional, de Rojas, Itziar, additional, Dalmasso, Carolina, additional, Zhou, Xiaopu, additional, Guen, Yann Le, additional, Arboleda-Bustos, Carlos E, additional, Camargos Bicalho, Maria Aparecida, additional, Guerchet, Maëlenn, additional, van der Lee, Sven, additional, Goss, Monica, additional, Castillo, Atahualpa, additional, Bellenguez, Céline, additional, Küçükali, Fahri, additional, Satizabal Barrera, Claudia, additional, Fongang, Bernard, additional, yang, Qiong, additional, Peters, Oliver, additional, Schneider, Anja, additional, Dichgans, Martin, additional, Rujescu, Dan, additional, Scherbaum, Norbert, additional, Deckert, Jürgen, additional, Riedel-Heller, Steffi, additional, Hausner, Lucrezia, additional, Molina Porcel, Laura, additional, Düzel, Emrah, additional, Grimmer, Timo, additional, Wiltfang, Jens, additional, Heilmann-Heimbach, Stefanie, additional, Moebus, Susanne, additional, Tegos, Thomas, additional, Scarmeas, Nikolaos, additional, Dols-Icardo, Oriol, additional, Moreno, Fermin, additional, Pérez-Tur, Jordi, additional, Bullido, María J., additional, Pastor, Pau, additional, Sánchez-Valle, Raquel, additional, Álvarez, Victoria, additional, Cao, Han, additional, Ip, Nancy Y., additional, Fu, Amy K. Y., additional, Ip, Fanny C. F., additional, Olivar, Natividad, additional, Muchnik, Carolina, additional, Cuesta, Carolina, additional, Campanelli, Lorenzo, additional, Solis, Patricia, additional, Politis, Daniel Gustavo, additional, Kochen, Silvia, additional, Brusco, Luis Ignacio, additional, Boada, Mercè, additional, García-González, Pablo, additional, Puerta, Raquel, additional, Mir, Pablo, additional, Real, Luis M, additional, Piñol-Ripoll, Gerard, additional, María García-Alberca, Jose, additional, Luís Royo, Jose, additional, Rodriguez-Rodriguez, Eloy, additional, Soininen, Hilkka, additional, Heikkinen, Sami, additional, de Mendonça, Alexandre, additional, Mehrabian, Shima, additional, Traykov, Latchezar, additional, Hort, Jakub, additional, Vyhnalek, Martin, additional, Rasmussen, Katrine Laura, additional, Qvist Thomassen, Jesper, additional, Pijnenburg, Yolande A.L., additional, Holstege, Henne, additional, van Swieten, John, additional, Ramakers, Inez, additional, Verhey, Frans, additional, van der Lugt, Aad, additional, Scheltens, Philip, additional, Ortega-Rojas, Jenny, additional, Concha Mera, Ana Gabriela, additional, Mahecha, Maria F., additional, Pardo, Rodrogo, additional, Arboleda, Gonzalo, additional, Graff, Caroline, additional, Papenberg, Goran, additional, Giedraitis, Vilmantas, additional, Boland, Anne, additional, Deleuze, Jean-François, additional, Armando de Marco, Luiz, additional, Nunes de Moraes, Edgar, additional, de Viana, Bernardo, additional, Túlio Gualberto Cintra, Marco, additional, Grsiwold, Anthony, additional, Forund, Tatiana, additional, Cruchaga, Carlos, additional, Haines, Jonathan, additional, Farrer, Lindsay, additional, DeStefano, Anita, additional, Wijsman, Ellen, additional, Mayeux, Richard, additional, Pericak-Vance, Margaret, additional, Kunkle, Brian, additional, Goate, Alison, additional, Schellenberg, Gerard D., additional, Vardarajan, Badri, additional, Wang, Li-San, additional, Leung, Yuk Yee, additional, Dalgard, Clifton, additional, Nicolas, Gael, additional, Wallon, David, additional, Dufouil, Carole, additional, Pasquier, Florence, additional, Hanon, Olivier, additional, Debette, Stéphanie, additional, Grünblatt, Edna, additional, Popp, Julius, additional, Angel, Bárbara, additional, Golger, Sergio, additional, Victoria Chacon, Maria, additional, Aranguiz, Rafael, additional, Orellana, Paulina, additional, Slachevsky, Andrea, additional, Gonzalez-Billault, Christian, additional, Albala, Cecilia, additional, Fuentes, Patricio, additional, Porter, Tenielle, additional, Laws, Simon M, additional, Sachdev, Perminder, additional, Mather, Karen, additional, Hauger, Richard L., additional, Merritt, Victoria, additional, Panizzon, Matthew, additional, Zhang, Rui, additional, Gaziano, Michael, additional, Ghidoni, Roberta, additional, Galimberti, Daniela, additional, Arosio, Beatrice, additional, Mecocci, Patrizia, additional, Solfrizzi, Vincenzo, additional, Parnetti, Lucilla, additional, Squassina, Alessio, additional, Tremolizzo, Lucio, additional, Borroni, Barbara, additional, Nacmias, Benedetta, additional, Caffarra, Paolo, additional, Seripa, Davide, additional, Rainero, Innocenzo, additional, Daniele, Antonio, additional, Piras, Fabrizio, additional, Miyashita, Akinori, additional, Hara, Norikazu, additional, Ozaki, Kouichi, additional, Niida, Shumpei, additional, Williams, Julie, additional, Masullo, Carlo, additional, Amouyel, Philippe, additional, Preux, Pierre-Marie, additional, Mbelesso, Pascal, additional, Bandzouzi, Bébène, additional, Saykin, Andy, additional, Jessen, Frank, additional, Kehoe, Patrick, additional, Van Duijn, Cornelia, additional, Gim, Jungsoo, additional, Ben Salem, Nesrine, additional, Frikke-Schmidt, Ruth, additional, Cherni, Lofti, additional, Greicius, Michael D., additional, Tsolaki, Magda, additional, Sánchez-Juan, Pascual, additional, Romano Silva, Marco Aurélio, additional, Sleegers, Kristel, additional, Ingelsson, Martin, additional, Dartigues, Jean-François, additional, Seshadri, Sudha, additional, Rossi, Giacomina, additional, Morelli, Laura, additional, Hiltunen, Mikko, additional, Sims, Rebecca, additional, van der Flier, Wiesje, additional, Andreassen, Ole, additional, Arboleda, Humberto, additional, Escott-Price, Valentina, additional, Ruiz, Agustín, additional, Lee, Kun Ho, additional, Ikeuchi, Takeshi, additional, Ramirez, Alfredo, additional, Logue, Mark, additional, and Lambert, Jean-Charles, additional

