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2. Author Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Author

Kunkle, Brian W., Grenier-Boley, Benjamin, Sims, Rebecca, Bis, Joshua C., Damotte, Vincent, Naj, Adam C., Boland, Anne, Vronskaya, Maria, van der Lee, Sven J., Amlie-Wolf, Alexandre, Bellenguez, Céline, Frizatti, Aura, Chouraki, Vincent, Martin, Eden R., Sleegers, Kristel, Badarinarayan, Nandini, Jakobsdottir, Johanna, Hamilton-Nelson, Kara L., Moreno-Grau, Sonia, Olaso, Robert, Raybould, Rachel, Chen, Yuning, Kuzma, Amanda B., Hiltunen, Mikko, Morgan, Taniesha, Ahmad, Shahzad, Vardarajan, Badri N., Epelbaum, Jacques, Hoffmann, Per, Boada, Merce, Beecham, Gary W., Garnier, Jean-Guillaume, Harold, Denise, Fitzpatrick, Annette L., Valladares, Otto, Moutet, Marie-Laure, Gerrish, Amy, Smith, Albert V., Qu, Liming, Bacq, Delphine, Denning, Nicola, Jian, Xueqiu, Zhao, Yi, Del Zompo, Maria, Fox, Nick C., Choi, Seung-Hoan, Mateo, Ignacio, Hughes, Joseph T., Adams, Hieab H., Malamon, John, Sanchez-Garcia, Florentino, Patel, Yogen, Brody, Jennifer A., Dombroski, Beth A., Naranjo, Maria Candida Deniz, Daniilidou, Makrina, Eiriksdottir, Gudny, Mukherjee, Shubhabrata, Wallon, David, Uphill, James, Aspelund, Thor, Cantwell, Laura B., Garzia, Fabienne, Galimberti, Daniela, Hofer, Edith, Butkiewicz, Mariusz, Fin, Bertrand, Scarpini, Elio, Sarnowski, Chloe, Bush, Will S., Meslage, Stéphane, Kornhuber, Johannes, White, Charles C., Song, Yuenjoo, Barber, Robert C., Engelborghs, Sebastiaan, Sordon, Sabrina, Voijnovic, Dina, Adams, Perrie M., Vandenberghe, Rik, Mayhaus, Manuel, Cupples, L. Adrienne, Albert, Marilyn S., De Deyn, Peter P., Gu, Wei, Himali, Jayanadra J., Beekly, Duane, Squassina, Alessio, Hartmann, Annette M., Orellana, Adelina, Blacker, Deborah, Rodriguez-Rodriguez, Eloy, Lovestone, Simon, Garcia, Melissa E., Doody, Rachelle S., Munoz-Fernadez, Carmen, Sussams, Rebecca, Lin, Honghuang, Fairchild, Thomas J., Benito, Yolanda A., Holmes, Clive, Karamujić-Čomić, Hata, Frosch, Matthew P., Thonberg, Hakan, Maier, Wolfgang, Roshchupkin, Gennady, Ghetti, Bernardino, Giedraitis, Vilmantas, Kawalia, Amit, Li, Shuo, Huebinger, Ryan M., Kilander, Lena, Moebus, Susanne, Hernández, Isabel, Kamboh, M. Ilyas, Brundin, RoseMarie, Turton, James, Yang, Qiong, Katz, Mindy J., Concari, Letizia, Lord, Jenny, Beiser, Alexa S., Keene, C. Dirk, Helisalmi, Seppo, Kloszewska, Iwona, Kukull, Walter A., Koivisto, Anne Maria, Lynch, Aoibhinn, Tarraga, Lluís, Larson, Eric B., Haapasalo, Annakaisa, Lawlor, Brian, Mosley, Thomas H., Lipton, Richard B., Solfrizzi, Vincenzo, Gill, Michael, Longstreth, Jr, W. T., Montine, Thomas J., Frisardi, Vincenza, Diez-Fairen, Monica, Rivadeneira, Fernando, Petersen, Ronald C., Deramecourt, Vincent, Alvarez, Ignacio, Salani, Francesca, Ciaramella, Antonio, Boerwinkle, Eric, Reiman, Eric M., Fievet, Nathalie, Rotter, Jerome I., Reisch, Joan S., Hanon, Olivier, Cupidi, Chiara, Uitterlinden, A. G. Andre, Royall, Donald R., Dufouil, Carole, Maletta, Raffaele Giovanni, de Rojas, Itziar, Sano, Mary, Brice, Alexis, Cecchetti, Roberta, George-Hyslop, Peter St, Ritchie, Karen, Tsolaki, Magda, Tsuang, Debby W., Dubois, Bruno, Craig, David, Wu, Chuang-Kuo, Soininen, Hilkka, Avramidou, Despoina, Albin, Roger L., Fratiglioni, Laura, Germanou, Antonia, Apostolova, Liana G., Keller, Lina, Koutroumani, Maria, Arnold, Steven E., Panza, Francesco, Gkatzima, Olymbia, Asthana, Sanjay, Hannequin, Didier, Whitehead, Patrice, Atwood, Craig S., Caffarra, Paolo, Hampel, Harald, Quintela, Inés, Carracedo, Ángel, Lannfelt, Lars, Rubinsztein, David C., Barnes, Lisa L., Pasquier, Florence, Frölich, Lutz, Barral, Sandra, McGuinness, Bernadette, Beach, Thomas G., Johnston, Janet A., Becker, James T., Passmore, Peter, Bigio, Eileen H., Schott, Jonathan M., Bird, Thomas D., Warren, Jason D., Boeve, Bradley F., Lupton, Michelle K., Bowen, James D., Proitsi, Petra, Boxer, Adam, Powell, John F., Burke, James R., Kauwe, John S. K., Burns, Jeffrey M., Mancuso, Michelangelo, Buxbaum, Joseph D., Bonuccelli, Ubaldo, Cairns, Nigel J., McQuillin, Andrew, Cao, Chuanhai, Livingston, Gill, Carlson, Chris S., Bass, Nicholas J., Carlsson, Cynthia M., Hardy, John, Carney, Regina M., Bras, Jose, Carrasquillo, Minerva M., Guerreiro, Rita, Allen, Mariet, Chui, Helena C., Fisher, Elizabeth, Masullo, Carlo, Crocco, Elizabeth A., DeCarli, Charles, Bisceglio, Gina, Dick, Malcolm, Ma, Li, Duara, Ranjan, Graff-Radford, Neill R., Evans, Denis A., Hodges, Angela, Faber, Kelley M., Scherer, Martin, Fallon, Kenneth B., Riemenschneider, Matthias, Fardo, David W., Heun, Reinhard, Farlow, Martin R., Kölsch, Heike, Ferris, Steven, Leber, Markus, Foroud, Tatiana M., Heuser, Isabella, Galasko, Douglas R., Giegling, Ina, Gearing, Marla, Hüll, Michael, Geschwind, Daniel H., Gilbert, John R., Morris, John, Green, Robert C., Mayo, Kevin, Growdon, John H., Feulner, Thomas, Hamilton, Ronald L., Harrell, Lindy E., Drichel, Dmitriy, Honig, Lawrence S., Cushion, Thomas D., Huentelman, Matthew J., Hollingworth, Paul, Hulette, Christine M., Hyman, Bradley T., Marshall, Rachel, Jarvik, Gail P., Meggy, Alun, Abner, Erin, Menzies, Georgina E., Jin, Lee-Way, Leonenko, Ganna, Real, Luis M., Jun, Gyungah R., Baldwin, Clinton T., Grozeva, Detelina, Karydas, Anna, Russo, Giancarlo, Kaye, Jeffrey A., Kim, Ronald, Jessen, Frank, Kowall, Neil W., Vellas, Bruno, Kramer, Joel H., Vardy, Emma, LaFerla, Frank M., Jöckel, Karl-Heinz, Lah, James J., Dichgans, Martin, Leverenz, James B., Mann, David, Levey, Allan I., Pickering-Brown, Stuart, Lieberman, Andrew P., Klopp, Norman, Lunetta, Kathryn L., Wichmann, H-Erich, Lyketsos, Constantine G., Morgan, Kevin, Marson, Daniel C., Brown, Kristelle, Martiniuk, Frank, Medway, Christopher, Mash, Deborah C., Nöthen, Markus M., Masliah, Eliezer, Hooper, Nigel M., McCormick, Wayne C., Daniele, Antonio, McCurry, Susan M., Bayer, Anthony, McDavid, Andrew N., Gallacher, John, McKee, Ann C., van den Bussche, Hendrik, Mesulam, Marsel, Brayne, Carol, Miller, Bruce L., Riedel-Heller, Steffi, Miller, Carol A., Miller, Joshua W., Al-Chalabi, Ammar, Morris, John C., Shaw, Christopher E., Myers, Amanda J., Wiltfang, Jens, O’Bryant, Sid, Olichney, John M., Alvarez, Victoria, Parisi, Joseph E., Singleton, Andrew B., Paulson, Henry L., Collinge, John, Perry, William R., Mead, Simon, Peskind, Elaine, Cribbs, David H., Rossor, Martin, Pierce, Aimee, Ryan, Natalie S., Poon, Wayne W., Nacmias, Benedetta, Potter, Huntington, Sorbi, Sandro, Quinn, Joseph F., Sacchinelli, Eleonora, Raj, Ashok, Spalletta, Gianfranco, Raskind, Murray, Caltagirone, Carlo, Bossù, Paola, Orfei, Maria Donata, Reisberg, Barry, Clarke, Robert, Reitz, Christiane, Smith, A David, Ringman, John M., Warden, Donald, Roberson, Erik D., Wilcock, Gordon, Rogaeva, Ekaterina, Bruni, Amalia Cecilia, Rosen, Howard J., Gallo, Maura, Rosenberg, Roger N., Ben-Shlomo, Yoav, Sager, Mark A., Mecocci, Patrizia, Saykin, Andrew J., Pastor, Pau, Cuccaro, Michael L., Vance, Jeffery M., Schneider, Julie A., Schneider, Lori S., Slifer, Susan, Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tang, Mitchell, Tanzi, Rudolph E., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Wingo, Thomas S., Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Saba, Yasaman, Alzheimer Disease Genetics Consortium (ADGC), The European Alzheimer’s Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES), Pilotto, Alberto, Bullido, Maria J., Peters, Oliver, Crane, Paul K., Bennett, David, Bosco, Paola, Coto, Eliecer, Boccardi, Virginia, De Jager, Phil L., Lleo, Alberto, Warner, Nick, Lopez, Oscar L., Ingelsson, Martin, Deloukas, Panagiotis, Cruchaga, Carlos, Graff, Caroline, Gwilliam, Rhian, Fornage, Myriam, Goate, Alison M., Sanchez-Juan, Pascual, Kehoe, Patrick G., Amin, Najaf, Ertekin-Taner, Nilifur, Berr, Claudine, Debette, Stéphanie, Love, Seth, Launer, Lenore J., Younkin, Steven G., Dartigues, Jean-Francois, Corcoran, Chris, Ikram, M. Arfan, Dickson, Dennis W., Nicolas, Gael, Campion, Dominique, Tschanz, JoAnn, Schmidt, Helena, Hakonarson, Hakon, Clarimon, Jordi, Munger, Ron, Schmidt, Reinhold, Farrer, Lindsay A., Van Broeckhoven, Christine, O’Donovan, Michael C., DeStefano, Anita L., Jones, Lesley, Haines, Jonathan L., Deleuze, Jean-Francois, Owen, Michael J., Gudnason, Vilmundur, Mayeux, Richard, Escott-Price, Valentina, Psaty, Bruce M., Ramirez, Alfredo, Wang, Li-San, Ruiz, Agustin, van Duijn, Cornelia M., Holmans, Peter A., Seshadri, Sudha, Williams, Julie, Amouyel, Phillippe, Schellenberg, Gerard D., Lambert, Jean-Charles, and Pericak-Vance, Margaret A.

Published
2019
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4. The Uppsala APP deletion causes early onset autosomal dominant Alzheimer’s disease by altering APP processing and increasing amyloid β fibril formation

Author

Pagnon de la Vega, María, primary, Giedraitis, Vilmantas, additional, Michno, Wojciech, additional, Kilander, Lena, additional, Güner, Gökhan, additional, Zielinski, Mara, additional, Löwenmark, Malin, additional, Brundin, RoseMarie, additional, Danfors, Torsten, additional, Söderberg, Linda, additional, Alafuzoff, Irina, additional, Nilsson, Lars N.G., additional, Erlandsson, Anna, additional, Willbold, Dieter, additional, Müller, Stephan A., additional, Schröder, Gunnar F., additional, Hanrieder, Jörg, additional, Lichtenthaler, Stefan F., additional, Lannfelt, Lars, additional, Sehlin, Dag, additional, and Ingelsson, Martin, additional

Published
2021
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5. The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid beta fibril formation

Author

de la Vega, Maria Pagnon, Giedraitis, Vilmantas, Michno, Wojciech, Kilander, Lena, Guener, Goekhan, Zielinski, Mara, Degerman Gunnarsson, Malin, Brundin, RoseMarie, Danfors, Torsten, Soderberg, Linda, Alafuzoff, Irina, Nilsson, Lars N. G., Erlandsson, Anna, Willbold, Dieter, Mueller, Stephan A., Schroeder, Gunnar F., Hanrieder, Jorg, Lichtenthaler, Stefan F., Lannfelt, Lars, Sehlin, Dag, Ingelsson, Martin, de la Vega, Maria Pagnon, Giedraitis, Vilmantas, Michno, Wojciech, Kilander, Lena, Guener, Goekhan, Zielinski, Mara, Degerman Gunnarsson, Malin, Brundin, RoseMarie, Danfors, Torsten, Soderberg, Linda, Alafuzoff, Irina, Nilsson, Lars N. G., Erlandsson, Anna, Willbold, Dieter, Mueller, Stephan A., Schroeder, Gunnar F., Hanrieder, Jorg, Lichtenthaler, Stefan F., Lannfelt, Lars, Sehlin, Dag, and Ingelsson, Martin

Abstract

Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid beta (A beta). Here, we describe the Uppsala APP mutation (Delta 690-695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) A beta 42 and only slightly pathological amyloid-positron emission tomography signals. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing beta-secretase cleavage and affecting alpha-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated A beta, A beta Upp1-42(Delta 19-24), accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.

Published
2021
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6. Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers

Author

Emami Khoonsari, Payam, Shevchenko, Ganna, Herman, Stephanie, Remnestal, Julia, Giedraitis, Vilmantas, Brundin, RoseMarie, Degerman Gunnarsson, Malin, Kilander, Lena, Zetterberge, Henrik, Nilsson, Peter, Lannfelt, Lars, Ingelsson, Martin, Kultima, Kim, Emami Khoonsari, Payam, Shevchenko, Ganna, Herman, Stephanie, Remnestal, Julia, Giedraitis, Vilmantas, Brundin, RoseMarie, Degerman Gunnarsson, Malin, Kilander, Lena, Zetterberge, Henrik, Nilsson, Peter, Lannfelt, Lars, Ingelsson, Martin, and Kultima, Kim

Abstract

Background: Alzheimer’s disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD. Objective: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects. Methods: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4–9 years and 21 of these converted to AD, whereas 53 remained stable. Results: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCI/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively. Conclusions: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects.

Published
2019
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7. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Author

Kunkle, Brian W., Giedraitis, Vilmantas, Kilander, Lena, Brundin, RoseMarie, Lannfelt, Lars, Ingelsson, Martin, Pericak-Vance, Margaret A., Kunkle, Brian W., Giedraitis, Vilmantas, Kilander, Lena, Brundin, RoseMarie, Lannfelt, Lars, Ingelsson, Martin, and Pericak-Vance, Margaret A.

