Browsing by Author "Saltvedt, Ingvild"

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    Genetic associations with psychosis and affective disturbance in Alzheimer's disease
    (Wiley, 2024-05-23) Antonsdottir, Inga Margret; Creese, Byron; Klei, Lambertus; DeMichele-Sweet, Mary Ann A.; Weamer, Elise A.; Garcia-Gonzalez, Pablo; Marquie, Marta; Boada, Mercè; Alarcón-Martín, Emilio; Valero, Sergi; NIA-LOAD Family Based Study Consortium; Alzheimer's Disease Genetics Consortium (ADGC); AddNeuroMed Consortium; Liu, Yushi; Hooli, Basavaraj; Aarsland, Dag; Selbaek, Geir; Bergh, Sverre; Rongve, Arvid; Saltvedt, Ingvild; Skjellegrind, Håvard K.; Engdahl, Bo; Andreassen, Ole A.; Borroni, Barbara; Mecocci, Patrizia; Wedatilake, Yehani; Mayeux, Richard; Foroud, Tatiana; Ruiz, Agustín; Lopez, Oscar L.; Kamboh, M. Ilyas; Ballard, Clive; Devlin, Bernie; Lyketsos, Constantine; Sweet, Robert A.; Medical and Molecular Genetics, School of Medicine
    Introduction: Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes. Methods: Genome-wide association meta-analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P). Results: AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. AD+P was negatively genetically correlated with bipolar disorder and positively with depressive symptoms. AD+A was positively correlated with anxiety disorder and more strongly correlated than AD+P with depressive symptoms. AD+P and AD+A+P had significant estimated heritability, whereas AD+A did not. Examination of the loci most strongly associated with the three phenotypes revealed overlapping and unique associations. Discussion: AD+P, AD+A, and AD+A+P have both shared and divergent genetic associations pointing to the importance of incorporating genetic insights into future treatment development. Highlights: It has long been known that psychotic and affective symptoms are often comorbid in individuals diagnosed with Alzheimer's disease. Here we examined for the first time the genetic architecture underlying this clinical observation, determining that psychotic and affective phenotypes in Alzheimer's disease are genetically correlated. Nevertheless, psychotic and affective phenotypes in Alzheimer's disease diverged in their genetic correlations with psychiatric phenotypes assessed in individuals without Alzheimer's disease. Psychosis in Alzheimer's disease was negatively genetically correlated with bipolar disorder and positively with depressive symptoms, whereas the affective phenotypes in Alzheimer's disease were positively correlated with anxiety disorder and more strongly correlated than psychosis with depressive symptoms. Psychosis in Alzheimer's disease, and the joint psychotic and affective phenotype, had significant estimated heritability, whereas the affective in AD did not. Examination of the loci most strongly associated with the psychotic, affective, or joint phenotypes revealed overlapping and unique associations.
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    Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease
    (Springer Nature, 2021) DeMichele-Sweet, Mary Ann A.; Klei, Lambertus; Creese, Byron; Harwood, Janet C.; Weamer, Elise A.; McClain, Lora; Sims, Rebecca; Hernandez, Isabel; Moreno-Grau, Sonia; Tárraga, Lluís; Boada, Mercè; Alarcón-Martín, Emilio; Valero, Sergi; NIA-LOAD Family Based Study Consortium; Alzheimer’s Disease Genetics Consortium (ADGC); Liu, Yushi; Hooli, Basavaraj; Aarsland, Dag; Selbaek, Geir; Bergh, Sverre; Rongve, Arvid; Saltvedt, Ingvild; Skjellegrind, Håvard K.; Engdahl, Bo; Stordal, Eystein; Andreassen, Ole A.; Djurovic, Srdjan; Athanasiu, Lavinia; Seripa, Davide; Borroni, Barbara; Albani, Diego; Forloni, Gianluigi; Mecocci, Patrizia; Serretti, Alessandro; De Ronchi, Diana; Politis, Antonis; Williams, Julie; Mayeux, Richard; Foroud, Tatiana; Ruiz, Agustín; Ballard, Clive; Holmans, Peter; Lopez, Oscar L.; Kamboh, M. Ilyas; Devlin, Bernie; Sweet, Robert A.; Medical and Molecular Genetics, School of Medicine
    Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10-8) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10-8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.