Published
2023
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8. Rare missense variant (R251G) on APOE counterbalances the Alzheimer’s disease risk associated with APOE‐ε4

Author

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

Published
2022
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10. 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

14. Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer’s Disease Pathology

Author

Shi, Liu, primary, Winchester, Laura M., additional, Liu, Benjamine Y., additional, Killick, Richard, additional, Ribe, Elena M., additional, Westwood, Sarah, additional, Baird, Alison L., additional, Buckley, Noel J., additional, Hong, Shengjun, additional, Dobricic, Valerija, additional, Kilpert, Fabian, additional, Franke, Andre, additional, Kiddle, Steven, additional, Sattlecker, Martina, additional, Dobson, Richard, additional, Cuadrado, Antonio, additional, Hye, Abdul, additional, Ashton, Nicholas J., additional, Morgan, Angharad R., additional, Bos, Isabelle, additional, Vos, Stephanie J.B., additional, ten Kate, Mara, additional, Scheltens, Philip, additional, Vandenberghe, Rik, additional, Gabel, Silvy, additional, Meersmans, Karen, additional, Engelborghs, Sebastiaan, additional, De Roeck, Ellen E., additional, Sleegers, Kristel, additional, Frisoni, Giovanni B., additional, Blin, Olivier, additional, Richardson, Jill C., additional, Bordet, Régis, additional, Molinuevo, José L., additional, Rami, Lorena, additional, Wallin, Anders, additional, Kettunen, Petronella, additional, Tsolaki, Magda, additional, Verhey, Frans, additional, Lleó, Alberto, additional, Alcolea, Daniel, additional, Popp, Julius, additional, Peyratout, Gwendoline, additional, Martinez-Lage, Pablo, additional, Tainta, Mikel, additional, Johannsen, Peter, additional, Teunissen, Charlotte E., additional, Freund-Levi, Yvonne, additional, Frölich, Lutz, additional, Legido-Quigley, Cristina, additional, Barkhof, Frederik, additional, Blennow, Kaj, additional, Rasmussen, Katrine Laura, additional, Nordestgaard, Børge Grønne, additional, Frikke-Schmidt, Ruth, additional, Nielsen, Sune Fallgaard, additional, Soininen, Hilkka, additional, Vellas, Bruno, additional, Kloszewska, Iwona, additional, Mecocci, Patrizia, additional, Zetterberg, Henrik, additional, Morgan, B. Paul, additional, Streffer, Johannes, additional, Visser, Pieter Jelle, additional, Bertram, Lars, additional, Nevado-Holgado, Alejo J., additional, and Lovestone, Simon, additional