Abstract

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and A beta processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 x 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education., For complete list of authors see http://dx.doi.org/10.1038/s41588-019-0358-2

Published
2019
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8. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates A beta, tau, immunity and lipid processing

Author

Kunkle, Brian W., Grenier-Boley, Benjamin, Sims, Rebecca, Bis, Joshua C., Damotte, Vincent, Naj, Adam C., Boland, Anne, Vronskaya, Maria, van der Lee, Sven J., Amlie-Wolf, Alexandre, Bellenguez, Celine, Frizatti, Aura, Chouraki, Vincent, Martin, Eden R., Sleegers, Kristel, Badarinarayan, Nandini, Jakobsdottir, Johanna, Hamilton-Nelson, Kara L., Moreno-Grau, Sonia, Olaso, Robert, Raybould, Rachel, Chen, Yuning, Kuzma, Amanda B., Hiltunen, Mikko, Morgan, Taniesha, Ahmad, Shahzad, Vardarajan, Badri N., Epelbaum, Jacques, Hoffmann, Per, Boada, Merce, Beecham, Gary W., Garnier, Jean-Guillaume, Harold, Denise, Fitzpatrick, Annette L., Valladares, Otto, Moutet, Marie-Laure, Gerrish, Amy, Smith, Albert, V, Qu, Liming, Bacq, Delphine, Denning, Nicola, Jian, Xueqiu, Zhao, Yi, Del Zompo, Maria, Fox, Nick C., Choi, Seung-Hoan, Mateo, Ignacio, Hughes, Joseph T., Adams, Hieab H., Malamon, John, Sanchez-Garcia, Florentino, Patel, Yogen, Brody, Jennifer A., Dombroski, Beth A., Naranjo, Maria Candida Deniz, Daniilidou, Makrina, Eiriksdottir, Gudny, Mukherjee, Shubhabrata, Wallon, David, Uphill, James, Aspelund, Thor, Cantwell, Laura B., Garzia, Fabienne, Galimberti, Daniela, Hofer, Edith, Butkiewicz, Mariusz, Fin, Bertrand, Scarpini, Elio, Sarnowski, Chloe, Bush, Will S., Meslage, Stphane, Kornhuber, Johannes, White, Charles C., Song, Yuenjoo, Barber, Robert C., Engelborghs, Sebastiaan, Sordon, Sabrina, Voijnovic, Dina, Adams, Perrie M., Vandenberghe, Rik, Mayhaus, Manuel, Cupples, L. Adrienne, Albert, Marilyn S., De Deyn, Peter P., Gu, Wei, Himali, Jayanadra J., Beekly, Duane, Squassina, Alessio, Hartmann, Annette M., Orellana, Adelina, Blacker, Deborah, Rodriguez-Rodriguez, Eloy, Lovestone, Simon, Garcia, Melissa E., Doody, Rachelle S., Munoz-Fernadez, Carmen, Sussams, Rebecca, Lin, Honghuang, Fairchild, Thomas J., Benito, Yolanda A., Holmes, Clive, Karamujic-Comic, Hata, Frosch, Matthew P., Thonberg, Hakan, Maier, Wolfgang, Roschupkin, Gena, Ghetti, Bernardino, Giedraitis, Vilmantas, Kawalia, Amit, Li, Shuo, Huebinger, Ryan M., Kilander, Lena, Moebus, Susanne, Hernandez, Isabel, Kamboh, M. Ilyas, Brundin, Rosemarie, Turton, James, Yang, Qiong, Katz, Mindy J., Concari, Letizia, Lord, Jenny, Beiser, Alexa S., Keene, C. Dirk, Helisalmi, Seppo, Kloszewska, Iwona, Kukull, Walter A., Koivisto, Anne Maria, Lynch, Aoibhinn, Tarraga, Lluis, Larson, Eric B., Haapasalo, Annakaisa, Lawlor, Brian, Mosley, Thomas H., Lipton, Richard B., Solfrizzi, Vincenzo, Gill, Michael, Longstreth, W. T., Jr., Montine, Thomas J., Frisardi, Vincenza, Diez-Fairen, Monica, Rivadeneira, Fernando, Petersen, Ronald C., Deramecourt, Vincent, Alvarez, Ignacio, Salani, Francesca, Ciaramella, Antonio, Boerwinkle, Eric, Reiman, Eric M., Fievet, Nathalie, Rotter, Jerome, I, Reisch, Joan S., Hanon, Olivier, Cupidi, Chiara, Uitterlinden, A. G. Andre, Royall, Donald R., Dufouil, Carole, Maletta, Raffaele Giovanni, de Rojas, Itziar, Sano, Mary, Brice, Alexis, Cecchetti, Roberta, St George-Hyslop, Peter, Ritchie, Karen, Tsolaki, Magda, Tsuang, Debby W., Dubois, Bruno, Craig, David, Wu, Chuang-Kuo, Soininen, Hilkka, Avramidou, Despoina, Albin, Roger L., Fratiglioni, Laura, Germanou, Antonia, Apostolova, Liana G., Keller, Lina, Koutroumani, Maria, Arnold, Steven E., Panza, Francesco, Gkatzima, Olymbia, Asthana, Sanjay, Hannequin, Didier, Whitehead, Patrice, Atwood, Craig S., Caffarra, Paolo, Hampel, Harald, Quintela, Ines, Carracedo, Angel, Lannfelt, Lars, Rubinsztein, David C., Barnes, Lisa L., Pasquier, Florence, Froelich, Lutz, Barral, Sandra, McGuinness, Bernadette, Beach, Thomas G., Johnston, Janet A., Becker, James T., Passmore, Peter, Bigio, Eileen H., Schott, Jonathan M., Bird, Thomas D., Warren, Jason D., Boeve, Bradley F., Lupton, Michelle K., Bowen, James D., Proitsi, Petra, Boxer, Adam, Powell, John F., Burke, James R., Kauwe, John S. K., Burns, Jeffrey M., Mancuso, Michelangelo, Buxbaum, Joseph D., Bonuccelli, Ubaldo, Cairns, Nigel J., McQuillin, Andrew, Cao, Chuanhai, Livingston, Gill, Carlson, Chris S., Bass, Nicholas J., Carlsson, Cynthia M., Hardy, John, Carney, Regina M., Bras, Jose, Carrasquillo, Minerva M., Guerreiro, Rita, Allen, Mariet, Chui, Helena C., Fisher, Elizabeth, Masullo, Carlo, Crocco, Elizabeth A., DeCarli, Charles, Bisceglio, Gina, Dick, Malcolm, Ma, Li, Duara, Ranjan, Graff-Radford, Neill R., Evans, Denis A., Hodges, Angela, Faber, Kelley M., Scherer, Martin, Fallon, Kenneth B., Riemenschneider, Matthias, Fardo, David W., Heun, Reinhard, Farlow, Martin R., Koelsch, Heike, Ferris, Steven, Leber, Markus, Foroud, Tatiana M., Heuser, Isabella, Galasko, Douglas R., Giegling, Ina, Gearing, Marla, Huell, Michael, Geschwind, Daniel H., Gilbert, John R., Morris, John, Green, Robert C., Mayo, Kevin, Growdon, John H., Feulner, Thomas, Hamilton, Ronald L., Harrell, Lindy E., Drichel, Dmitriy, Honig, Lawrence S., Cushion, Thomas D., Huentelman, Matthew J., Hollingworth, Paul, Hulette, Christine M., Hyman, Bradley T., Marshall, Rachel, Jarvik, Gail P., Meggy, Alun, Abner, Erin, Menzies, Georgina E., Jin, Lee-Way, Leonenko, Ganna, Real, Luis M., Jun, Gyungah R., Baldwin, Clinton T., Grozeva, Detelina, Karydas, Anna, Russo, Giancarlo, Kaye, Jeffrey A., Kim, Ronald, Jessen, Frank, Kowall, Neil W., Vellas, Bruno, Kramer, Joel H., Vardy, Emma, LaFerla, Frank M., Joeckel, Karl-Heinz, Lah, James J., Dichgans, Martin, Leverenz, James B., Mann, David, Levey, Allan, I, Pickering-Brown, Stuart, Lieberman, Andrew P., Klopp, Norman, Lunetta, Kathryn L., Wichmann, H-Erich, Lyketsos, Constantine G., Morgan, Kevin, Marson, Daniel C., Brown, Kristelle, Martiniuk, Frank, Medway, Christopher, Mash, Deborah C., Noethen, Markus M., Masliah, Eliezer, Hooper, Nigel M., McCormick, Wayne C., Daniele, Antonio, McCurry, Susan M., Bayer, Anthony, McDavid, Andrew N., Gallacher, John, McKee, Ann C., van den Bussche, Hendrik, Mesulam, Marsel, Brayne, Carol, Miller, Bruce L., Riedel-Heller, Steffi, Miller, Carol A., Miller, Joshua W., Al-Chalabi, Ammar, Morris, John C., Shaw, Christopher E., Myers, Amanda J., Wiltfang, Jens, O'Bryant, Sid, Olichney, John M., Alvarez, Victoria, Parisi, Joseph E., Singleton, Andrew B., Paulson, Henry L., Collinge, John, Perry, William R., Mead, Simon, Peskind, Elaine, Cribbs, David H., Rossor, Martin, Pierce, Aimee, Ryan, Natalie S., Poon, Wayne W., Nacmias, Benedetta, Potter, Huntington, Sorbi, Sandro, Quinn, Joseph F., Sacchinelli, Eleonora, Raj, Ashok, Spalletta, Gianfranco, Raskind, Murray, Caltagirone, Carlo, Bossu, Paola, Orfei, Maria Donata, Reisberg, Barry, Clarke, Robert, Reitz, Christiane, Smith, A. David, Ringman, John M., Warden, Donald, Roberson, Erik D., Wilcock, Gordon, Rogaeva, Ekaterina, Bruni, Amalia Cecilia, Rosen, Howard J., Gallo, Maura, Rosenberg, Roger N., Ben-Shlomo, Yoav, Sager, Mark A., Mecocci, Patrizia, Saykin, Andrew J., Pastor, Pau, Cuccaro, Michael L., Vance, Jeffery M., Schneider, Julie A., Schneider, Lori S., Slifer, Susan, Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tang, Mitchell, Tanzi, Rudolph E., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Wingo, Thomas S., Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Saba, Yasaman, Pilotto, Alberto, Bullido, Maria J., Peters, Oliver, Crane, Paul K., Bennett, David, Bosco, Paola, Coto, Eliecer, Boccardi, Virginia, De Jager, Phil L., Lleo, Alberto, Warner, Nick, Lopez, Oscar L., Ingelsson, Martin, Deloukas, Panagiotis, Cruchaga, Carlos, Graff, Caroline, Gwilliam, Rhian, Fornage, Myriam, Goate, Alison M., Sanchez-Juan, Pascual, Kehoe, Patrick G., Amin, Najaf, Ertekin-Taner, Nilifur, Berr, Claudine, Debette, Stphanie, Love, Seth, Launer, Lenore J., Younkin, Steven G., Dartigues, Jean-Francois, Corcoran, Chris, Ikram, M. 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Adrienne, Albert, Marilyn S., De Deyn, Peter P., Gu, Wei, Himali, Jayanadra J., Beekly, Duane, Squassina, Alessio, Hartmann, Annette M., Orellana, Adelina, Blacker, Deborah, Rodriguez-Rodriguez, Eloy, Lovestone, Simon, Garcia, Melissa E., Doody, Rachelle S., Munoz-Fernadez, Carmen, Sussams, Rebecca, Lin, Honghuang, Fairchild, Thomas J., Benito, Yolanda A., Holmes, Clive, Karamujic-Comic, Hata, Frosch, Matthew P., Thonberg, Hakan, Maier, Wolfgang, Roschupkin, Gena, Ghetti, Bernardino, Giedraitis, Vilmantas, Kawalia, Amit, Li, Shuo, Huebinger, Ryan M., Kilander, Lena, Moebus, Susanne, Hernandez, Isabel, Kamboh, M. Ilyas, Brundin, Rosemarie, Turton, James, Yang, Qiong, Katz, Mindy J., Concari, Letizia, Lord, Jenny, Beiser, Alexa S., Keene, C. 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K., Burns, Jeffrey M., Mancuso, Michelangelo, Buxbaum, Joseph D., Bonuccelli, Ubaldo, Cairns, Nigel J., McQuillin, Andrew, Cao, Chuanhai, Livingston, Gill, Carlson, Chris S., Bass, Nicholas J., Carlsson, Cynthia M., Hardy, John, Carney, Regina M., Bras, Jose, Carrasquillo, Minerva M., Guerreiro, Rita, Allen, Mariet, Chui, Helena C., Fisher, Elizabeth, Masullo, Carlo, Crocco, Elizabeth A., DeCarli, Charles, Bisceglio, Gina, Dick, Malcolm, Ma, Li, Duara, Ranjan, Graff-Radford, Neill R., Evans, Denis A., Hodges, Angela, Faber, Kelley M., Scherer, Martin, Fallon, Kenneth B., Riemenschneider, Matthias, Fardo, David W., Heun, Reinhard, Farlow, Martin R., Koelsch, Heike, Ferris, Steven, Leber, Markus, Foroud, Tatiana M., Heuser, Isabella, Galasko, Douglas R., Giegling, Ina, Gearing, Marla, Huell, Michael, Geschwind, Daniel H., Gilbert, John R., Morris, John, Green, Robert C., Mayo, Kevin, Growdon, John H., Feulner, Thomas, Hamilton, Ronald L., Harrell, Lindy E., Drichel, Dmitriy, Honig, Lawrence S., Cushion, Thomas D., Huentelman, Matthew J., Hollingworth, Paul, Hulette, Christine M., Hyman, Bradley T., Marshall, Rachel, Jarvik, Gail P., Meggy, Alun, Abner, Erin, Menzies, Georgina E., Jin, Lee-Way, Leonenko, Ganna, Real, Luis M., Jun, Gyungah R., Baldwin, Clinton T., Grozeva, Detelina, Karydas, Anna, Russo, Giancarlo, Kaye, Jeffrey A., Kim, Ronald, Jessen, Frank, Kowall, Neil W., Vellas, Bruno, Kramer, Joel H., Vardy, Emma, LaFerla, Frank M., Joeckel, Karl-Heinz, Lah, James J., Dichgans, Martin, Leverenz, James B., Mann, David, Levey, Allan, I, Pickering-Brown, Stuart, Lieberman, Andrew P., Klopp, Norman, Lunetta, Kathryn L., Wichmann, H-Erich, Lyketsos, Constantine G., Morgan, Kevin, Marson, Daniel C., Brown, Kristelle, Martiniuk, Frank, Medway, Christopher, Mash, Deborah C., Noethen, Markus M., Masliah, Eliezer, Hooper, Nigel M., McCormick, Wayne C., Daniele, Antonio, McCurry, Susan M., Bayer, Anthony, McDavid, Andrew N., Gallacher, John, McKee, Ann C., van den Bussche, Hendrik, Mesulam, Marsel, Brayne, Carol, Miller, Bruce L., Riedel-Heller, Steffi, Miller, Carol A., Miller, Joshua W., Al-Chalabi, Ammar, Morris, John C., Shaw, Christopher E., Myers, Amanda J., Wiltfang, Jens, O'Bryant, Sid, Olichney, John M., Alvarez, Victoria, Parisi, Joseph E., Singleton, Andrew B., Paulson, Henry L., Collinge, John, Perry, William R., Mead, Simon, Peskind, Elaine, Cribbs, David H., Rossor, Martin, Pierce, Aimee, Ryan, Natalie S., Poon, Wayne W., Nacmias, Benedetta, Potter, Huntington, Sorbi, Sandro, Quinn, Joseph F., Sacchinelli, Eleonora, Raj, Ashok, Spalletta, Gianfranco, Raskind, Murray, Caltagirone, Carlo, Bossu, Paola, Orfei, Maria Donata, Reisberg, Barry, Clarke, Robert, Reitz, Christiane, Smith, A. David, Ringman, John M., Warden, Donald, Roberson, Erik D., Wilcock, Gordon, Rogaeva, Ekaterina, Bruni, Amalia Cecilia, Rosen, Howard J., Gallo, Maura, Rosenberg, Roger N., Ben-Shlomo, Yoav, Sager, Mark A., Mecocci, Patrizia, Saykin, Andrew J., Pastor, Pau, Cuccaro, Michael L., Vance, Jeffery M., Schneider, Julie A., Schneider, Lori S., Slifer, Susan, Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tang, Mitchell, Tanzi, Rudolph E., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Wingo, Thomas S., Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Saba, Yasaman, Pilotto, Alberto, Bullido, Maria J., Peters, Oliver, Crane, Paul K., Bennett, David, Bosco, Paola, Coto, Eliecer, Boccardi, Virginia, De Jager, Phil L., Lleo, Alberto, Warner, Nick, Lopez, Oscar L., Ingelsson, Martin, Deloukas, Panagiotis, Cruchaga, Carlos, Graff, Caroline, Gwilliam, Rhian, Fornage, Myriam, Goate, Alison M., Sanchez-Juan, Pascual, Kehoe, Patrick G., Amin, Najaf, Ertekin-Taner, Nilifur, Berr, Claudine, Debette, Stphanie, Love, Seth, Launer, Lenore J., Younkin, Steven G., Dartigues, Jean-Francois, Corcoran, Chris, Ikram, M. Arfan, Dickson, Dennis W., Nicolas, Gael, Campion, Dominique, Tschanz, JoAnn, Schmidt, Helena, Hakonarson, Hakon, Clarimon, Jordi, Munger, Ron, Schmidt, Reinhold, Farrer, Lindsay A., Van Broeckhoven, Christine, O'Donovan, Michael C., DeStefano, Anita L., Jones, Lesley, Haines, Jonathan L., Deleuze, Jean-Francois, Owen, Michael J., Gudnason, Vilmundur, Mayeux, Richard, Escott-Price, Valentina, Psaty, Bruce M., Ramirez, Alfredo, Wang, Li-San, Ruiz, Agustin, van Duijn, Cornelia M., Holmans, Peter A., Seshadri, Sudha, Williams, Julie, Amouyel, Phillippe, Schellenberg, Gerard D., Lambert, Jean-Charles, and Pericak-Vance, Margaret A.

