Towards cascading genetic risk in Alzheimer’s disease

作者：André Altmann, Leon Aksman, Neil P. Oxtoby, Alexandra L. Young, ADNI, Michael W. Weiner, Paul Aisen, Ronald Petersen, Michael Weiner, Paul Aisen, Ronald Petersen, Clifford R Jack, William Jagust, Susan Landau, Mónica Rivera Mindt, Ozioma C. Okonkwo, Leslie M Shaw, Edward B Lee, Arthur W Toga, Laurel Beckett, Danielle Harvey, Robert C Green, Andrew J. Saykin, Kwangsik Nho, Richard J Perrin, Duygu Tosun, Pallavi Sachdev, Robert C Green, Tom Montine, Cat Conti, Michael W. Weiner, Rachel L. Nosheny, Juliet Fockler, Melanie J. Miller, Catherine Conti, Winnie Kwang, Chengshi Jin, Adam Diaz, Miriam T. Ashford, Derek Flenniken, Adrienne Kormos, Ronald Petersen, Paul Aisen, Michael Rafii, Rema Raman, Gustavo Jimenez‐Maggiora, Michael Donohue, Jennifer Salazar, Andrea Fidell, Virginia Boatwright, Justin Robison, Caileigh Zimmerman, Yuliana Cabrera, Sarah Walter, Taylor Clanton, Elizabeth Shaffer, Caitlin Webb, Lindsey Hergesheimer, Stephanie Smith, Sheila Ogwang, Olusegun Adegoke, Payam Mahboubi, Jeremy Pizzola, Cecily Jenkins, Laurel Beckett, Danielle Harvey, Michael Donohue, Naomi Saito, Adam Diaz, Kedir Adem Hussen, Ozioma C. Okonkwo, Mónica Rivera Mindt, Hannatu Amaza, Mai Seng Thao, Shaniya Parkins, Omobolanle Ayo, Matt Glittenberg, Isabella Hoang, Kaori Kubo Germano, Joe Strong, Trinity Weisensel, Fabiola Magana, Lisa Thomas, Vanessa Guzmán, Adeyinka Ajayi, Joseph Di Benedetto, Sandra Talavera, Clifford R Jack, Joel P. Felmlee, Nick C. Fox, Paul Thompson, Charles DeCarli, Arvin Forghanian-Arani, Bret Borowski, Calvin Reyes, Caitie Hedberg, Chad Ward, Christopher G. Schwarz, Denise Reyes, Jeff Gunter, John Moore-Weiss, Kejal Kantarci, Leonard Matoush, Matthew L. Senjem, Prashanthi Vemuri, Robert W. Reid, Ian G. Malone, Sophia I. Thomopoulos, Talia M. Nir, Neda Jahanshad, Alexander Knaack, Evan Fletcher, Danielle Harvey, Duygu Tosun, Stephanie Rossi Chen, Mark Choe, Karen Crawford, Paul A. Yushkevich, Sandhitsu R. Das, William Jagust, Susan Landau, Robert A. Koeppe, Gil D. Rabinovici, Victor L. Villemagne, Brian J. Lopresti, Richard J Perrin, John C. Morris, Erin Franklin, Haley Bernhardt, Nigel J. Cairns, Lisa Taylor‐Reinwald, Leslie Shaw, Edward B Lee, Maxwell Lee, Magdalena Korecka, Magdalena Brylska, Yang Wan, John Q. Trojanowki, Arthur W Toga, Karen Crawford, Scott Neu, Andrew J. Saykin, Kwangsik Nho, Tatiana M. Foroud, Taeho Jo, Shannon L. Risacher, Hannah Craft, Liana G. Apostolova, Kelly Nudelman, Kelley Faber, Zoë Potter, Kaci Lacy, Rima Kaddurah-Daouk, Li Shen, Jason Karlawish, Claire M. Erickson, Joshua D. Grill, Emily A. Largent, Kristin Harkins, Michael W. Weiner, Leon J. Thal, Zaven