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    New insights into the genetic etiology of Alzheimer's disease and related dementias
    (Springer Nature, 2022) Bellenguez, Céline; Küçükali, Fahri; Jansen, Iris E.; Kleineidam, Luca; Moreno-Grau, Sonia; Amin, Najaf; Naj, Adam C.; Campos-Martin, Rafael; Grenier-Boley, Benjamin; Andrade, Victor; Holmans, Peter A.; Boland, Anne; Damotte, Vincent; van der Lee, Sven J.; Costa, Marcos R.; Kuulasmaa, Teemu; Yang, Qiong; de Rojas, Itziar; Bis, Joshua C.; Yaqub, Amber; Prokic, Ivana; Chapuis, Julien; Ahmad, Shahzad; Giedraitis, Vilmantas; Aarsland, Dag; Garcia-Gonzalez, Pablo; Abdelnour, Carla; Alarcón-Martín, Emilio; Alcolea, Daniel; Alegret, Montserrat; Alvarez, Ignacio; Álvarez, Victoria; Armstrong, Nicola J.; Tsolaki, Anthoula; Antúnez, Carmen; Appollonio, Ildebrando; Arcaro, Marina; Archetti, Silvana; Arias Pastor, Alfonso; Arosio, Beatrice; Athanasiu, Lavinia; Bailly, Henri; Banaj, Nerisa; Baquero, Miquel; Barral, Sandra; Beiser, Alexa; Belén Pastor, Ana; Below, Jennifer E.; Benchek, Penelope; Benussi, Luisa; Berr, Claudine; Besse, Céline; Bessi, Valentina; Binetti, Giuliano; Bizarro, Alessandra; Blesa, Rafael; Boada, Mercè; Boerwinkle, Eric; Borroni, Barbara; Boschi, Silvia; Bossù, Paola; Bråthen, Geir; Bressler, Jan; Bresner, Catherine; Brodaty, Henry; Brookes, Keeley J.; Brusco, Luis Ignacio; Buiza-Rueda, Dolores; Bûrger, Katharina; Burholt, Vanessa; Bush, William S.; Calero, Miguel; Cantwell, Laura B.; Chene, Geneviève; Chung, Jaeyoon; Cuccaro, Michael L.; Carracedo, Ángel; Cecchetti, Roberta; Cervera-Carles, Laura; Charbonnier, Camille; Chen, Hung-Hsin; Chillotti, Caterina; Ciccone, Simona; Claassen, Jurgen A. H. R.; Clark, Christopher; Conti, Elisa; Corma-Gómez, Anaïs; Costantini, Emanuele; Custodero, Carlo; Daian, Delphine; Dalmasso, Maria Carolina; Daniele, Antonio; Dardiotis, Efthimios; Dartigues, Jean-François; de Deyn, Peter Paul; de Paiva Lopes, Katia; de Witte, Lot D.; Debette, Stéphanie; Deckert, Jürgen; Del Ser, Teodoro; Denning, Nicola; DeStefano, Anita; Dichgans, Martin; Diehl-Schmid, Janine; Diez-Fairen, Mónica; Dionigi Rossi, Paolo; Djurovic, Srdjan; Duron, Emmanuelle; Düzel, Emrah; Dufouil, Carole; Eiriksdottir, Gudny; Engelborghs, Sebastiaan; Escott-Price, Valentina; Espinosa, Ana; Ewers, Michael; Faber, Kelley M.; Fabrizio, Tagliavini; Fallgaard Nielsen, Sune; Fardo, David W.; Farotti, Lucia; Fenoglio, Chiara; Fernández-Fuertes, Marta; Ferrari, Raffaele; Ferreira, Catarina B.; Ferri, Evelyn; Fin, Bertrand; Fischer, Peter; Fladby, Tormod; Fließbach, Klaus; Fongang, Bernard; Fornage, Myriam; Fortea, Juan; Foroud, Tatiana M.; Fostinelli, Silvia; Fox, Nick C.; Franco-Macías, Emlio; Bullido, María J.; Frank-García, Ana; Froelich, Lutz; Fulton-Howard, Brian; Galimberti, Daniela; García-Alberca, Jose Maria; García-González, Pablo; Garcia-Madrona, Sebastian; Garcia-Ribas, Guillermo; Ghidoni, Roberta; Giegling, Ina; Giorgio, Giaccone; Goate, Alison M.; Goldhardt, Oliver; Gomez-Fonseca, Duber; González-Pérez, Antonio; Graff, Caroline; Grande, Giulia; Green, Emma; Grimmer, Timo; Grünblatt, Edna; Grunin, Michelle; Gudnason, Vilmundur; Guetta-Baranes, Tamar; Haapasalo, Annakaisa; Hadjigeorgiou, Georgios; Haines, Jonathan L.; Hamilton-Nelson, Kara L.; Hampel, Harald; Hanon, Olivier; Hardy, John; Hartmann, Annette M.; Hausner, Lucrezia; Harwood, Janet; Heilmann-Heimbach, Stefanie; Helisalmi, Seppo; Heneka, Michael T.; Hernández, Isabel; Herrmann, Martin J.; Hoffmann, Per; Holmes, Clive; Holstege, Henne; Huerto