Abstract

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and A beta processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 x 10(-7)), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Published
2019

9. Improved Differential Diagnosis of Alzheimer’s Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers

Author

Khoonsari, Payam Emami, primary, Shevchenko, Ganna, additional, Herman, Stephanie, additional, Remnestål, Julia, additional, Giedraitis, Vilmantas, additional, Brundin, RoseMarie, additional, Degerman Gunnarsson, Malin, additional, Kilander, Lena, additional, Zetterberg, Henrik, additional, Nilsson, Peter, additional, Lannfelt, Lars, additional, Ingelsson, Martin, additional, and Kultima, Kim, additional

Published
2019
Full Text
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10. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Author

Sims, Rebecca, van der Lee, Sven J., Naj, Adam C., Bellenguez, Celine, Badarinarayan, Nandini, Jakobsdottir, Johanna, Kunkle, Brian W., Boland, Anne, Raybould, Rachel, Bis, Joshua C., Martin, Eden R., Grenier-Boley, Benjamin, Heilmann-Heimbach, Stefanie, Chouraki, Vincent, Kuzma, Amanda B., Sleegers, Kristel, Vronskaya, Maria, Ruiz, Agustin, Graham, Robert R., Olaso, Robert, Hoffmann, Per, Grove, Megan L., Vardarajan, Badri N., Hiltunen, Mikko, Noethen, Markus M., White, Charles C., Hamilton-Nelson, Kara L., Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W., Dulary, Cecile, Herms, Stefan, Smith, Albert V., Funk, Cory C., Derbois, Celine, Forstner, Andreas J., Ahmad, Shahzad, Li, Hongdong, Bacq, Delphine, Harold, Denise, Satizabal, Claudia L., Valladares, Otto, Squassina, Alessio, Thomas, Rhodri, Brody, Jennifer A., Qu, Liming, Sanchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J., Zhao, Yi, Sanchez Garcia, Florentino, Denning, Nicola, Fornage, Myriam, Malamon, John, Deniz Naranjo, Maria Candida, Majounie, Elisa, Mosley, Thomas H., Dombroski, Beth, Wallon, David, Lupton, Michelle K., Dupuis, Josee, Whitehead, Patrice, Fratiglioni, Laura, Medway, Christopher, Jian, Xueqiu, Mukherjee, Shubhabrata, Keller, Lina, Brown, Kristelle, Lin, Honghuang, Cantwell, Laura B., Panza, Francesco, McGuinness, Bernadette, Moreno-Grau, Sonia, Burgess, Jeremy D., Solfrizzi, Vincenzo, Proitsi, Petra, Adams, Hieab H., Allen, Mariet, Seripa, Davide, Pastor, Pau, Cupples, L. Adrienne, Price, Nathan D., Hannequin, Didier, Frank-Garcia, Ana, Levy, Daniel, Chakrabarty, Paramita, Caffarra, Paolo, Giegling, Ina, Beiser, Alexa S., Giedraitis, Vilmantas, Hampel, Harald, Garcia, Melissa E., Wang, Xue, Lannfelt, Lars, Mecocci, Patrizia, Eiriksdottir, Gudny, Crane, Paul K., Pasquier, Florence, Boccardi, Virginia, Henandez, Isabel, Barber, Robert C., Scherer, Martin, Tarraga, Lluis, Adams, Perrie M., Leber, Markus, Chen, Yuning, Albert, Marilyn S., Riedel-Heller, Steffi, Emilsson, Valur, Beekly, Duane, Braae, Anne, Schmidt, Reinhold, Blacker, Deborah, Masullo, Carlo, Schmidt, Helena, Doody, Rachelle S., Spalletta, Gianfranco, Longstreth, W. T., Jr., Fairchild, Thomas J., Bossu, Paola, Lopez, Oscar L., Frosch, Matthew P., Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M., Jessen, Frank, Li, Shuo, Kamboh, M. Ilyas, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J., Corcoran, Chris, Dunstan, Melanie, Braddel, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Gerrish, Amy, Chapman, Jade, Aguilar, Miquel, Taylor, Sarah, Hill, Matt, Diez Fairen, Mnica, Hodges, Angela, Vellas, Bruno, Soininen, Hilkka, Kloszewska, Iwona, Daniilidou, Makrina, Uphill, James, Patel, Yogen, Hughes, Joseph T., Lord, Jenny, Turton, James, Hartmann, Annette M., Cecchetti, Roberta, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Caltagirone, Carlo, Orfei, Maria Donata, Ciaramella, Antonio, Pichler, Sabrina, Mayhaus, Manuel, Gu, Wei, Lleo, Alberto, Forte, Juan, Blesa, Rafael, Barber, Imelda S., Brookes, Keeley, Cupidi, Chiara, Maletta, Raffaele Giovanni, Carrell, David, Sorbi, Sandro, Moebus, Susanne, Urbano, Maria, Pilotto, Alberto, Kornhuber, Johannes, Bosco, Paolo, Todd, Stephen, Craig, David, Johnston, Janet, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Fox, Nick C., Hardy, John, Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Asthana, Sanjay, Atwood, Craig S., Baldwin, Clinton T., Barnes, Lisa L., Barral, Sandra, Beach, Thomas G., Becker, James T., Bigio, Eileen H., Bird, Thomas D., Boeve, Bradley F., Bowen, James D., Boxer, Adam, Burke, James R., Burns, Jeffrey M., Buxbaum, Joseph D., Cairns, Nigel J., Cao, Chuanhai, Carlson, Chris S., Carlsson, Cynthia M., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Diaz, Carolina Ceballos, Chui, Helena C., Clark, David G., Cribbs, David H., Crocco, Elizabeth A., DeCarli, Charles, Dick, Malcolm, Duara, Ranjan, Evans, Denis A., Faber, Kelley M., Fallon, Kenneth B., Fardo, David W., Farlow, Martin R., Ferris, Steven, Foroud, Tatiana M., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Gilbert, John R., Graff-Radford, Neill R., Green, Robert C., Growdon, John H., Hamilton, Ronald L., Harrell, Lindy E., Honig, Lawrence S., Huentelman, Matthew J., Hulette, Christine M., Hyman, Bradley T., Jarvik, Gail P., Abner, Erin, Jin, Lee-Way, Jun, Gyungah, Karydas, Anna, Kaye, Jeffrey A., Kim, Ronald, Kowall, Neil W., Kramer, Joel H., LaFerla, Frank M., Lah, James J., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Lunetta, Kathryn L., Lyketsos, Constantine G., Marson, Daniel C., Martiniuk, Frank, Mash, Deborah C., Masliah, Eliezer, McCormick, Wayne C., McCurry, Susan M., McDavid, Andrew N., Mckee, Ann C., Mesulam, Marsel, Miller, Bruce L., Miller, Carol A., Miller, Joshua W., Morris, John C., Murrell, Jill R., Myers, Amanda J., O'Bryant, Sid, Pankratz, Vernon S., Parisi, Joseph E., Paulson, Henry L., Perry, William, Peskind, Elaine, Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rogaeva, Ekaterina, Rosen, Howard J., Rosenberg, Roger N., Sager, Mark A., Saykin, Andrew J., Schneider, Julie A., Schneider, Lon S., Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tanzi, Rudolph E., Thornton-Wells, Tricia A., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Garzia, Fabienne, Golamaully, Feroze, Septier, Gislain, Engelborghs, Sebastien, Vandenberghe, Rik, De Deyn, Peter P., Munoz Fernadez, Carmen, Aladro Benito, Yoland, Thonberg, Hakan, Forsell, Charlotte, Lilius, Lena, Kinhult-Stahlbom, Anne, Kilander, Lena, Brundin, RoseMarie, Concari, Letizia, Helisalmi, Seppo, Koivisto, Anne Maria, Haapasalo, Annakaisa, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Ritchie, Karen, Dubois, Bruno, Himali, Jayanadra J., Keene, C. Dirk, Tschanz, Joann, Fitzpatrick, Annette L., Kukull, Walter A., Norton, Maria, Aspelund, Thor, Larson, Eric B., Munger, Ron, Rotter, Jerome I., Lipton, Richard B., Bullido, Maria J., Hofman, Albert, Montine, Thomas J., Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C., Alvarez, Victoria, Rivadeneira, Fernando, Reiman, Eric M., Gallo, Maura, O'Donnell, Christopher J., Reisch, Joan S., Bruni, Amalia Cecilia, Royall, Donald R., Dichgans, Martin, Sano, Mary, Galimberti, Daniela, St George-Hyslop, Peter, Scarpini, Elio, Tsuang, Debby W., Mancuso, Michelangelo, Bonuccelli, Ubaldo, Winslow, Ashley R., Daniele, Antonio, Wu, Chuang-Kuo, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol, Rubinsztein, David C., Bras, Jose, Guerreiro, Rita, Al-Chalabi, Ammar, Shaw, Christopher E., Collinge, John, Mann, David, Tsolaki, Magda, Clarimon, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C., Owen, Michael J., Behrens, Timothy W., Mead, Simon, Goate, Alison M., Uitterlinden, Andre G., Holmes, Clive, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A., Powell, John, Golde, Todd E., Graff, Caroline, De Jager, Philip L., Morgan, Kevin, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M., Passmore, Peter, Younkin, Steven G., Berr, Claudine, Gudnason, Vilmundur, Rujescu, Dan, Dickson, Dennis W., Dartigues, Jean-Francois, DeStefano, Anita L., Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A., Van Broeckhoven, Christine, Ikram, M. Arfan, Jones, Lesley, Haines, Jonathan L., Tzourio, Christophe, Launer, Lenore J., Escott-Price, Valentina, Mayeux-, Richard, Deleuze, Jean-Francois, Amin, Najaf, Holmans, Peter A., Pericak-Vance, Margaret A., Amouyel, Philippe, van Duijn, Cornelia M., Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie, Schellenberg, Gerard D., Sims, Rebecca, van der Lee, Sven J., Naj, Adam C., Bellenguez, Celine, Badarinarayan, Nandini, Jakobsdottir, Johanna, Kunkle, Brian W., Boland, Anne, Raybould, Rachel, Bis, Joshua C., Martin, Eden R., Grenier-Boley, Benjamin, Heilmann-Heimbach, Stefanie, Chouraki, Vincent, Kuzma, Amanda B., Sleegers, Kristel, Vronskaya, Maria, Ruiz, Agustin, Graham, Robert R., Olaso, Robert, Hoffmann, Per, Grove, Megan L., Vardarajan, Badri N., Hiltunen, Mikko, Noethen, Markus M., White, Charles C., Hamilton-Nelson, Kara L., Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W., Dulary, Cecile, Herms, Stefan, Smith, Albert V., Funk, Cory C., Derbois, Celine, Forstner, Andreas J., Ahmad, Shahzad, Li, Hongdong, Bacq, Delphine, Harold, Denise, Satizabal, Claudia L., Valladares, Otto, Squassina, Alessio, Thomas, Rhodri, Brody, Jennifer A., Qu, Liming, Sanchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J., Zhao, Yi, Sanchez Garcia, Florentino, Denning, Nicola, Fornage, Myriam, Malamon, John, Deniz Naranjo, Maria Candida, Majounie, Elisa, Mosley, Thomas H., Dombroski, Beth, Wallon, David, Lupton, Michelle K., Dupuis, Josee, Whitehead, Patrice, Fratiglioni, Laura, Medway, Christopher, Jian, Xueqiu, Mukherjee, Shubhabrata, Keller, Lina, Brown, Kristelle, Lin, Honghuang, Cantwell, Laura B., Panza, Francesco, McGuinness, Bernadette, Moreno-Grau, Sonia, Burgess, Jeremy D., Solfrizzi, Vincenzo, Proitsi, Petra, Adams, Hieab H., Allen, Mariet, Seripa, Davide, Pastor, Pau, Cupples, L. Adrienne, Price, Nathan D., Hannequin, Didier, Frank-Garcia, Ana, Levy, Daniel, Chakrabarty, Paramita, Caffarra, Paolo, Giegling, Ina, Beiser, Alexa S., Giedraitis, Vilmantas, Hampel, Harald, Garcia, Melissa E., Wang, Xue, Lannfelt, Lars, Mecocci, Patrizia, Eiriksdottir, Gudny, Crane, Paul K., Pasquier, Florence, Boccardi, Virginia, Henandez, Isabel, Barber, Robert C., Scherer, Martin, Tarraga, Lluis, Adams, Perrie M., Leber, Markus, Chen, Yuning, Albert, Marilyn S., Riedel-Heller, Steffi, Emilsson, Valur, Beekly, Duane, Braae, Anne, Schmidt, Reinhold, Blacker, Deborah, Masullo, Carlo, Schmidt, Helena, Doody, Rachelle S., Spalletta, Gianfranco, Longstreth, W. T., Jr., Fairchild, Thomas J., Bossu, Paola, Lopez, Oscar L., Frosch, Matthew P., Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M., Jessen, Frank, Li, Shuo, Kamboh, M. Ilyas, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J., Corcoran, Chris, Dunstan, Melanie, Braddel, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Gerrish, Amy, Chapman, Jade, Aguilar, Miquel, Taylor, Sarah, Hill, Matt, Diez Fairen, Mnica, Hodges, Angela, Vellas, Bruno, Soininen, Hilkka, Kloszewska, Iwona, Daniilidou, Makrina, Uphill, James, Patel, Yogen, Hughes, Joseph T., Lord, Jenny, Turton, James, Hartmann, Annette M., Cecchetti, Roberta, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Caltagirone, Carlo, Orfei, Maria Donata, Ciaramella, Antonio, Pichler, Sabrina, Mayhaus, Manuel, Gu, Wei, Lleo, Alberto, Forte, Juan, Blesa, Rafael, Barber, Imelda S., Brookes, Keeley, Cupidi, Chiara, Maletta, Raffaele Giovanni, Carrell, David, Sorbi, Sandro, Moebus, Susanne, Urbano, Maria, Pilotto, Alberto, Kornhuber, Johannes, Bosco, Paolo, Todd, Stephen, Craig, David, Johnston, Janet, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Fox, Nick C., Hardy, John, Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Asthana, Sanjay, Atwood, Craig S., Baldwin, Clinton T., Barnes, Lisa L., Barral, Sandra, Beach, Thomas G., Becker, James T., Bigio, Eileen H., Bird, Thomas D., Boeve, Bradley F., Bowen, James D., Boxer, Adam, Burke, James R., Burns, Jeffrey M., Buxbaum, Joseph D., Cairns, Nigel J., Cao, Chuanhai, Carlson, Chris S., Carlsson, Cynthia M., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Diaz, Carolina Ceballos, Chui, Helena C., Clark, David G., Cribbs, David H., Crocco, Elizabeth A., DeCarli, Charles, Dick, Malcolm, Duara, Ranjan, Evans, Denis A., Faber, Kelley M., Fallon, Kenneth B., Fardo, David W., Farlow, Martin R., Ferris, Steven, Foroud, Tatiana M., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Gilbert, John R., Graff-Radford, Neill R., Green, Robert C., Growdon, John H., Hamilton, Ronald L., Harrell, Lindy E., Honig, Lawrence S., Huentelman, Matthew J., Hulette, Christine M., Hyman, Bradley T., Jarvik, Gail P., Abner, Erin, Jin, Lee-Way, Jun, Gyungah, Karydas, Anna, Kaye, Jeffrey A., Kim, Ronald, Kowall, Neil W., Kramer, Joel H., LaFerla, Frank M., Lah, James J., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Lunetta, Kathryn L., Lyketsos, Constantine G., Marson, Daniel C., Martiniuk, Frank, Mash, Deborah C., Masliah, Eliezer, McCormick, Wayne C., McCurry, Susan M., McDavid, Andrew N., Mckee, Ann C., Mesulam, Marsel, Miller, Bruce L., Miller, Carol A., Miller, Joshua W., Morris, John C., Murrell, Jill R., Myers, Amanda J., O'Bryant, Sid, Pankratz, Vernon S., Parisi, Joseph E., Paulson, Henry L., Perry, William, Peskind, Elaine, Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rogaeva, Ekaterina, Rosen, Howard J., Rosenberg, Roger N., Sager, Mark A., Saykin, Andrew J., Schneider, Julie A., Schneider, Lon S., Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tanzi, Rudolph E., Thornton-Wells, Tricia A., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Garzia, Fabienne, Golamaully, Feroze, Septier, Gislain, Engelborghs, Sebastien, Vandenberghe, Rik, De Deyn, Peter P., Munoz Fernadez, Carmen, Aladro Benito, Yoland, Thonberg, Hakan, Forsell, Charlotte, Lilius, Lena, Kinhult-Stahlbom, Anne, Kilander, Lena, Brundin, RoseMarie, Concari, Letizia, Helisalmi, Seppo, Koivisto, Anne Maria, Haapasalo, Annakaisa, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Ritchie, Karen, Dubois, Bruno, Himali, Jayanadra J., Keene, C. Dirk, Tschanz, Joann, Fitzpatrick, Annette L., Kukull, Walter A., Norton, Maria, Aspelund, Thor, Larson, Eric B., Munger, Ron, Rotter, Jerome I., Lipton, Richard B., Bullido, Maria J., Hofman, Albert, Montine, Thomas J., Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C., Alvarez, Victoria, Rivadeneira, Fernando, Reiman, Eric M., Gallo, Maura, O'Donnell, Christopher J., Reisch, Joan S., Bruni, Amalia Cecilia, Royall, Donald R., Dichgans, Martin, Sano, Mary, Galimberti, Daniela, St George-Hyslop, Peter, Scarpini, Elio, Tsuang, Debby W., Mancuso, Michelangelo, Bonuccelli, Ubaldo, Winslow, Ashley R., Daniele, Antonio, Wu, Chuang-Kuo, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol, Rubinsztein, David C., Bras, Jose, Guerreiro, Rita, Al-Chalabi, Ammar, Shaw, Christopher E., Collinge, John, Mann, David, Tsolaki, Magda, Clarimon, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C., Owen, Michael J., Behrens, Timothy W., Mead, Simon, Goate, Alison M., Uitterlinden, Andre G., Holmes, Clive, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A., Powell, John, Golde, Todd E., Graff, Caroline, De Jager, Philip L., Morgan, Kevin, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M., Passmore, Peter, Younkin, Steven G., Berr, Claudine, Gudnason, Vilmundur, Rujescu, Dan, Dickson, Dennis W., Dartigues, Jean-Francois, DeStefano, Anita L., Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A., Van Broeckhoven, Christine, Ikram, M. Arfan, Jones, Lesley, Haines, Jonathan L., Tzourio, Christophe, Launer, Lenore J., Escott-Price, Valentina, Mayeux-, Richard, Deleuze, Jean-Francois, Amin, Najaf, Holmans, Peter A., Pericak-Vance, Margaret A., Amouyel, Philippe, van Duijn, Cornelia M., Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie, and Schellenberg, Gerard D.

Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 x 10(-4)) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 x 10(-8)) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p. Pro522Arg, P = 5.38 x 10(-10), odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p. Ser209Phe, P = 4.56 x 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p. Arg62His, P = 1.55 x 10(-14), OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Published
2017
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11. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Sims, Rebecca, van der Lee, Sven J., Naj, Adam C., Bellenguez, Celine, Badarinarayan, Nandini, Jakobsdottir, Johanna, Kunkle, Brian W., Boland, Anne, Raybould, Rachel, Bis, Joshua C., Martin, Eden R., Grenier-Boley, Benjamin, Heilmann-Heimbach, Stefanie, Chouraki, Vincent, Kuzma, Amanda B., Sleegers, Kristel, Vronskaya, Maria, Ruiz, Agustin, Graham, Robert R., Olaso, Robert, Hoffmann, Per, Grove, Megan L., Vardarajan, Badri N., Hiltunen, Mikko, Nothen, Markus M., White, Charles C., Hamilton-Nelson, Kara L., Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W., Dulary, Cecile, Herms, Stefan, Smith, Albert V., Funk, Cory C., Derbois, Celine, Forstner, Andreas J., Ahmad, Shahzad, Li, Hongdong, Bacq, Delphine, Harold, Denise, Satizabal, Claudia L., Valladares, Otto, Squassina, Alessio, Thomas, Rhodri, Brody, Jennifer A., Qu, Liming, Sanchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J., Zhao, Yi, Garcia, Florentino Sanchez, Denning, Nicola, Fornage, Myriam, Malamon, John, Naranjo, Maria Candida Deniz, Majounie, Elisa, Mosley, Thomas H., Dombroski, Beth, Wallon, David, Lupton, Michelle K., Dupuis, Josee, Whitehead, Patrice, Fratiglioni, Laura, Medway, Christopher, Jian, Xueqiu, Mukherjee, Shubhabrata, Keller, Lina, Brown, Kristelle, Lin, Honghuang, Cantwell, Laura B., Panza, Francesco, McGuinness, Bernadette, Moreno-Grau, Sonia, Burgess, Jeremy D., Solfrizzi, Vincenzo, Proitsi, Petra, Adams, Hieab H., Allen, Mariet, Seripa, Davide, Pastor, Pau, Cupples, L. Adrienne, Price, Nathan D., Hannequin, Didier, Frank-Garcia, Ana, Levy, Daniel, Chakrabarty, Paramita, Caffarra, Paolo, Giegling, Ina, Beiser, Alexa S., Giedraitis, Vilmantas, Hampel, Harald, Garcia, Melissa E., Wang, Xue, Lannfelt, Lars, Mecocci, Patrizia, Eiriksdottir, Gudny, Crane, Paul K., Pasquier, Florence, Boccardi, Virginia, Henandez, Isabel, Barber, Robert C., Scherer, Martin, Tarraga, Lluis, Adams, Perrie M., Leber, Markus, Chen, Yuning, Albert, Marilyn S., Riedel-Heller, Steffi, Emilsson, Valur, Beekly, Duane, Braae, Anne, Schmidt, Reinhold, Blacker, Deborah, Masullo, Carlo, Schmidt, Helena, Doody, Rachelle S., Spalletta, Gianfranco, Jr, W. T. Longstreth, Fairchild, Thomas J., Bossu, Paola, Lopez, Oscar L., Frosch, Matthew P., Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M., Jessen, Frank, Li, Shuo, Kamboh, M. Ilyas, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J., Corcoran, Chris, Dunstan, Melanie, Braddel, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Gerrish, Amy, Chapman, Jade, Aguilar, Miquel, Taylor, Sarah, Hill, Matt, Fairen, Monica Diez, Hodges, Angela, Vellas, Bruno, Soininen, Hilkka, Kloszewska, Iwona, Daniilidou, Makrina, Uphill, James, Patel, Yogen, Hughes, Joseph T., Lord, Jenny, Turton, James, Hartmann, Annette M., Cecchetti, Roberta, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Caltagirone, Carlo, Orfei, Maria Donata, Ciaramella, Antonio, Pichler, Sabrina, Mayhaus, Manuel, Gu, Wei, Lleo, Alberto, Fortea, Juan, Blesa, Rafael, Barber, Imelda S., Brookes, Keeley, Cupidi, Chiara, Maletta, Raffaele Giovanni, Carrell, David, Sorbi, Sandro, Moebus, Susanne, Urbano, Maria, Pilotto, Alberto, Kornhuber, Johannes, Bosco, Paolo, Todd, Stephen, Craig, David, Johnston, Janet, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Fox, Nick C., Hardy, John, Consortium, A. R. U. K., Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Asthana, Sanjay, Atwood, Craig S., Baldwin, Clinton T., Barnes, Lisa L., Barral, Sandra, Beach, Thomas G., Becker, James T., Bigio, Eileen H., Bird, Thomas D., Boeve, Bradley F., Bowen, James D., Boxer, Adam, Burke, James R., Burns, Jeffrey M., Buxbaum, Joseph D., Cairns, Nigel J., Cao, Chuanhai, Carlson, Chris S., Carlsson, Cynthia M., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Diaz, Carolina Ceballos, Chui, Helena C., Clark, David G., Cribbs, David H., Crocco, Elizabeth A., DeCarli, Charles, Dick, Malcolm, Duara, Ranjan, Evans, Denis A., Faber, Kelley M., Fallon, Kenneth B., Fardo, David W., Farlow, Martin R., Ferris, Steven, Foroud, Tatiana M., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Gilbert, John R., Graff-Radford, Neill R., Green, Robert C., Growdon, John H., Hamilton, Ronald L., Harrell, Lindy E., Honig, Lawrence S., Huentelman, Matthew J., Hulette, Christine M., Hyman, Bradley T., Jarvik, Gail P., Abner, Erin, Jin, Lee-Way, Jun, Gyungah, Karydas, Anna, Kaye, Jeffrey A., Kim, Ronald, Kowall, Neil W., Kramer, Joel H., LaFerla, Frank M., Lah, James J., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Lunetta, Kathryn L., Lyketsos, Constantine G., Marson, Daniel C., Martiniuk, Frank, Mash, Deborah C., Masliah, Eliezer, McCormick, Wayne C., McCurry, Susan M., McDavid, Andrew N., McKee, Ann C., Mesulam, Marsel, Miller, Bruce L., Miller, Carol A., Miller, Joshua W., Morris, John C., Murrell, Jill R., Myers, Amanda J., O'Bryant, Sid, Olichney, John M., Pankratz, Vernon S., Parisi, Joseph E., Paulson, Henry L., Perry, William, Peskind, Elaine, Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rogaeva, Ekaterina, Rosen, Howard J., Rosenberg, Roger N., Sager, Mark A., Saykin, Andrew J., Schneider, Julie A., Schneider, Lon S., Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tanzi, Rudolph E., Thornton-Wells, Tricia A., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Wingo, Thomas S., Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Garzia, Fabienne, Golamaully, Feroze, Septier, Gislain, Engelborghs, Sebastien, Vandenberghe, Rik, De Deyn, Peter P., Fernadez, Carmen Munoz, Benito, Yoland Aladro, Thonberg, Hakan, Forsell, Charlotte, Lilius, Lena, Kinhult-Stahlbom, Anne, Kilander, Lena, Brundin, Rosemarie, Concari, Letizia, Helisalmi, Seppo, Koivisto, Anne Maria, Haapasalo, Annakaisa, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Ritchie, Karen, Dubois, Bruno, Himali, Jayanadra J., Keene, C. Dirk, Tschanz, Joann, Fitzpatrick, Annette L., Kukull, Walter A., Norton, Maria, Aspelund, Thor, Larson, Eric B., Munger, Ron, Rotter, Jerome I., Lipton, Richard B., Bullido, Maria J., Hofman, Albert, Montine, Thomas J., Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C., Alvarez, Victoria, Rivadeneira, Fernando, Reiman, Eric M., Gallo, Maura, O'Donnell, Christopher J., Reisch, Joan S., Bruni, Amalia Cecilia, Royall, Donald R., Dichgans, Martin, Sano, Mary, Galimberti, Daniela, St George-Hyslop, Peter, Scarpini, Elio, Tsuang, Debby W., Mancuso, Michelangelo, Bonuccelli, Ubaldo, Winslow, Ashley R., Daniele, Antonio, Wu, Chuang-Kuo, GERAD/PERADES, Charge Adgc Eadi, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol, Rubinsztein, David C., Bras, Jose, Guerreiro, Rita, Al-Chalabi, Ammar, Shaw, Christopher E., Collinge, John, Mann, David, Tsolaki, Magda, Clarimon, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C., Owen, Michael J., Behrens, Timothy W., Mead, Simon, Goate, Alison M., Uitterlinden, Andre G., Holmes, Clive, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A., Powell, John, Golde, Todd E., Graff, Caroline, De Jager, Philip L., Morgan, Kevin, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M., Passmore, Peter, Younkin, Steven G., Berr, Claudine, Gudnason, Vilmundur, Rujescu, Dan, Dickson, Dennis W., Dartigues, Jean-Francois, DeStefano, Anita L., Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A., Van Broeckhoven, Christine, Ikram, M. Arfan, Jones, Lesley, Haines, Jonathan L., Tzourio, Christophe, Launer, Lenore J., Escott-Price, Valentina, Mayeux, Richard, Deleuze, Jean-Francois, Amin, Najaf, Holmans, Peter A., Pericak-Vance, Margaret A., Amouyel, Philippe, van Duijn, Cornelia M., Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie, Schellenberg, Gerard D., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Sims, Rebecca, van der Lee, Sven J., Naj, Adam C., Bellenguez, Celine, Badarinarayan, Nandini, Jakobsdottir, Johanna, Kunkle, Brian W., Boland, Anne, Raybould, Rachel, Bis, Joshua C., Martin, Eden R., Grenier-Boley, Benjamin, Heilmann-Heimbach, Stefanie, Chouraki, Vincent, Kuzma, Amanda B., Sleegers, Kristel, Vronskaya, Maria, Ruiz, Agustin, Graham, Robert R., Olaso, Robert, Hoffmann, Per, Grove, Megan L., Vardarajan, Badri N., Hiltunen, Mikko, Nothen, Markus M., White, Charles C., Hamilton-Nelson, Kara L., Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W., Dulary, Cecile, Herms, Stefan, Smith, Albert V., Funk, Cory C., Derbois, Celine, Forstner, Andreas J., Ahmad, Shahzad, Li, Hongdong, Bacq, Delphine, Harold, Denise, Satizabal, Claudia L., Valladares, Otto, Squassina, Alessio, Thomas, Rhodri, Brody, Jennifer A., Qu, Liming, Sanchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J., Zhao, Yi, Garcia, Florentino Sanchez, Denning, Nicola, Fornage, Myriam, Malamon, John, Naranjo, Maria Candida Deniz, Majounie, Elisa, Mosley, Thomas H., Dombroski, Beth, Wallon, David, Lupton, Michelle K., Dupuis, Josee, Whitehead, Patrice, Fratiglioni, Laura, Medway, Christopher, Jian, Xueqiu, Mukherjee, Shubhabrata, Keller, Lina, Brown, Kristelle, Lin, Honghuang, Cantwell, Laura B., Panza, Francesco, McGuinness, Bernadette, Moreno-Grau, Sonia, Burgess, Jeremy D., Solfrizzi, Vincenzo, Proitsi, Petra, Adams, Hieab H., Allen, Mariet, Seripa, Davide, Pastor, Pau, Cupples, L. Adrienne, Price, Nathan D., Hannequin, Didier, Frank-Garcia, Ana, Levy, Daniel, Chakrabarty, Paramita, Caffarra, Paolo, Giegling, Ina, Beiser, Alexa S., Giedraitis, Vilmantas, Hampel, Harald, Garcia, Melissa E., Wang, Xue, Lannfelt, Lars, Mecocci, Patrizia, Eiriksdottir, Gudny, Crane, Paul K., Pasquier, Florence, Boccardi, Virginia, Henandez, Isabel, Barber, Robert C., Scherer, Martin, Tarraga, Lluis, Adams, Perrie M., Leber, Markus, Chen, Yuning, Albert, Marilyn S., Riedel-Heller, Steffi, Emilsson, Valur, Beekly, Duane, Braae, Anne, Schmidt, Reinhold, Blacker, Deborah, Masullo, Carlo, Schmidt, Helena, Doody, Rachelle S., Spalletta, Gianfranco, Jr, W. T. Longstreth, Fairchild, Thomas J., Bossu, Paola, Lopez, Oscar L., Frosch, Matthew P., Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M., Jessen, Frank, Li, Shuo, Kamboh, M. Ilyas, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J., Corcoran, Chris, Dunstan, Melanie, Braddel, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Gerrish, Amy, Chapman, Jade, Aguilar, Miquel, Taylor, Sarah, Hill, Matt, Fairen, Monica Diez, Hodges, Angela, Vellas, Bruno, Soininen, Hilkka, Kloszewska, Iwona, Daniilidou, Makrina, Uphill, James, Patel, Yogen, Hughes, Joseph T., Lord, Jenny, Turton, James, Hartmann, Annette M., Cecchetti, Roberta, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Caltagirone, Carlo, Orfei, Maria Donata, Ciaramella, Antonio, Pichler, Sabrina, Mayhaus, Manuel, Gu, Wei, Lleo, Alberto, Fortea, Juan, Blesa, Rafael, Barber, Imelda S., Brookes, Keeley, Cupidi, Chiara, Maletta, Raffaele Giovanni, Carrell, David, Sorbi, Sandro, Moebus, Susanne, Urbano, Maria, Pilotto, Alberto, Kornhuber, Johannes, Bosco, Paolo, Todd, Stephen, Craig, David, Johnston, Janet, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Fox, Nick C., Hardy, John, Consortium, A. R. U. K., Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Asthana, Sanjay, Atwood, Craig S., Baldwin, Clinton T., Barnes, Lisa L., Barral, Sandra, Beach, Thomas G., Becker, James T., Bigio, Eileen H., Bird, Thomas D., Boeve, Bradley F., Bowen, James D., Boxer, Adam, Burke, James R., Burns, Jeffrey M., Buxbaum, Joseph D., Cairns, Nigel J., Cao, Chuanhai, Carlson, Chris S., Carlsson, Cynthia M., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Diaz, Carolina Ceballos, Chui, Helena C., Clark, David G., Cribbs, David H., Crocco, Elizabeth A., DeCarli, Charles, Dick, Malcolm, Duara, Ranjan, Evans, Denis A., Faber, Kelley M., Fallon, Kenneth B., Fardo, David W., Farlow, Martin R., Ferris, Steven, Foroud, Tatiana M., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Gilbert, John R., Graff-Radford, Neill R., Green, Robert C., Growdon, John H., Hamilton, Ronald L., Harrell, Lindy E., Honig, Lawrence S., Huentelman, Matthew J., Hulette, Christine M., Hyman, Bradley T., Jarvik, Gail P., Abner, Erin, Jin, Lee-Way, Jun, Gyungah, Karydas, Anna, Kaye, Jeffrey A., Kim, Ronald, Kowall, Neil W., Kramer, Joel H., LaFerla, Frank M., Lah, James J., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Lunetta, Kathryn L., Lyketsos, Constantine G., Marson, Daniel C., Martiniuk, Frank, Mash, Deborah C., Masliah, Eliezer, McCormick, Wayne C., McCurry, Susan M., McDavid, Andrew N., McKee, Ann C., Mesulam, Marsel, Miller, Bruce L., Miller, Carol A., Miller, Joshua W., Morris, John C., Murrell, Jill R., Myers, Amanda J., O'Bryant, Sid, Olichney, John M., Pankratz, Vernon S., Parisi, Joseph E., Paulson, Henry L., Perry, William, Peskind, Elaine, Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rogaeva, Ekaterina, Rosen, Howard J., Rosenberg, Roger N., Sager, Mark A., Saykin, Andrew J., Schneider, Julie A., Schneider, Lon S., Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tanzi, Rudolph E., Thornton-Wells, Tricia A., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Wingo, Thomas S., Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Garzia, Fabienne, Golamaully, Feroze, Septier, Gislain, Engelborghs, Sebastien, Vandenberghe, Rik, De Deyn, Peter P., Fernadez, Carmen Munoz, Benito, Yoland Aladro, Thonberg, Hakan, Forsell, Charlotte, Lilius, Lena, Kinhult-Stahlbom, Anne, Kilander, Lena, Brundin, Rosemarie, Concari, Letizia, Helisalmi, Seppo, Koivisto, Anne Maria, Haapasalo, Annakaisa, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Ritchie, Karen, Dubois, Bruno, Himali, Jayanadra J., Keene, C. Dirk, Tschanz, Joann, Fitzpatrick, Annette L., Kukull, Walter A., Norton, Maria, Aspelund, Thor, Larson, Eric B., Munger, Ron, Rotter, Jerome I., Lipton, Richard B., Bullido, Maria J., Hofman, Albert, Montine, Thomas J., Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C., Alvarez, Victoria, Rivadeneira, Fernando, Reiman, Eric M., Gallo, Maura, O'Donnell, Christopher J., Reisch, Joan S., Bruni, Amalia Cecilia, Royall, Donald R., Dichgans, Martin, Sano, Mary, Galimberti, Daniela, St George-Hyslop, Peter, Scarpini, Elio, Tsuang, Debby W., Mancuso, Michelangelo, Bonuccelli, Ubaldo, Winslow, Ashley R., Daniele, Antonio, Wu, Chuang-Kuo, GERAD/PERADES, Charge Adgc Eadi, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol, Rubinsztein, David C., Bras, Jose, Guerreiro, Rita, Al-Chalabi, Ammar, Shaw, Christopher E., Collinge, John, Mann, David, Tsolaki, Magda, Clarimon, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C., Owen, Michael J., Behrens, Timothy W., Mead, Simon, Goate, Alison M., Uitterlinden, Andre G., Holmes, Clive, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A., Powell, John, Golde, Todd E., Graff, Caroline, De Jager, Philip L., Morgan, Kevin, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M., Passmore, Peter, Younkin, Steven G., Berr, Claudine, Gudnason, Vilmundur, Rujescu, Dan, Dickson, Dennis W., Dartigues, Jean-Francois, DeStefano, Anita L., Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A., Van Broeckhoven, Christine, Ikram, M. Arfan, Jones, Lesley, Haines, Jonathan L., Tzourio, Christophe, Launer, Lenore J., Escott-Price, Valentina, Mayeux, Richard, Deleuze, Jean-Francois, Amin, Najaf, Holmans, Peter A., Pericak-Vance, Margaret A., Amouyel, Philippe, van Duijn, Cornelia M., Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie, and Schellenberg, Gerard D.