Kachaturian, R.T. Frank, Peter J. Snyder, Neil Buckholtz, John Hsiao, Laurie Ryan, Susan Molchan, Zaven S. Khachaturian, Maria Carrillo, William Z. Potter, Lisa L. Barnes, Marie Bernard, Héctor Alfredo Baptista González, Carole Ho, John Hsiao, Jonathan Jackson, Eliezer Masliah, Donna Masterman, Ozioma C. Okonkwo, Richard J. Perrin, Laurie Ryan, Nina Silverberg, Lisa C. Silbert, Jeffrey Kaye, Sylvia S. White, Aimee Pierce, Amy Thomas, Tera Clay, Daniel L. Schwartz, G. Devereux, Janet Taylor, Jennifer D. Ryan, Mike Nguyen, Madison DeCapo, Yanan Shang, Lon S. Schneider, Cynthia Muñoz, Diana Ferman, Carlota Conant, Katherin Martin, Kristin Oleary, Sonia Pawluczyk, Elizabeth Trejo, Karen Dagerman, Liberty Teodoro, Mauricio Becerra, Madiha Fairooz, Sonia Garrison, Julia Boudreau, Yair Avila, James M. Brewer, Aaron Jacobson, Antonio Gama, Chi Kim, Emily Little, Jennifer C. Frascino, Nichol Ferng, Socorro Trujillo, Judith L. Heidebrink, Robert A. Koeppe, Steven MacDonald, Dariya Malyarenko, Jaimie Ziolkowski, James P.B. O’Connor, Nicole Robert, Suzan Lowe, Virginia Rogers, Ronald Petersen, Barbara Hackenmiller, Bradley Boeve, Colleen S. Albers, Connie Kreuger, David Jones, David S. Knopman, Hugo Botha, Jessica Magnuson, Jonathan Graff-Radford, Kerry Crawley, Michaël Schumacher, Sanna McKinzie, Steven Smith, Tascha Helland, Val J. Lowe, Vijay K. Ramanan, Valory Pavlik, Jacob Faircloth, Jeffrey Bishop, Jessica Nath, Maria Chaudhary, Maria Kataki, Melissa Yu, Nathiel Pacini, Randall Barker, Regan Brooks, Ruchi Aggarwal, Lawrence S. Honig, Yaakov Stern, Akiva Mintz, Jonathan Cordona, Michelle L. Hernandez, Justin M. Long, Abbey Arnold, Alex Groves, Anna Middleton, Blake Vogler, Cierra McCurry, Connie Mayo, Cyrus A. Raji, Fatima Amtashar, Heather Klemp, Heather Nicole Elmore, James Ruszkiewicz, Jasmina Kusuran, Jasmine Stewart, Jennifer Horenkamp, Julia Greeson, Kara Wever, Katie D. Vo, Kelly Larkin, Lesley Rao, Lisa Schoolcraft, Lora Gallagher, Madeline Paczynski, M. G. McMillan, Michael Holt, Nicole Gagliano, Rachel L. Henson, Renee LaBarge, Robert A. Swarm, Sarah Munie, Serena Cepeda, Stacey Winterton, Stephen Hegedus, TaNisha Wilson, Tanya Harte, Zach Bonacorsi, David Geldmacher, Amber Watkins, Brandi Barger, Bryan Smelser, Charna Bates, Cynthia Stover, Emily McKinley, Gregory Ikner, Haley Hendrix, Harold Matthew Cooper, J. A. Mahaffey, Lindsey Booth Robbins, Loren Brown Ashley, Marissa Natelson-Love, Princess Carter, Veronika Solomon, Hillel Grossman, Alexandra Groome, Allison Ardolino, Anthony Kaplan, Faye Sheppard, Genesis Burgos-Rivera, Gina Garcia-Camilo, Joanne Lim, Judith Neugroschl, Kimberly Jackson, Kirsten Evans, Laili Soleimani, Mary Sano, Nasrin Ghesani, Sarah