Vilas, Raquel; Hulsman, Marc; Humphrey, Jack; Jan Biessels, Geert; Jian, Xueqiu; Johansson, Charlotte; Jun, Gyungah R.; Kastumata, Yuriko; Kauwe, John; Kehoe, Patrick G.; Kilander, Lena; Kinhult Ståhlbom, Anne; Kivipelto, Miia; Koivisto, Anne; Kornhuber, Johannes; Kosmidis, Mary H.; Kukull, Walter A.; Kuksa, Pavel P.; Kunkle, Brian W.; Kuzma, Amanda B.; Lage, Carmen; Laukka, Erika J.; Launer, Lenore; Lauria, Alessandra; Lee, Chien-Yueh; Lehtisalo, Jenni; Lerch, Ondrej; Lleó, Alberto; Longstreth, William, Jr.; Lopez, Oscar; Lopez de Munain, Adolfo; Love, Seth; Löwemark, Malin; Luckcuck, Lauren; Lunetta, Kathryn L.; Ma, Yiyi; Macías, Juan; MacLeod, Catherine A.; Maier, Wolfgang; Mangialasche, Francesca; Spallazzi, Marco; Marquié, Marta; Marshall, Rachel; Martin, Eden R.; Martín Montes, Angel; Martínez Rodríguez, Carmen; Masullo, Carlo; Mayeux, Richard; Mead, Simon; Mecocci, Patrizia; Medina, Miguel; Meggy, Alun; Mehrabian, Shima; Mendoza, Silvia; Menéndez-González, Manuel; Mir, Pablo; Moebus, Susanne; Mol, Merel; Molina-Porcel, Laura; Montrreal, Laura; Morelli, Laura; Moreno, Fermin; Morgan, Kevin; Mosley, Thomas; Nöthen, Markus M.; Muchnik, Carolina; Mukherjee, Shubhabrata; Nacmias, Benedetta; Ngandu, Tiia; Nicolas, Gael; Nordestgaard, Børge G.; Olaso, Robert; Orellana, Adelina; Orsini, Michela; Ortega, Gemma; Padovani, Alessandro; Paolo, Caffarra; Papenberg, Goran; Parnetti, Lucilla; Pasquier, Florence; Pastor, Pau; Peloso, Gina; Pérez-Cordón, Alba; Pérez-Tur, Jordi; Pericard, Pierre; Peters, Oliver; Pijnenburg, Yolande A. L.; Pineda, Juan A.; Piñol-Ripoll, Gerard; Pisanu, Claudia; Polak, Thomas; Popp, Julius; Posthuma, Danielle; Priller, Josef; Puerta, Raquel; Quenez, Olivier; Quintela, Inés; Qvist Thomassen, Jesper; Rábano, Alberto; Rainero, Innocenzo; Rajabli, Farid; Ramakers, Inez; Real, Luis M.; Reinders, Marcel J. T.; Reitz, Christiane; Reyes-Dumeyer, Dolly; Ridge, Perry; Riedel-Heller, Steffi; Riederer, Peter; Roberto, Natalia; Rodriguez-Rodriguez, Eloy; Rongve, Arvid; Rosas Allende, Irene; Rosende-Roca, Maitée; Royo, Jose Luis; Rubino, Elisa; Rujescu, Dan; Sáez, María Eugenia; Sakka, Paraskevi; Saltvedt, Ingvild; Sanabria, Ángela; Sánchez-Arjona, María Bernal; Sanchez-Garcia, Florentino; Sánchez Juan, Pascual; Sánchez-Valle, Raquel; Sando, Sigrid B.; Sarnowski, Chloé; Satizabal, Claudia L.; Scamosci, Michela; Scarmeas, Nikolaos; Scarpini, Elio; Scheltens, Philip; Scherbaum, Norbert; Scherer, Martin; Schmid, Matthias; Schneider, Anja; Schott, Jonathan M.; Selbæk, Geir; Seripa, Davide; Serrano, Manuel; Sha, Jin; Shadrin, Alexey A.; Skrobot, Olivia; Slifer, Susan; Snijders, Gijsje J. L.; Soininen, Hilkka; Solfrizzi, Vincenzo; Solomon, Alina; Song, Yeunjoo; Sorbi, Sandro; Sotolongo-Grau, Oscar; Spalletta, Gianfranco; Spottke, Annika; Squassina, Alessio; Stordal, Eystein; Tartan, Juan Pablo; Tárraga, Lluís; Tesí, Niccolo; Thalamuthu, Anbupalam; Thomas, Tegos; Tosto, Giuseppe; Traykov, Latchezar; Tremolizzo, Lucio; Tybjærg-Hansen, Anne; Uitterlinden, Andre; Ullgren, Abbe; Ulstein, Ingun; Valero, Sergi; Valladares, Otto; Van Broeckhoven, Christine; Vance, Jeffery; Vardarajan, Badri N.; van der Lugt, Aad; Van Dongen, Jasper; van Rooij, Jeroen; van Swieten, John; Vandenberghe, Rik; Verhey, Frans; Vidal, Jean-Sébastien; Vogelgsang, Jonathan; Vyhnalek, Martin; Wagner, Michael; Wallon, David; Wang, Li-San; Wang, Ruiqi; Weinhold, Leonie; Wiltfang, Jens; Windle, Gill; Woods, Bob; Yannakoulia, Mary; Zare, Habil; Zhao, Yi; Zhang, Xiaoling; Zhu, Congcong; Zulaica, Miren; EADB; GR@ACE; DEGESCO; EADI; GERAD; Demgene; FinnGen; ADGC; CHARGE; Farrer, Lindsay