Published
2017

12. Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers.

Author

Nielsen, Henrietta, Khoonsari, Payam Emami, Herman, Stephanie, Kultima, Kim, Shevchenko, Ganna, Remnestål, Julia, Nilsson, Peter, Giedraitis, Vilmantas, Brundin, RoseMarie, Degerman Gunnarsson, Malin, Kilander, Lena, Lannfelt, Lars, Ingelsson, Martin, Gunnarsson, Malin Degerman, and Zetterberg, Henrik

Abstract

Background: Alzheimer's disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD.Objective: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects.Methods: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4-9 years and 21 of these converted to AD, whereas 53 remained stable.Results: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCI/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively.Conclusions: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects. [ABSTRACT FROM AUTHOR]

Published
2018
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14. The Arctic AβPP mutation leads to Alzheimer's disease pathology with highly variable topographic deposition of differentially truncated Aβ

Author

Kalimo, Hannu, Lalowski, Maciej, Bogdanovic, Nenad, Philipson, Ola, Bird, Thomas D, Nochlin, David, Schellenberg, Gerard D, Brundin, Rosemarie, Olofsson, Tommie, Soliymani, Rabah, Baumann, Marc, Wirths, Oliver, Bayer, Thomas A, Nilsson, Lars Ng, Basun, Hans, Lannfelt, Lars, Ingelsson, Martin, Kalimo, Hannu, Lalowski, Maciej, Bogdanovic, Nenad, Philipson, Ola, Bird, Thomas D, Nochlin, David, Schellenberg, Gerard D, Brundin, Rosemarie, Olofsson, Tommie, Soliymani, Rabah, Baumann, Marc, Wirths, Oliver, Bayer, Thomas A, Nilsson, Lars Ng, Basun, Hans, Lannfelt, Lars, and Ingelsson, Martin

Abstract

BACKGROUND: The Arctic mutation (p.E693G/p.E22G)fs within the β-amyloid (Aβ) region of the β-amyloid precursor protein gene causes an autosomal dominant disease with clinical picture of typical Alzheimer's disease. Here we report the special character of Arctic AD neuropathology in four deceased patients. RESULTS: Aβ deposition in the brains was wide-spread (Thal phase 5) and profuse. Virtually all parenchymal deposits were composed of non-fibrillar, Congo red negative Aβ aggregates. Congo red only stained angiopathic vessels. Mass spectrometric analyses showed that Aβ deposits contained variably truncated and modified wild type and mutated Aβ species. In three of four Arctic AD brains, most cerebral cortical plaques appeared targetoid with centres containing C-terminally (beyond aa 40) and variably N-terminally truncated Aβ surrounded by coronas immunopositive for Aβx-42. In the fourth patient plaque centres contained almost no Aβ making the plaques ring-shaped. The architectural pattern of plaques also varied between different anatomic regions. Tau pathology corresponded to Braak stage VI, and appeared mainly as delicate neuropil threads (NT) enriched within Aβ plaques. Dystrophic neurites were scarce, while neurofibrillary tangles were relatively common. Neuronal perikarya within the Aβ plaques appeared relatively intact. CONCLUSIONS: In Arctic AD brain differentially truncated abundant Aβ is deposited in plaques of variable numbers and shapes in different regions of the brain (including exceptional targetoid plaques in neocortex). The extracellular non-fibrillar Aβ does not seem to cause overt damage to adjacent neurons or to induce formation of neurofibrillary tangles, supporting the view that intracellular Aβ oligomers are more neurotoxic than extracellular Aβ deposits. However, the enrichment of NTs within plaques suggests some degree of intra-plaque axonal damage including accumulation of hp-tau, which may impair axoplasmic transport, and thereby contribute

Published
2013
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15. Interference from Heterophilic Antibodies in Amyloid-beta Oligomer ELISAs

Author

Sehlin, Dag, Söllvander, Sofia, Paulie, Staffan, Brundin, RoseMarie, Ingelsson, Martin, Lannfelt, Lars, Pettersson, Frida Ekholm, Englund, Hillevi, Sehlin, Dag, Söllvander, Sofia, Paulie, Staffan, Brundin, RoseMarie, Ingelsson, Martin, Lannfelt, Lars, Pettersson, Frida Ekholm, and Englund, Hillevi

Abstract

Amyloid-beta (Abeta) oligomers of different sizes and forms have recently been the focus for many Alzheimer's disease (AD) researchers. Various immunoassays have been used to detect low concentrations of these elusive Abeta species in different forms of human samples using little or no sample dilutions. However, the possibility that positive results may be caused by interference from heterophilic antibodies (HA) is often overlooked. HA, which recognize immunoglobulins from other species, are present in human plasma and cerebrospinal fluid (CSF) and may cause interference in sandwich immunoassays like enzyme-linked immunosorbent assays (ELISAs) by cross-binding the capture and detection antibodies of the assay. They thus may generate a false positive signal. Here we show that when assessing the Abeta oligomer content in plasma samples from 44 individuals with a sandwich ELISA, none of the 21 positive signals remained when the assay was repeated in the presence of factors blocking HA. Similarly, in CSF samples from 104 individuals, the signals from the 22 positive samples were strongly reduced when analyzed after anti-HA treatment. Taken together, HA interference is a problem that needs to be addressed when measuring low levels of an antigen in human plasma and CSF samples., Title also written as: Interference from Heterophilic Antibodies in Amyloid-β Oligomer ELISAs

Published
2010
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16. CALHM1 P86L polymorphism does not alter amyloid-beta or tau in cerebrospinal fluid

Author

Giedraitis, Vilmantas, Glaser, Anna, Sarajärvi, Timo, Brundin, RoseMarie, Gunnarsson, Malin Degerman, Schjeide, Brit-Maren, Tanzi, Rudolph E, Helisalmi, Seppo, Pirttilä, Tuula, Kilander, Lena, Lannfelt, Lars, Soininen, Hilkka, Bertram, Lars, Ingelsson, Martin, Hiltunen, Mikko, Giedraitis, Vilmantas, Glaser, Anna, Sarajärvi, Timo, Brundin, RoseMarie, Gunnarsson, Malin Degerman, Schjeide, Brit-Maren, Tanzi, Rudolph E, Helisalmi, Seppo, Pirttilä, Tuula, Kilander, Lena, Lannfelt, Lars, Soininen, Hilkka, Bertram, Lars, Ingelsson, Martin, and Hiltunen, Mikko

Abstract

Recently, the P86L alteration in CALHM1 (calcium homeostasis modulator-1) was reported to be associated with Alzheimer's disease (AD). Moreover, the risk allele increased amyloid-beta (A beta) levels in conditioned media from cultured cells. Therefore, we hypothesized that CALHM1 P86L may modulate A beta or tau levels in cerebrospinal fluid (CSF). Nearly 200 individuals with AD or other cognitive disorders were included for CSF analysis and CALHM1 genotyping. No significant differences in CSF levels of A beta 42, tau or phospho-tau were found across the various CALHM1 genotypes. In conclusion, we found no evidence that CALHM1 P86L is associated with altered CSF levels of the investigated AD biomarkers.

Published
2010
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17. Details of neuropathology in Arctic Alzheimer's disease

Author

Kalimo, H., Bogdanovic, N., Callaghan, Paul O., Bird, T. D., Nochlin, D., Schellenberg, G. D., Brundin, RoseMarie, Olofsson, T., Zhang, Xiao, Nilsson, Lars N. G., Basun, Hans, Lannfelt, Lars, Ingelsson, Martin, Kalimo, H., Bogdanovic, N., Callaghan, Paul O., Bird, T. D., Nochlin, D., Schellenberg, G. D., Brundin, RoseMarie, Olofsson, T., Zhang, Xiao, Nilsson, Lars N. G., Basun, Hans, Lannfelt, Lars, and Ingelsson, Martin

Published
2010
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18. No evidence of PGRN or MAPT gene dosage alterations in a collection of patients with frontotemporal lobar degeneration

Author

Skoglund, Lena, Ingvast, Sofie, Matsui, Toshifumi, Freeman, Stefanie, Frosch, Matthew, Brundin, Rosemarie, Giedraitis, Vilmantas, Growdon, John, Hyman, Bradley, Lannfelt, Lars, Ingelsson, Martin, Glaser, Anna, Skoglund, Lena, Ingvast, Sofie, Matsui, Toshifumi, Freeman, Stefanie, Frosch, Matthew, Brundin, Rosemarie, Giedraitis, Vilmantas, Growdon, John, Hyman, Bradley, Lannfelt, Lars, Ingelsson, Martin, and Glaser, Anna

Abstract

Background/Aims Alterations in gene dosage have recently been associated with neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, and deletions of the progranulin (PGRN) locus were recently described in patients with frontotemporal lobar degeneration (FTLD). FTLD is a genetically complex neurodegenerative disorder with mutations in the PGRN and the microtubule-associated protein tau (MAPT) genes being the most common known causes of familial FTLD. In this study, we investigated 39 patients with FTLD, previously found negative for mutations in PGRN and MAPT, for copy number alterations of these 2 genes. Methods Gene dosage analysis of PGRN and MAPT was performed using multiplex ligation-dependent probe amplification. Results We did not identify any PGRN or MAPT gene dosage variations in the 39 FTLD patients investigated. Conclusion We therefore conclude that alterations in gene copy number of PGRN and MAPT are not a cause of disease in this ollection of FTLD patients.