Published
2020
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16. Impact of cardiovascular risk factors and genetics on 10-year absolute risk of dementia: risk charts for targeted prevention.

Author

Rasmussen, Ida Juul, Rasmussen, Katrine Laura, Nordestgaard, Børge G, Tybjærg-Hansen, Anne, and Frikke-Schmidt, Ruth

Subjects
DEMENTIA risk factors, DEMENTIA prevention, CARDIOVASCULAR diseases risk factors, MEDICAL genetics, APOLIPOPROTEIN E
Abstract

Aims Dementia is a major global challenge for health and social care in aging populations. A third of all dementia may be preventable due to cardiovascular risk factors. Intensive multi-domain intervention trials targeting primarily cardiovascular risk factors show improved cognitive function in people at risk. Such interventions will, however, be expensive to implement in all individuals at risk and will represent unrealistic economic tasks for most societies. Therefore, a risk score identifying high-risk individuals is warranted. Methods and results In 61 664 individuals from two prospective cohorts of the Danish general population, we generated 10-year absolute risk scores for all-cause dementia from cardiovascular risk factors and genetics. In both sexes, 10-year absolute risk of all-cause dementia increased with increasing age, number of apolipoprotein E (APOE) ɛ4 alleles, number of genome-wide association studies (GWAS) risk alleles, and cardiovascular risk factors. The highest 10-year absolute risks of all-cause dementia seen in smoking women with diabetes, low education, APOE ɛ44 genotype, and 22–31 GWAS risk alleles were 6%, 23%, 48%, and 66% in those aged 50–59, 60–69, 70–79, and 80–100, respectively. Corresponding values for men were 5%, 19%, 42%, and 60%, respectively. Conclusion Ten-year absolute risk of all-cause dementia increased with age, APOE ɛ4 alleles, GWAS risk alleles, diabetes, low education, and smoking in both women and men. Ten-year absolute risk charts for dementia will facilitate identification of high-risk individuals, those who likely will benefit the most from an early intervention against cardiovascular risk factors. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Published
2020
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18. 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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20. [Diabetic retinopathy during pregnancy].

Author

Rasmussen KL, Laugesen CS, Datta N, Damm P, and Mathiesen ER

Subjects
Adult, Diabetes Mellitus, Type 1 complications, Diabetes Mellitus, Type 2 complications, Diabetic Retinopathy complications, Disease Progression, Female, Fluorescein Angiography, Humans, Pregnancy, Risk Factors, Diabetic Retinopathy diagnosis, Pregnancy Complications, Cardiovascular diagnosis, Pregnancy in Diabetics
Abstract

Introduction: The aim was to evaluate the prevalence and progression of diabetic retinopathy during pregnancy in women with type 1 or type 2 diabetes., Material and Methods: Dilated fundal photography was performed at approximately 10 and 28 gestational weeks in 58 and 18 women with type 1 and type 2 diabetes, respectively. Retinopathy was classified as five stages +/- macular oedema. Progression was defined as deterioration corresponding to at least one stage between the two examinations. Clinical parameters were obtained from the medical records., Results: Diabetic retinopathy was found in 36 (62%) women with type 1 and three (17%) with type 2 diabetes at the first examination. In 26 (34%) retinopathy progressed; four women developed proliferations, three macular oedema and three reduction of visual acuity >/=0.2 on Snellen's chart in at least one eye. HbA1c in early pregnancy was the only significant predictor of progression (odds ratio = 1.75, 95% confidence interval = 1.09-2.82). Progression of retinopathy also tended to be associated with type 1 diabetes and long diabetes duration., Conclusion: The risk of progression of diabetic retinopathy during pregnancy was considerable, especially among women with high HbA1c values in early pregnancy. A few women developed proliferations, macular oedema and reduction of visual acuity. Development of sight-threatening alterations during pregnancy remains a clinical problem.

Published
2008

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