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Item Convergent genetic and expression data implicate immunity in Alzheimer's disease(Elsevier, 2015-06) Jones, Lesley; Lambert, Jean-Charles; Wang, Li-San; Choi, Seung-Hoan; Harold, Denise; Vedernikov, Alexey; Escott-Price, Valentina; Stone, Timothy; Richards, Alexander; Bellenguez, Céline; Ibrahim-Verbaas, Carla A.; Naj, Adam C.; Sims, Rebecca; Gerrish, Amy; Jun, Gyungah; DeStefano, Anita L.; Bis, Joshua C.; Beecham, Gary W.; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A.; Jones, Nicola; Smith, Albert V.; Chouraki, Vincent; Thomas, Charlene; Ikram, M. Arfan; Zelenika, Diana; Vardarajan, Badri N.; Kamatani, Yoichiro; Lin, Chiao-Feng; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L.; Ruiz, Agustin; Bihoreau, Marie-Thérèse; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Hanon, Olivier; Fitzpatrick, Annette L.; Buxbaum, Joseph D.; Campion, Dominique; Crane, Paul K.; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L.; De Jager, Philip L.; Deramecourt, Vincent; Johnston, Janet A.; Evans, Denis; Lovestone, Simon; Letteneur, Luc; Kornhuber, Johanes; Tárraga, Lluís; Rubinsztein, David C.; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M.; Fiévet, Nathalie; Huentelman, Matthew J.; Gill, Michael; Emilsson, Valur; Brown, Kristelle; Kamboh, M. Ilyas; Keller, Lina; Barberger-Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B.; Myers, Amanda J.; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Kehoe, Pat; Rogaeva, Ekaterina; Gallacher, John; George-Hyslop, Peter St; Clarimon, Jordi; Lleὀ, Alberti; Bayer, Anthony; Tsuang, Debby W.; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petra; Collinge, John; Sorbi, Sandro; Garcia, Florentino Sanchez; Fox, Nick; Hardy, John; Naranjo, Maria Candida Deniz; Razquin, Cristina; Bosco, Paola; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Mancuso, Michelangelo; Moebus, Susanne; Mecocci, Patrizia; del Zompo, Maria; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Bullido, Maria; Panza, Francesco; Caffarra, Paolo; Nacmias, Benedetta; Gilbert, John R.; Mayhaus, Manuel; Jessen, Frank; Dichgans, Martin; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M.; Ingelsson, Martin; Beekly, Duane; Alavarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G.; Coto, Eliecer; Hamilton-Nelson, Kara L.; Mateo, Ignacio; Owen, Michael J.; Faber, Kelley M.; Jonsson, Palmi V.; Combarros, Onofre; O'Donovan, Michael C.; Cantwell, Laura B.; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H.; Bennett, David A.; Harris, Tamara B.; Fratiglioni, Laura; Holmes, Clive; de Bruijn, Renee FAG; Passmore, Peter; Montine, Thomas J.; Bettens, Karolien; Rotter, Jerome I.; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M.; Kukull, Walter A.; Hannequin, Didier; Powell, John F.; Nalls, Michael A.; Ritchie, Karen; Lunetta, Kathryn L.; Kauwe, John SK; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R.; Pastor, Pau; Schmidt, Reinhold; Rujescu, Dan; Dartigues, Jean-François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M.; Graff, Caroline; Psaty, Bruce M.; Haines, Jonathan L.; Lathrop, Mark; Pericak-Vance, Margaret A.; Launer, Lenore J.; Farrer, Lindsay A.; van Duijn, Cornelia M.; Van Broekhoven, Christine; Ramirez, Alfredo; Schellenberg, Gerard D.; Seshadri, Sudha; Amouyel, Philippe; Williams, Julie; Holmans, Peter A.; Department of Medical & Molecular Genetics, IU School of MedicineBackground Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics.Item Genetic Risk for Schizophrenia and Psychosis in Alzheimer Disease(Nature Publishing group, 2018-04) DeMichele-Sweet, Mary Ann A.; Weamer, Elise A.; Klei, Lambertus; Vrana, Dylan T.; Hollingshead, Deborah J.; Seltman, Howard J.; Sims, Rebecca; Foroud, Tatiana; Hernandez, Isabel; Moreno-Grau, Sonia; Tárraga, Lluís; Boada, Mercè; Ruiz, Agustin; Williams, Julie; Mayeux, Richard; Lopez, Oscar L.; Sibille, Etienne L.; Kamboh, M. Ilyas; Devlin, Bernie; Sweet, Robert A.; Medical and Molecular Genetics, School of MedicinePsychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer Disease, affecting ~ 40% to 60% of individuals with AD (AD with psychosis, AD+P). In comparison to AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate SNPs with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and Alzheimer disease. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy, and calcium channel signaling. These findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.Item 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 MedicinePsychotic 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.Item 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 MedicineCharacterization 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.Item Subjective Cognitive Decline in Older Adults: An Overview of Self-Report Measures Used Across 19 International Research Studies(IOS Press, 2015-09-24) Rabin, Laura A.; Smart, Colette M.; Crane, Paul K.; Amariglio, Rebecca E.; Berman, Lorin M.; Boada, Mercè; Buckley, Rachel F.; Chételat, Gaël; Dubois, Bruno; Ellis, Kathryn A.; Gifford, Katherine A.; Jefferson, Angela L.; Jessen, Frank; Katz, Mindy J.; Lipton, Richard B.; Luck, Tobias; Maruff, Paul; Mielke, Michelle M.; Molinuevo, José Luis; Naeem, Farnia; Perrotin, Audrey; Petersen, Ronald C.; Rami, Lorena; Reisberg, Barry; Rentz, Dorene M.; Riedel-Heller, Stefi G.; Risacher, Shannon L.; Rodriguez, Octavio; Sachdev, Perminder S.; Saykin, Andrew J.; Slavin, Melissa J.; Snitz, Beth E.; Sperling, Reisa A.; Tandetnik, Caroline; van der Flier, Wiesje M.; Wagner, Michael; Wolfsgruber, Steffen; Sikkes, Sietske A.M.; Department of Radiology and Imaging Sciences, IU School of MedicineResearch increasingly suggests that subjective cognitive decline (SCD) in older adults, in the absence of objective cognitive dysfunction or depression, may be a harbinger of non-normative cognitive decline and eventual progression to dementia. Little is known, however, about the key features of self-report measures currently used to assess SCD. The Subjective Cognitive Decline Initiative (SCD-I) Working Group is an international consortium established to develop a conceptual framework and research criteria for SCD (Jessen et al., 2014, Alzheimers Dement 10, 844-852). In the current study we systematically compared cognitive self-report items used by 19 SCD-I Working Group studies, representing 8 countries and 5 languages. We identified 34 self-report measures comprising 640 cognitive self-report items. There was little overlap among measures- approximately 75% of measures were used by only one study. Wide variation existed in response options and item content. Items pertaining to the memory domain predominated, accounting for about 60% of items surveyed, followed by executive function and attention, with 16% and 11% of the items, respectively. Items relating to memory for the names of people and the placement of common objects were represented on the greatest percentage of measures (56% each). Working group members reported that instrument selection decisions were often based on practical considerations beyond the study of SCD specifically, such as availability and brevity of measures. Results document the heterogeneity of approaches across studies to the emerging construct of SCD. We offer preliminary recommendations for instrument selection and future research directions including identifying items and measure formats associated with important clinical outcomesItem Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease(2018-01) Honig, Lawrence S.; Vellas, Bruno; Woodward, Michael; Boada, Mercè; Bullock, Roger; Borrie, Michael; Hager, Klaus; Andreasen, Niels; Scarpini, Elio; Liu‑Seifert, Hong; Case, Michael; Dean, Robert A.; Hake, Ann; Sundell, Karen; Hoffmann, Vicki Poole; Carlson, Christopher; Khanna, Rashna; Mintun, Mark; DeMattos, Ronald; Selzler, Katherine J.; Siemers, Eric; Pathology and Laboratory Medicine, School of MedicineBACKGROUND Alzheimer’s disease is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid. METHODS We conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild dementia due to Alzheimer’s disease, defined as a Mini–Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron-emission tomography or Aβ1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). RESULTS A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS-cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference at week 80 (difference, −0.80; 95% confidence interval, −1.73 to 0.14; P=0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was −3.17 in the solanezumab group and −3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group. CONCLUSIONS Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer’s disease did not significantly affect cognitive decline.