Published
2009
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19. Oligomerization partially explains the lowering of Aβ42 in Alzheimer's disease cerebrospinal fluid

Author

Englund, Hillevi, Degerman Gunnarsson, Malin, Brundin, RoseMarie, Hedlund, Marie, Kilander, Lena, Lannfelt, Lars, Ekholm Pettersson, Frida, Englund, Hillevi, Degerman Gunnarsson, Malin, Brundin, RoseMarie, Hedlund, Marie, Kilander, Lena, Lannfelt, Lars, and Ekholm Pettersson, Frida

Abstract

Background/aim: The lowering of natively analyzed Aβ42 in cerebrospinal fluid (CSF) is used as a diagnostic tool in Alzheimer’s disease (AD). Presence of Aβ oligomers can interfere with such analyses causing underestimation of Aβ levels due to epitope masking. The aim was to investigate if the lowering of CSF Aβ42 seen is caused by oligomerization. Methods: Aβ42 was analyzed under both denaturing and non-denaturing conditions. An Aβ42 oligomer ratio was calculated from these quantifications. Presence of oligomers leads to Aβ42 epitope masking during non-denaturing assays, resulting in a higher ratio. Results: The Aβ42 oligomer ratio was used for assessment of oligomerized Aβ in human CSF, after being evaluated in transgenic mouse brain homogenates. AD and mild cognitive impairment (MCI) samples displayed the expected decrease in natively measured Aβ42 compared to healthy controls and frontotemporal dementia, but not when analyzing under denaturing conditions. Accordingly, AD and MCI CSF had a higher Aβ42 oligomer ratio in CSF. Conclusion: Combining denaturing and non-denaturing quantifications of Aβ42 into an oligomer ratio enables assessment of Aβ oligomers in biological samples. The increased Aβ42 oligomer ratio for AD and MCI indicates presence of oligomers in CSF and that the lowering of natively measured Aβ42 is caused by oligomerization.

Published
2009
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20. The Arctic AβPP mutation leads to Alzheimer’s disease pathology with highly variable topographic deposition of differentially truncated Aβ

Author

Kalimo, Hannu, primary, Lalowski, Maciej, additional, Bogdanovic, Nenad, additional, Philipson, Ola, additional, Bird, Thomas D, additional, Nochlin, David, additional, Schellenberg, Gerard D, additional, Brundin, RoseMarie, additional, Olofsson, Tommie, additional, Soliymani, Rabah, additional, Baumann, Marc, additional, Wirths, Oliver, additional, Bayer, Thomas A, additional, Nilsson, Lars NG, additional, Basun, Hans, additional, Lannfelt, Lars, additional, and Ingelsson, Martin, additional

Published
2013
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21. New Alzheimer's disease locus on chromosome 8

Author

Giedraitis, Vilmantas, Hedlund, M., Skoglund, Lena, Blom, Elin, Ingvast, Sofie, Brundin, RoseMarie, Lannfelt, Lars, Glaser, Anna, Giedraitis, Vilmantas, Hedlund, M., Skoglund, Lena, Blom, Elin, Ingvast, Sofie, Brundin, RoseMarie, Lannfelt, Lars, and Glaser, Anna

Abstract

Background: Family history is one of the most consistent risk factors for dementia. Therefore, analysis of families with a distinct inheritance pattern of disease can be a powerful approach for the identification of previously unknown disease genes. Objective: To map susceptibility regions for Alzheimer's disease. Methods: A complete genome scan with 369 microsatellite markers was carried out in 12 extended families collected in Sweden. Age at disease onset ranged from 53 to 78 years, but in 10 of the families there was at least one member with age at onset of <= 65 years. Mutations in known early-onset Alzheimer's disease susceptibility genes have been excluded. All people were genotyped for APOE, but no clear linkage with the epsilon 4 allele was observed. Results: Although no common disease locus could be found in all families, in two families an extended haplotype was identified on chromosome 8q shared by all affected members. In one of the families, a non-parametric multi-marker logarithm of the odds (LOD) score of 4.2 (p = 0.004) was obtained and analysis based on a dominant model showed a parametric LOD score of 2.4 for this region. All six affected members of this family shared a haplotype of 10 markers spanning about 40 cM. Three affected members in another family also shared a haplotype in the same region. Conclusion: On the basis of our data, we propose the existence of a dominantly acting Alzheimer's disease susceptibility locus on chromosome 8.

Published
2006
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23. No Evidence of PGRN or MAPT Gene Dosage Alterations in a Collection of Patients with Frontotemporal Lobar Degeneration

Author

Skoglund, Lena, primary, Ingvast, Sofie, additional, Matsui, Toshifumi, additional, Freeman, Stefanie H., additional, Frosch, Matthew P., additional, Brundin, Rosemarie, additional, Giedraitis, Vilmantas, additional, Growdon, John H., additional, Hyman, Bradley T., additional, Lannfelt, Lars, additional, Ingelsson, Martin, additional, and Glaser, Anna, additional

Published
2009
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26. The Uppsala APPdeletion causes early onset autosomal dominant Alzheimer’s disease by altering APP processing and increasing amyloid β fibril formation

Author

Pagnon de la Vega, María, Giedraitis, Vilmantas, Michno, Wojciech, Kilander, Lena, Güner, Gökhan, Zielinski, Mara, Löwenmark, Malin, Brundin, RoseMarie, Danfors, Torsten, Söderberg, Linda, Alafuzoff, Irina, Nilsson, Lars N.G., Erlandsson, Anna, Willbold, Dieter, Müller, Stephan A., Schröder, Gunnar F., Hanrieder, Jörg, Lichtenthaler, Stefan F., Lannfelt, Lars, Sehlin, Dag, and Ingelsson, Martin

Abstract

The Uppsala APPdeletion leads to Alzheimer’s disease by modulating α- and β-secretase cleavage of APP and by accelerating Aβ fibrillization.

Published
2021
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27. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Author

Sims, Rebecca, Van Der Lee, Sven J, Naj, Adam C, Bellenguez, Céline, Badarinarayan, Nandini, Jakobsdottir, Johanna, Kunkle, Brian W, Boland, Anne, Raybould, Rachel, Bis, Joshua C, Martin, Eden R, Grenier-Boley, Benjamin, Heilmann-Heimbach, Stefanie, Chouraki, Vincent, Kuzma, Amanda B, Sleegers, Kristel, Vronskaya, Maria, Ruiz, Agustin, Graham, Robert R, Olaso, Robert, Hoffmann, Per, Grove, Megan L, Vardarajan, Badri N, Hiltunen, Mikko, Nöthen, Markus M, White, Charles C, Hamilton-Nelson, Kara L, Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W, Dulary, Cécile, Herms, Stefan, Smith, Albert V, Funk, Cory C, Derbois, Céline, Forstner, Andreas J, Ahmad, Shahzad, Li, Hongdong, Bacq, Delphine, Harold, Denise, Satizabal, Claudia L, Valladares, Otto, Squassina, Alessio, Thomas, Rhodri, Brody, Jennifer A, Qu, Liming, Sánchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J, Zhao, Yi, Garcia, Florentino Sanchez, Denning, Nicola, Fornage, Myriam, Malamon, John, Naranjo, Maria Candida Deniz, Majounie, Elisa, Mosley, Thomas H, Dombroski, Beth, Wallon, David, Lupton, Michelle K, Dupuis, Josée, Whitehead, Patrice, Fratiglioni, Laura, Medway, Christopher, Jian, Xueqiu, Mukherjee, Shubhabrata, Keller, Lina, Brown, Kristelle, Lin, Honghuang, Cantwell, Laura B, Panza, Francesco, McGuinness, Bernadette, Moreno-Grau, Sonia, Burgess, Jeremy D, Solfrizzi, Vincenzo, Proitsi, Petra, Adams, Hieab H, Allen, Mariet, Seripa, Davide, Pastor, Pau, Cupples, L Adrienne, Price, Nathan D, Hannequin, Didier, Frank-García, Ana, Levy, Daniel, Chakrabarty, Paramita, Caffarra, Paolo, Giegling, Ina, Beiser, Alexa S, Giedraitis, Vilmantas, Hampel, Harald, Garcia, Melissa E, Wang, Xue, Lannfelt, Lars, Mecocci, Patrizia, Eiriksdottir, Gudny, Crane, Paul K, Pasquier, Florence, Boccardi, Virginia, Henández, Isabel, Barber, Robert C, Scherer, Martin, Tarraga, Lluis, Adams, Perrie M, Leber, Markus, Chen, Yuning, Albert, Marilyn S, Riedel-Heller, Steffi, Emilsson, Valur, Beekly, Duane, Braae, Anne, Schmidt, Reinhold, Blacker, Deborah, Masullo, Carlo, Schmidt, Helena, Doody, Rachelle S, Spalletta, Gianfranco, Longstreth, WT, Fairchild, Thomas J, Bossù, Paola, Lopez, Oscar L, Frosch, Matthew P, Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M, Jessen, Frank, Li, Shuo, Kamboh, M Ilyas, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J, Corcoran, Chris, Dunstan, Melanie, Braddel, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Gerrish, Amy, Chapman, Jade, Aguilar, Miquel, Taylor, Sarah, Hill, Matt, Fairén, Mònica Díez, Hodges, Angela, Vellas, Bruno, Soininen, Hilkka, Kloszewska, Iwona, Daniilidou, Makrina, Uphill, James, Patel, Yogen, Hughes, Joseph T, Lord, Jenny, Turton, James, Hartmann, Annette M, Cecchetti, Roberta, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Caltagirone, Carlo, Orfei, Maria Donata, Ciaramella, Antonio, Pichler, Sabrina, Mayhaus, Manuel, Gu, Wei, Lleó, Alberto, Fortea, Juan, Blesa, Rafael, Barber, Imelda S, Brookes, Keeley, Cupidi, Chiara, Maletta, Raffaele Giovanni, Carrell, David, Sorbi, Sandro, Moebus, Susanne, Urbano, Maria, Pilotto, Alberto, Kornhuber, Johannes, Bosco, Paolo, Todd, Stephen, Craig, David, Johnston, Janet, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Fox, Nick C, Hardy, John, ARUK Consortium, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Baldwin, Clinton T, Barnes, Lisa L, Barral, Sandra, Beach, Thomas G, Becker, James T, Bigio, Eileen H, Bird, Thomas D, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Burns, Jeffrey M, Buxbaum, Joseph D, Cairns, Nigel J, Cao, Chuanhai, Carlson, Chris S, Carlsson, Cynthia M, Carney, Regina M, Carrasquillo, Minerva M, Carroll, Steven L, Diaz, Carolina Ceballos, Chui, Helena C, Clark, David G, Cribbs, David H, Crocco, Elizabeth A, DeCarli, Charles, Dick, Malcolm, Duara, Ranjan, Evans, Denis A, Faber, Kelley M, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Ferris, Steven, Foroud, Tatiana M, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Gilbert, John R, Graff-Radford, Neill R, Green, Robert C, Growdon, John H, Hamilton, Ronald L, Harrell, Lindy E, Honig, Lawrence S, Huentelman, Matthew J, Hulette, Christine M, Hyman, Bradley T, Jarvik, Gail P, Abner, Erin, Jin, Lee-Way, Jun, Gyungah, Karydas, Anna, Kaye, Jeffrey A, Kim, Ronald, Kowall, Neil W, Kramer, Joel H, LaFerla, Frank M, Lah, James J, Leverenz, James B, Levey, Allan I, Li, Ge, Lieberman, Andrew P, Lunetta, Kathryn L, Lyketsos, Constantine G, Marson, Daniel C, Martiniuk, Frank, Mash, Deborah C, Masliah, Eliezer, McCormick, Wayne C, McCurry, Susan M, McDavid, Andrew N, McKee, Ann C, Mesulam, Marsel, Miller, Bruce L, Miller, Carol A, Miller, Joshua W, Morris, John C, Murrell, Jill R, Myers, Amanda J, O'Bryant, Sid, Olichney, John M, Pankratz, Vernon S, Parisi, Joseph E, Paulson, Henry L, Perry, William, Peskind, Elaine, Pierce, Aimee, Poon, Wayne W, Potter, Huntington, Quinn, Joseph F, Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reitz, Christiane, Ringman, John M, Roberson, Erik D, Rogaeva, Ekaterina, Rosen, Howard J, Rosenberg, Roger N, Sager, Mark A, Saykin, Andrew J, Schneider, Julie A, Schneider, Lon S, Seeley, William W, Smith, Amanda G, Sonnen, Joshua A, Spina, Salvatore, Stern, Robert A, Swerdlow, Russell H, Tanzi, Rudolph E, Thornton-Wells, Tricia A, Trojanowski, John Q, Troncoso, Juan C, Van Deerlin, Vivianna M, Van Eldik, Linda J, Vinters, Harry V, Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A, Wilhelmsen, Kirk C, Williamson, Jennifer, Wingo, Thomas S, Woltjer, Randall L, Wright, Clinton B, Yu, Chang-En, Yu, Lei, Garzia, Fabienne, Golamaully, Feroze, Septier, Gislain, Engelborghs, Sebastien, Vandenberghe, Rik, De Deyn, Peter P, Fernadez, Carmen Muñoz, Benito, Yoland Aladro, Thonberg, Hakan, Forsell, Charlotte, Lilius, Lena, Kinhult-Stählbom, Anne, Kilander, Lena, Brundin, RoseMarie, Concari, Letizia, Helisalmi, Seppo, Koivisto, Anne Maria, Haapasalo, Annakaisa, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Ritchie, Karen, Dubois, Bruno, Himali, Jayanadra J, Keene, C Dirk, Tschanz, JoAnn, Fitzpatrick, Annette L, Kukull, Walter A, Norton, Maria, Aspelund, Thor, Larson, Eric B, Munger, Ron, Rotter, Jerome I, Lipton, Richard B, Bullido, María J, Hofman, Albert, Montine, Thomas J, Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C, Alvarez, Victoria, Rivadeneira, Fernando, Reiman, Eric M, Gallo, Maura, O'Donnell, Christopher J, Reisch, Joan S, Bruni, Amalia Cecilia, Royall, Donald R, Dichgans, Martin, Sano, Mary, Galimberti, Daniela, St George-Hyslop, Peter, Scarpini, Elio, Tsuang, Debby W, Mancuso, Michelangelo, Bonuccelli, Ubaldo, Winslow, Ashley R, Daniele, Antonio, Wu, Chuang-Kuo, GERAD/PERADES, CHARGE, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol, Rubinsztein, David C, Bras, Jose, Guerreiro, Rita, Al-Chalabi, Ammar, Shaw, Christopher E, Collinge, John, Mann, David, Tsolaki, Magda, Clarimón, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C, Owen, Michael J, Behrens, Timothy W, Mead, Simon, Goate, Alison M, Uitterlinden, Andre G, Holmes, Clive, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A, Powell, John, Golde, Todd E, Graff, Caroline, De Jager, Philip L, Morgan, Kevin, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M, Passmore, Peter, Younkin, Steven G, Berr, Claudine, Gudnason, Vilmundur, Rujescu, Dan, Dickson, Dennis W, Dartigues, Jean-François, DeStefano, Anita L, Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A, Van Broeckhoven, Christine, Ikram, M Arfan, Jones, Lesley, Haines, Jonathan L, Tzourio, Christophe, Launer, Lenore J, Escott-Price, Valentina, Mayeux, Richard, Deleuze, Jean-François, Amin, Najaf, Holmans, Peter A, Pericak-Vance, Margaret A, Amouyel, Philippe, Van Duijn, Cornelia M, Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie, and Schellenberg, Gerard D