A.; Psaty, Bruce M.; Ghanbari, Mohsen; Raj, Towfique; Sachdev, Perminder; Mather, Karen; Jessen, Frank; Ikram, M. Arfan; de Mendonça, Alexandre; Hort, Jakub; Tsolaki, Magda; Pericak-Vance, Margaret A.; Amouyel, Philippe; Williams, Julie; Frikke-Schmidt, Ruth; Clarimon, Jordi; Deleuze, Jean-François; Rossi, Giacomina; Seshadri, Sudha; Andreassen, Ole A.; Ingelsson, Martin; Hiltunen, Mikko; Sleegers, Kristel; Schellenberg, Gerard D.; van Duijn, Cornelia M.; Sims, Rebecca; van der Flier, Wiesje M.; Ruiz, Agustín; Ramirez, Alfredo; Lambert, Jean-Charles; Medical and Molecular Genetics, School of Medicine
    Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
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    Predicting the Emergence of Major Neurocognitive Disorder Within Three Months After a Stroke
    (Frontiers Media, 2021-08-16) Aamodt, Eva Birgitte; Schellhorn, Till; Stage, Edwin; Sanjay, Apoorva Bharthur; Logan, Paige E.; Otero Svaldi, Diana; Apostolova, Liana G.; Saltvedt, Ingvild; Kristiansen Beyer, Mona; Neurology, School of Medicine
    Background: Neurocognitive disorder (NCD) is common after stroke, with major NCD appearing in about 10% of survivors of a first-ever stroke. We aimed to classify clinical- and imaging factors related to rapid development of major NCD 3 months after a stroke, so as to examine the optimal composition of factors for predicting rapid development of the disorder. We hypothesized that the prediction would mainly be driven by neurodegenerative as opposed to vascular brain changes. Methods: Stroke survivors from five Norwegian hospitals were included from the “Norwegian COgnitive Impairment After STroke” (Nor-COAST) study. A support vector machine (SVM) classifier was trained to distinguish between patients who developed major NCD 3 months after the stroke and those who did not. Potential predictor factors were based on previous literature and included both vascular and neurodegenerative factors from clinical and structural magnetic resonance imaging findings. Cortical thickness was obtained via FreeSurfer segmentations, and volumes of white matter hyperintensities (WMH) and stroke lesions were semi-automatically gathered using FSL BIANCA and ITK-SNAP, respectively. The predictive value of the classifier was measured, compared between classifier models and cross-validated. Results: Findings from 227 stroke survivors [age = 71.7 (11.3), males = (56.4%), stroke severity NIHSS = 3.8 (4.8)] were included. The best predictive accuracy (AUC = 0.876) was achieved by an SVM classifier with 19 features. The model with the fewest number of features that achieved statistically comparable accuracy (AUC = 0.850) was the 8-feature model. These features ranked by their weighting were; stroke lesion volume, WMH volume, left occipital and temporal cortical thickness, right cingulate cortical thickness, stroke severity (NIHSS), antiplatelet medication intake, and education. Conclusion: The rapid (<3 months) development of major NCD after stroke is possible to predict with an 87.6% accuracy and seems dependent on both neurodegenerative and vascular factors, as well as aspects of the stroke itself. In contrast to previous literature, we also found that vascular changes are more important than neurodegenerative ones. Although possible to predict with relatively high accuracy, our findings indicate that the development of rapid onset post-stroke NCD may be more complex than earlier suggested.