Subjects
Membrane Glycoproteins, Genotype, Sequence Homology, Amino Acid, Phospholipase C gamma, Gene Expression Profiling, Polymorphism, Single Nucleotide, Immunity, Innate, Linkage Disequilibrium, 3. Good health, Gene Frequency, Alzheimer Disease, Case-Control Studies, Odds Ratio, Humans, Exome, Genetic Predisposition to Disease, Amino Acid Sequence, Microglia, Protein Interaction Maps, Receptors, Immunologic, Adaptor Proteins, Signal Transducing
Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

28. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Author

Taylor, Sarah, Craig, David, Qu, Liming, Haines, Jonathan L., Morgan, Taniesha, Sager, Mark A., Jun, Gyungah, Beiser, Alexa S., St George-Hyslop, Peter, Levey, Allan I., Vellas, Bruno, Collinge, John, Himali, Jayanadra J., Katz, Mindy J., Frank-García, Ana, Thonberg, Hakan, Grenier-Boley, Benjamin, Emilsson, Valur, Chouraki, Vincent, Jarvik, Gail P., Rotter, Jerome I., Nacmias, Benedetta, Chapman, Jade, Coto, Eliecer, Eiriksdottir, Gudny, Burgess, Jeremy D., Tsolaki, Magda, Saykin, Andrew J., Clarimón, Jordi, Hartmann, Annette M., Beekly, Duane, Peters, Oliver, Fairén, Mònica Díez, Brayne, Carol, Bras, Jose, Zhao, Yi, Riemenschneider, Matthias, Corcoran, Chris, Norton, Maria, Ikram, M Arfan, Gudnason, Vilmundur, Wallon, David, Serpente, Maria, Septier, Gislain, Atwood, Craig S., Yu, Chang-En, Sorbi, Sandro, Carlsson, Cynthia M., McCormick, Wayne C., Urbano, Maria, Galasko, Douglas R., Potter, Huntington, Raj, Ashok, Dufouil, Carole, Reisberg, Barry, Braae, Anne, Fratiglioni, Laura, Forsell, Charlotte, Shaw, Christopher E., Pastor, Pau, Jin, Lee-Way, Carrasquillo, Minerva M., Epelbaum, Jacques, Psaty, Bruce M., McDavid, Andrew N., Lilius, Lena, Ramirez, Alfredo, Berr, Claudine, Green, Robert C., Riedel-Heller, Steffi, Kornhuber, Johannes, Heilmann-Heimbach, Stefanie, Kauwe, John Keoni, Dunstan, Melanie, Miller, Bruce L., McKee, Ann C., Van Broeckhoven, Christine, Harold, Denise, Turton, James, Brookes, Keeley, Owen, Michael J., Brown, Kristelle, Dick, Malcolm, Pilotto, Alberto, Hill, Matt, Carney, Regina M., Thomas, Rhodri, Barber, Imelda S., Gearing, Marla, Brody, Jennifer A, Scarpini, Elio, Graff, Caroline, Pierce, Aimee, Miller, Joshua W., Ruiz, Agustin, Hofman, Albert, Seeley, William W., Hyman, Bradley T., Schellenberg, Gerard D., Campion, Dominique, Patel, Yogen, Welsh-Bohmer, Kathleen A., Martiniuk, Frank, Moreno-Grau, Sonia, Funk, Cory C., Hamilton-Nelson, Kara L., Cribbs, David H., Chakrabarty, Paramita, Keller, Lina, Golde, Todd E., Cao, Chuanhai, Petersen, Ronald C., Evans, Denis A., Leverenz, James B., Frosch, Matthew P., Laferla, Frank M., Pericak-Vance, Margaret A., Woltjer, Randall L., Smith, Albert V., Rogaeva, Ekaterina, Fenoglio, Chiara, Lyketsos, Constantine G., Sussams, Rebecca, Kamboh, M Ilyas, Becker, James T., Mayeux, Richard, Raybould, Rachel, Alvarez, Victoria, Yu, Lei, O'Bryant, Sid, Kim, Ronald, Vinters, Harry V., Aspelund, Thor, Lieberman, Andrew P., Vardarajan, Badri N., Tzourio, Christophe, Tsuang, Debby W., Albert, Marilyn S., Hodges, Angela, Honig, Lawrence S., Sonnen, Joshua A., Hughes, Joseph T., Sacchinelli, Eleonora, Pankratz, Vernon S., Koivisto, Anne Maria, Sleegers, Kristel, Dickson, Dennis W, Vronskaya, Maria, Mead, Simon, Rosenberg, Roger N., Boccardi, Virginia, Graff-Radford, Neill R., Sotolongo-Grau, Oscar, Maier, Wolfgang, Gerrish, Amy, Peskind, Elaine, O'Donnell, Christopher J., Carroll, Steven L., Masullo, Carlo, Garcia, Florentino Sanchez, Sano, Mary, Schmidt, Reinhold, Vonsattel, Jean Paul, Raskind, Murray, McCurry, Susan M., Reitz, Christiane, Dermecourt, Vincent, Hannequin, Didier, Lynch, Aoibhinn, Adams, Perrie M., Gill, Michael, Ahmad, Shahzad, Bacq, Delphine, Stern, Robert A., Burke, James R., Hakonarson, Hakon, Naj, Adam C, Fallon, Kenneth B., De Deyn, Peter P., Masliah, Eliezer, Brundin, Rosemarie, Dubois, Bruno, Schneider, Lon S., Morris, John C., Holmes, Clive, Lunetta, Kathryn L., Duara, Ranjan, Boeve, Bradley F., Larson, Eric B., Fornage, Myriam, Lopez, Oscar L., Lupton, Michelle K., Winslow, Ashley R., Giegling, Ina, Spina, Salvatore, Nöthen, Markus M., Paulson, Henry L., Uphill, James, Blacker, Deborah, Arnold, Steven E., Jakobsdottir, Johanna, Li, Hongdong, Choi, Seung-Hoan, Arcaro, Marina, Dupuis, Josée, Schmidt, Helena, Majounie, Elisa, Powell, John, Pichler, Sabrina, Thornton-Wells, Tricia A., Foroud, Tatiana M., Carlson, Chris S., Jessen, Frank, Boerwinkle, Eric, Younkin, Steven G., Amin, Najaf, Van Deerlin, Vivianna M., Ferris, Steven, Leber, Markus, Thomas, Charlene, Johnston, Janet, Whitehead, Patrice, Dombroski, Beth, Kaye, Jeffrey A., Royall, Donald R., Engelborghs, Sebastien, Spalletta, Gianfranco, Hoffmann, Per, Marshall, Rachel, Orfei, Maria Donata, Bellenguez, Céline, Beach, Thomas G., Haapasalo, Annakaisa, Perry, William, Cecchetti, Roberta, Blesa, Rafael, Bullido, María J., Daniele, Antonio, Fievet, Nathalie, Troncoso, Juan C., Chui, Helena C., Benito, Yoland Aladro, Grove, Megan L., Lord, Jenny, Daniilidou, Makrina, Cairns, Nigel J., Cupples, L Adrienne, Tanzi, Rudolph E., Lipton, Richard B., Galimberti, Daniela, Parisi, Joseph E., Garcia, Melissa E., Ciaramella, Antonio, Mesulam, Marsel, Bigio, Eileen H., Tschanz, Joann, Fernadez, Carmen Muñoz, Giedraitis, Vilmantas, Van Eldik, Linda J., Weintraub, Sandra, Karydas, Anna, Burns, Jeffrey M., Van Duijn, Cornelia M., Farrer, Lindsay A., Derbois, Céline, Combarros, Onofre, Growdon, John H., Satizabal, Claudia L., Escott-Price, Valentina, Ritchie, Karen, Kinhult-Stählbom, Anne, Braddel, Amy, Barnes, Lisa L., Diaz, Carolina Ceballos, Morgan, Kevin, Kramer, Joel H., Ingelsson, Martin, Williams, Julie, Boxer, Adam, Caffarra, Paolo, Aguilar, Miquel, Barral, Sandra, Doody, Rachelle S., Hiltunen, Mikko, Ortega-Cubero, Sara, Concari, Letizia, Passmore, Peter, Huebinger, Ryan M., Sánchez-Juan, Pascual, Fardo, David W., Olichney, John M., Dichgans, Martin, Lambert, Jean-Charles, Gu, Wei, Hardy, John, Gallo, Maura, Lannfelt, Lars, Allen, Mariet, Yang, Qiong, Behrens, Timothy W., Uitterlinden, Andre G., Adams, Hieab H, Henández, Isabel, Levy, Daniel, Cantwell, Laura B., Hulette, Christine M., Lin, Honghuang, Crocco, Elizabeth A., Deleuze, Jean-François, Keene, C Dirk, De Jager, Philip L, Boada, Merce, Soininen, Hilkka, Olaso, Robert, Mayhaus, Manuel, Maletta, Raffaele Giovanni, Graham, Robert R, Trojanowski, John Q., Mancuso, Michelangelo, Mash, Deborah C., Golamaully, Feroze, Naranjo, Maria Candida Deniz, Hamilton, Ronald L., Wang, Xue, Kowall, Neil W., Fox, Nick C., Valladares, Otto, Buxbaum, Joseph D., Bis, Joshua C., Quinn, Joseph F., Martin, Eden R., Brice, Alexis, Cupidi, Chiara, Farlow, Martin R., Wright, Clinton B., Badarinarayan, Nandini, Kukull, Walter A., Price, Nathan D., Hanon, Olivier, Mosley, Thomas H., Chen, Yuning, Proitsi, Petra, Swerdlow, Russell H., Al-Chalabi, Ammar, Williamson, Jennifer, Murrell, Jill R., Panza, Francesco, Boland, Anne, Wolters, Frank J, Rosen, Howard J., Dulary, Cécile, Goate, Alison M., Li, Shuo, Hampel, Harald, Pasquier, Florence, Clark, David G., Schneider, Julie A., Jr, W T Longstreth, Todd, Stephen, Roberson, Erik D., Bird, Thomas D., Lleó, Alberto, Bowen, James D., Reisch, Joan S., Fairchild, Thomas J., Malamon, John, Bosco, Paolo, Garzia, Fabienne, Marson, Daniel C., Reiman, Eric M., Bossù, Paola, Kuzma, Amanda B., Kloszewska, Iwona, Apostolova, Liana G., Carrell, David, Mecocci, Patrizia, Ertekin-Taner, Nilufer, Wilhelmsen, Kirk C., Miller, Carol A., Ghetti, Bernardino, Montine, Thomas J., Kilander, Lena, Jones, Lesley, Lovestone, Simon, Gilbert, John R., Forstner, Andreas J., Wang, Li-San, Smith, Amanda G., Decarli, Charles, Tarraga, Lluis, Seshadri, Sudha, Rivadeneira, Fernando, Crane, Paul K., Helisalmi, Seppo, Squassina, Alessio, Heun, Reinhard, Bonuccelli, Ubaldo, Amouyel, Philippe, Ringman, John M., Destefano, Anita L., Myers, Amanda J., Meggy, Alun, Van Der Lee, Sven J, White, Charles C., Lah, James J., McGuinness, Bernadette, Rubinsztein, David C, Bruni, Amalia Cecilia, Seripa, Davide, Denning, Nicola, Baldwin, Clinton T., Caltagirone, Carlo, Huentelman, Matthew J., Albin, Roger L., Rujescu, Dan, Solfrizzi, Vincenzo, Bennett, David A., Harrell, Lindy E., Herms, Stefan, Faber, Kelley M., Geschwind, Daniel H., Asthana, Sanjay, Beecham, Gary W., Barber, Robert C., Fortea, Juan, Poon, Wayne W., Jian, Xueqiu, Moebus, Susanne, O'Donovan, Michael C., Abner, Erin, Fitzpatrick, Annette L., Mukherjee, Shubhabrata, Wu, Chuang-Kuo, Lawlor, Brian, Guerreiro, Rita, Vandenberghe, Rik, Sims, Rebecca, Kunkle, Brian W., Dartigues, Jean-François, Munger, Ron, Medway, Christopher, Wingo, Thomas S., Li, Ge, Scherer, Martin, and Cruchaga, Carlos

Subjects
3. Good health
Abstract

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P

29. Chitinase-3-like protein 1 (CH3L1) and Neurosecretory protein VGF (VGF) as two novel CSF biomarker candidates for improved diagnostics in Alzheimer’s disease

Author

Emami Khoonsari, Payam, Shevchenko, Ganna, Herman, Stephanie, Musunuri, Sravani, Remnestål, Julia, Brundin, RoseMarie, Degerman Gunnarsson, Malin, Kilander, Lena, Zetterberg, Henrik, Nilsson, Peter, Lannfelt, Lars, Ingelsson, Martin, Kultima, Kim, Emami Khoonsari, Payam, Shevchenko, Ganna, Herman, Stephanie, Musunuri, Sravani, Remnestål, Julia, Brundin, RoseMarie, Degerman Gunnarsson, Malin, Kilander, Lena, Zetterberg, Henrik, Nilsson, Peter, Lannfelt, Lars, Ingelsson, Martin, and Kultima, Kim

Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by amyloid-β (Aβ) plaque deposition and accumulation of intracellular neurofibrillary tangles. This pathology is mirrored in the cerebrospinal fluid (CSF), where decreased Aβ42 together with increased total (t-tau) and phospho-tau (p-tau) today is used as a diagnostic marker. Although these biomarkers have a fairly good sensitivity and specificity, additional biomarkers are needed to further improve the accuracy for early disease detection and to monitor disease development. In this study, we used mass spectrometry-based shotgun proteomics to investigate the CSF proteome of patients with AD and mild cognitive impairment (MCI) as well as of non-demented controls. By combining the diagnostic markers (Aβ42, total t-tau, and p-tau) with a selection of proteomics biomarkers, the accuracy of predicting MCI to AD conversion increased from 83% to 92% with a specificity of 1.0 and sensitivity of 0.86. Among these markers, the levels of protein chitinase-3-like protein 1 (CH3L1) were significantly higher in AD and MCI converters compared to controls. In addition to Aβ42, t-tau, and p-tau the protein CH3L1 contributed mostly to the prediction accuracy. We also found statistically significant lower CSF levels of the neurosecretory protein VGF (VGF) in AD compared to controls. Taken together, our findings suggest that incorporating new CSF biomarkers can further enhance early diagnosis of AD.

31. The Uppsala APP deletion causes early onset autosomal dominant Alzheimer’s disease by altering APP processing and increasing amyloid-β fibril formation

Author

Pagnon de la Vega, María, Giedraitis, Vilmantas, Michno, Wojciech, Kilander, Lena, Güner, Gökhan, Zielinski, Mara, Löwenmark, Malin, Brundin, RoseMarie, Danfors, Torsten, Söderberg, Linda, Alafuzoff, Irina, Nilsson, Lars, Erlandsson, Anna, Willbold, Dieter, Müller, Stephan A., Schöder, Gunnar F., Hanrieder, Jörg, Lichtenthaler, Stefan F., Lannfelt, Lars, Sehlin, Dag, Ingelsson, Martin, Pagnon de la Vega, María, Giedraitis, Vilmantas, Michno, Wojciech, Kilander, Lena, Güner, Gökhan, Zielinski, Mara, Löwenmark, Malin, Brundin, RoseMarie, Danfors, Torsten, Söderberg, Linda, Alafuzoff, Irina, Nilsson, Lars, Erlandsson, Anna, Willbold, Dieter, Müller, Stephan A., Schöder, Gunnar F., Hanrieder, Jörg, Lichtenthaler, Stefan F., Lannfelt, Lars, Sehlin, Dag, and Ingelsson, Martin

32. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Author

Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A, Bellenguez C, Frizatti A, Chouraki V, Martin ER, Sleegers K, Badarinarayan N, Jakobsdottir J, Hamilton-Nelson KL, Moreno-Grau S, Olaso R, Raybould R, Chen Y, Kuzma AB, Hiltunen M, Morgan T, Ahmad S, Vardarajan BN, Epelbaum J, Hoffmann P, Boada M, Beecham GW, Garnier JG, Harold D, Fitzpatrick AL, Valladares O, Moutet ML, Gerrish A, Smith AV, Qu L, Bacq D, Denning N, Jian X, Zhao Y, Del Zompo M, Fox NC, Choi SH, Mateo I, Hughes JT, Adams HH, Malamon J, Sanchez-Garcia F, Patel Y, Brody JA, Dombroski BA, Naranjo MCD, Daniilidou M, Eiriksdottir G, Mukherjee S, Wallon D, Uphill J, Aspelund T, Cantwell LB, Garzia F, Galimberti D, Hofer E, Butkiewicz M, Fin B, Scarpini E, Sarnowski C, Bush WS, Meslage S, Kornhuber J, White CC, Song Y, Barber RC, Engelborghs S, Sordon S, Voijnovic D, Adams PM, Vandenberghe R, Mayhaus M, Cupples LA, Albert MS, De Deyn PP, Gu W, Himali JJ, Beekly D, Squassina A, Hartmann AM, Orellana A, Blacker D, Rodriguez-Rodriguez E, Lovestone S, Garcia ME, Doody RS, Munoz-Fernadez C, Sussams R, Lin H, Fairchild TJ, Benito YA, Holmes C, Karamujić-Čomić H, Frosch MP, Thonberg H, Maier W, Roshchupkin G, Ghetti B, Giedraitis V, Kawalia A, Li S, Huebinger RM, Kilander L, Moebus S, Hernández I, Kamboh MI, Brundin R, Turton J, Yang Q, Katz MJ, Concari L, Lord J, Beiser AS, Keene CD, Helisalmi S, Kloszewska I, Kukull WA, Koivisto AM, Lynch A, Tarraga L, Larson EB, Haapasalo A, Lawlor B, Mosley TH, Lipton RB, Solfrizzi V, Gill M, Longstreth WT Jr, Montine TJ, Frisardi V, Diez-Fairen M, Rivadeneira F, Petersen RC, Deramecourt V, Alvarez I, Salani F, Ciaramella A, Boerwinkle E, Reiman EM, Fievet N, Rotter JI, Reisch JS, Hanon O, Cupidi C, Andre Uitterlinden AG, Royall DR, Dufouil C, Maletta RG, de Rojas I, Sano M, Brice A, Cecchetti R, George-Hyslop PS, Ritchie K, Tsolaki M, Tsuang DW, Dubois B, Craig D, Wu CK, Soininen H, Avramidou D, Albin RL, Fratiglioni L, Germanou A, Apostolova LG, Keller L, Koutroumani M, Arnold SE, Panza F, Gkatzima O, Asthana S, Hannequin D, Whitehead P, Atwood CS, Caffarra P, Hampel H, Quintela I, Carracedo Á, Lannfelt L, Rubinsztein DC, Barnes LL, Pasquier F, Frölich L, Barral S, McGuinness B, Beach TG, Johnston JA, Becker JT, Passmore P, Bigio EH, Schott JM, Bird TD, Warren JD, Boeve BF, Lupton MK, Bowen JD, Proitsi P, Boxer A, Powell JF, Burke JR, Kauwe JSK, Burns JM, Mancuso M, Buxbaum JD, Bonuccelli U, Cairns NJ, McQuillin A, Cao C, Livingston G, Carlson CS, Bass NJ, Carlsson CM, Hardy J, Carney RM, Bras J, Carrasquillo MM, Guerreiro R, Allen M, Chui HC, Fisher E, Masullo C, Crocco EA, DeCarli C, Bisceglio G, Dick M, Ma L, Duara R, Graff-Radford NR, Evans DA, Hodges A, Faber KM, Scherer M, Fallon KB, Riemenschneider M, Fardo DW, Heun R, Farlow MR, Kölsch H, Ferris S, Leber M, Foroud TM, Heuser I, Galasko DR, Giegling I, Gearing M, Hüll M, Geschwind DH, Gilbert JR, Morris J, Green RC, Mayo K, Growdon JH, Feulner T, Hamilton RL, Harrell LE, Drichel D, Honig LS, Cushion TD, Huentelman MJ, Hollingworth P, Hulette CM, Hyman BT, Marshall R, Jarvik GP, Meggy A, Abner E, Menzies GE, Jin LW, Leonenko G, Real LM, Jun GR, Baldwin CT, Grozeva D, Karydas A, Russo G, Kaye JA, Kim R, Jessen F, Kowall NW, Vellas B, Kramer JH, Vardy E, LaFerla FM, Jöckel KH, Lah JJ, Dichgans M, Leverenz JB, Mann D, Levey AI, Pickering-Brown S, Lieberman AP, Klopp N, Lunetta KL, Wichmann HE, Lyketsos CG, Morgan K, Marson DC, Brown K, Martiniuk F, Medway C, Mash DC, Nöthen MM, Masliah E, Hooper NM, McCormick WC, Daniele A, McCurry SM, Bayer A, McDavid AN, Gallacher J, McKee AC, van den Bussche H, Mesulam M, Brayne C, Miller BL, Riedel-Heller S, Miller CA, Miller JW, Al-Chalabi A, Morris JC, Shaw CE, Myers AJ, Wiltfang J, O'Bryant S, Olichney JM, Alvarez V, Parisi JE, Singleton AB, Paulson HL, Collinge J, Perry WR, Mead S, Peskind E, Cribbs DH, Rossor M, Pierce A, Ryan NS, Poon WW, Nacmias B, Potter H, Sorbi S, Quinn JF, Sacchinelli E, Raj A, Spalletta G, Raskind M, Caltagirone C, Bossù P, Orfei MD, Reisberg B, Clarke R, Reitz C, Smith AD, Ringman JM, Warden D, Roberson ED, Wilcock G, Rogaeva E, Bruni AC, Rosen HJ, Gallo M, Rosenberg RN, Ben-Shlomo Y, Sager MA, Mecocci P, Saykin AJ, Pastor P, Cuccaro ML, Vance JM, Schneider JA, Schneider LS, Slifer S, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Swerdlow RH, Tang M, Tanzi RE, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Van Eldik LJ, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Wilhelmsen KC, Williamson J, Wingo TS, Woltjer RL, Wright CB, Yu CE, Yu L, Saba Y, Pilotto A, Bullido MJ, Peters O, Crane PK, Bennett D, Bosco P, Coto E, Boccardi V, De Jager PL, Lleo A, Warner N, Lopez OL, Ingelsson M, Deloukas P, Cruchaga C, Graff C, Gwilliam R, Fornage M, Goate AM, Sanchez-Juan P, Kehoe PG, Amin N, Ertekin-Taner N, Berr C, Debette S, Love S, Launer LJ, Younkin SG, Dartigues JF, Corcoran C, Ikram MA, Dickson DW, Nicolas G, Campion D, Tschanz J, Schmidt H, Hakonarson H, Clarimon J, Munger R, Schmidt R, Farrer LA, Van Broeckhoven C, C O'Donovan M, DeStefano AL, Jones L, Haines JL, Deleuze JF, Owen MJ, Gudnason V, Mayeux R, Escott-Price V, Psaty BM, Ramirez A, Wang LS, Ruiz A, van Duijn CM, Holmans PA, Seshadri S, Williams J, Amouyel P, Schellenberg GD, Lambert JC, and Pericak-Vance MA

Subjects
Aged, Case-Control Studies, Female, Genetic Testing methods, Genome-Wide Association Study methods, Haplotypes genetics, Humans, Lipid Metabolism genetics, Male, Alzheimer Disease genetics, Amyloid beta-Peptides genetics, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Immunity genetics, Lipids genetics, tau Proteins genetics
Abstract

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10 -7 ), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Published
2019
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33. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

Author

Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, Kunkle BW, Boland A, Raybould R, Bis JC, Martin ER, Grenier-Boley B, Heilmann-Heimbach S, Chouraki V, Kuzma AB, Sleegers K, Vronskaya M, Ruiz A, Graham RR, Olaso R, Hoffmann P, Grove ML, Vardarajan BN, Hiltunen M, Nöthen MM, White CC, Hamilton-Nelson KL, Epelbaum J, Maier W, Choi SH, Beecham GW, Dulary C, Herms S, Smith AV, Funk CC, Derbois C, Forstner AJ, Ahmad S, Li H, Bacq D, Harold D, Satizabal CL, Valladares O, Squassina A, Thomas R, Brody JA, Qu L, Sánchez-Juan P, Morgan T, Wolters FJ, Zhao Y, Garcia FS, Denning N, Fornage M, Malamon J, Naranjo MCD, Majounie E, Mosley TH, Dombroski B, Wallon D, Lupton MK, Dupuis J, Whitehead P, Fratiglioni L, Medway C, Jian X, Mukherjee S, Keller L, Brown K, Lin H, Cantwell LB, Panza F, McGuinness B, Moreno-Grau S, Burgess JD, Solfrizzi V, Proitsi P, Adams HH, Allen M, Seripa D, Pastor P, Cupples LA, Price ND, Hannequin D, Frank-García A, Levy D, Chakrabarty P, Caffarra P, Giegling I, Beiser AS, Giedraitis V, Hampel H, Garcia ME, Wang X, Lannfelt L, Mecocci P, Eiriksdottir G, Crane PK, Pasquier F, Boccardi V, Henández I, Barber RC, Scherer M, Tarraga L, Adams PM, Leber M, Chen Y, Albert MS, Riedel-Heller S, Emilsson V, Beekly D, Braae A, Schmidt R, Blacker D, Masullo C, Schmidt H, Doody RS, Spalletta G, Longstreth WT Jr, Fairchild TJ, Bossù P, Lopez OL, Frosch MP, Sacchinelli E, Ghetti B, Yang Q, Huebinger RM, Jessen F, Li S, Kamboh MI, Morris J, Sotolongo-Grau O, Katz MJ, Corcoran C, Dunstan M, Braddel A, Thomas C, Meggy A, Marshall R, Gerrish A, Chapman J, Aguilar M, Taylor S, Hill M, Fairén MD, Hodges A, Vellas B, Soininen H, Kloszewska I, Daniilidou M, Uphill J, Patel Y, Hughes JT, Lord J, Turton J, Hartmann AM, Cecchetti R, Fenoglio C, Serpente M, Arcaro M, Caltagirone C, Orfei MD, Ciaramella A, Pichler S, Mayhaus M, Gu W, Lleó A, Fortea J, Blesa R, Barber IS, Brookes K, Cupidi C, Maletta RG, Carrell D, Sorbi S, Moebus S, Urbano M, Pilotto A, Kornhuber J, Bosco P, Todd S, Craig D, Johnston J, Gill M, Lawlor B, Lynch A, Fox NC, Hardy J, Albin RL, Apostolova LG, Arnold SE, Asthana S, Atwood CS, Baldwin CT, Barnes LL, Barral S, Beach TG, Becker JT, Bigio EH, Bird TD, Boeve BF, Bowen JD, Boxer A, Burke JR, Burns JM, Buxbaum JD, Cairns NJ, Cao C, Carlson CS, Carlsson CM, Carney RM, Carrasquillo MM, Carroll SL, Diaz CC, Chui HC, Clark DG, Cribbs DH, Crocco EA, DeCarli C, Dick M, Duara R, Evans DA, Faber KM, Fallon KB, Fardo DW, Farlow MR, Ferris S, Foroud TM, Galasko DR, Gearing M, Geschwind DH, Gilbert JR, Graff-Radford NR, Green RC, Growdon JH, Hamilton RL, Harrell LE, Honig LS, Huentelman MJ, Hulette CM, Hyman BT, Jarvik GP, Abner E, Jin LW, Jun G, Karydas A, Kaye JA, Kim R, Kowall NW, Kramer JH, LaFerla FM, Lah JJ, Leverenz JB, Levey AI, Li G, Lieberman AP, Lunetta KL, Lyketsos CG, Marson DC, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Morris JC, Murrell JR, Myers AJ, O'Bryant S, Olichney JM, Pankratz VS, Parisi JE, Paulson HL, Perry W, Peskind E, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Raskind M, Reisberg B, Reitz C, Ringman JM, Roberson ED, Rogaeva E, Rosen HJ, Rosenberg RN, Sager MA, Saykin AJ, Schneider JA, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Swerdlow RH, Tanzi RE, Thornton-Wells TA, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Van Eldik LJ, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Wilhelmsen KC, Williamson J, Wingo TS, Woltjer RL, Wright CB, Yu CE, Yu L, Garzia F, Golamaully F, Septier G, Engelborghs S, Vandenberghe R, De Deyn PP, Fernadez CM, Benito YA, Thonberg H, Forsell C, Lilius L, Kinhult-Stählbom A, Kilander L, Brundin R, Concari L, Helisalmi S, Koivisto AM, Haapasalo A, Dermecourt V, Fievet N, Hanon O, Dufouil C, Brice A, Ritchie K, Dubois B, Himali JJ, Keene CD, Tschanz J, Fitzpatrick AL, Kukull WA, Norton M, Aspelund T, Larson EB, Munger R, Rotter JI, Lipton RB, Bullido MJ, Hofman A, Montine TJ, Coto E, Boerwinkle E, Petersen RC, Alvarez V, Rivadeneira F, Reiman EM, Gallo M, O'Donnell CJ, Reisch JS, Bruni AC, Royall DR, Dichgans M, Sano M, Galimberti D, St George-Hyslop P, Scarpini E, Tsuang DW, Mancuso M, Bonuccelli U, Winslow AR, Daniele A, Wu CK, Peters O, Nacmias B, Riemenschneider M, Heun R, Brayne C, Rubinsztein DC, Bras J, Guerreiro R, Al-Chalabi A, Shaw CE, Collinge J, Mann D, Tsolaki M, Clarimón J, Sussams R, Lovestone S, O'Donovan MC, Owen MJ, Behrens TW, Mead S, Goate AM, Uitterlinden AG, Holmes C, Cruchaga C, Ingelsson M, Bennett DA, Powell J, Golde TE, Graff C, De Jager PL, Morgan K, Ertekin-Taner N, Combarros O, Psaty BM, Passmore P, Younkin SG, Berr C, Gudnason V, Rujescu D, Dickson DW, Dartigues JF, DeStefano AL, Ortega-Cubero S, Hakonarson H, Campion D, Boada M, Kauwe JK, Farrer LA, Van Broeckhoven C, Ikram MA, Jones L, Haines JL, Tzourio C, Launer LJ, Escott-Price V, Mayeux R, Deleuze JF, Amin N, Holmans PA, Pericak-Vance MA, Amouyel P, van Duijn CM, Ramirez A, Wang LS, Lambert JC, Seshadri S, Williams J, and Schellenberg GD

Subjects
Amino Acid Sequence, Case-Control Studies, Exome genetics, Gene Expression Profiling, Gene Frequency, Genetic Predisposition to Disease genetics, Genotype, Humans, Linkage Disequilibrium, Odds Ratio, Protein Interaction Maps genetics, Sequence Homology, Amino Acid, Adaptor Proteins, Signal Transducing genetics, Alzheimer Disease genetics, Immunity, Innate genetics, Membrane Glycoproteins genetics, Microglia metabolism, Phospholipase C gamma genetics, Polymorphism, Single Nucleotide, Receptors, Immunologic genetics
Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10 -4 ) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10 -8 ) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10 -10 , odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 -10 , OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 -14 , OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Published
2017
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