Binder, Xiomara Mendoza Apuango, Ajay Sood, Amelia Troutman, Kimberly S. Blanchard, Arlene Richards, Grace Nelson, Kirsten Hendrickson, Erin Yurko, J. Plenge, Victoria Rufo, Raj C. Shah, Ranjan Duara, Brendan Lynch, Cesar Chirinos, Christine Dittrich, Debbie Campbell, Diego Mejia, Gilberto Perez, Helena Colvee, Joanna Gonzalez, Josalen Gondrez, J Knaack, Mara Acevedo, Maria Cereijo, Maria T. Greig‐Custo, Michelle Villar, Morris Wishnia, Sheryl Detling, Warren Barker, Marilyn Albert, Abhay Moghekar, Barbara Rodzon, Corey Demsky, Gregory M. Pontone, Jim Pekar, Leonie Farrington, Martin G. Pomper, Nicole L. Johnson, Tolulope Alo, Martin Sadowski, Anaztasia Ulysse, Arjun V. Masurkar, B Marti, David Mossa, Emilie Geesey, Emily Petrocca, Evan T. Schulze, Jennifer Wong, Joseph Boonsiri, Sunnie Kenowsky, Tatianne Martinez, Veronica Briglall, P. Murali Doraiswamy, Adaora Nwosu, Alisa Adhikari, Cammie Hellegers, Jeffrey R. Petrella, Olga James, Terence Z. Wong, Thomas C. Hawk, Sanjeev Vaishnavi, Hannah McCoubrey, Ilya M. Nasrallah, Rachel Rovere, Jeffrey Maneval, Elizabeth J. Robinson, Francisco Rivera, Jade Uffelman, Martha A. Combs, Patricia O’Donnell, Sara L. Manning, Richard King, Alayne Nieto, Amanda C. Glueck, Anjana Mandal, Audrie Swain, Bethanie Gamble, Beverly Meacham, Denece Forenback, Dorothy Ross, Elizabeth Cheatham, Ellen Hartman, Gary Cornell, Jordan P. Harp, Laura Ashe, Laura Goins, Linda Watts, Morgan Yazell, Prabin Mandal, Regan Buckler, S.R. Vincent, Triana Rudd, Oscar L. López, Ann Arlene Malia, Caitlin Chiado, Cary Zik, James Ruszkiewicz, K. E. Savage, Linda Fenice, MaryAnn Oakley, Paige C Tacey, Sarah Berman, Sarah Bowser, Stephen Hegedus, Xanthia Saganis, Anton P. Porsteinsson, Abigail Mathewson, Asa Widman, Bridget Holvey, Emily Clark, Esmeralda Morales, I.D. Young, James Ruszkiewicz, Kevin Hopkins, Kimberly Martin, Nancy Kowalski, Rebecca Hunt, Roberta Calzavara, Russell Kurvach, Stephen D’Ambrosio, Gaby Thai, Beatriz Vides, Brigit Lieb, Catherine Mc-Adams-Ortiz, Cyndy Toso, Ivan Mares, Kathryn Moorlach, Luter Liu, Maria Corona, Mary Nguyen, Melanie Tallakson, Michelle N. McDonnell, Milagros Rangel, Neetha Basheer, Patricia Place, Romina A. Romero, Steven Tam, Trung Dung Nguyen, Abey Thomas, Alexander O. Frolov, Alka Khera, Amy Browning, Brendan Kelley, Courtney Dawson, Dana Mathews, Elaine Most, Elizeva Phillips, Lynn Nguyen, Maribel Nunez, Matalin Miller, Matthew R. Jones, Natalie Martinez, Rebecca Logan, Roderick McColl, Sari Pham, Tiffani Fox, Tracey Moore, Allan I. Levey, Abby Brown, Andrea Kippels, Ashton Ellison, Casie Lyons, Chadwick M. Hales, Cindy Parry, Courtney Williams, Elizabeth McCorkle, Guy H. Harris, Heather Rose, Inara Jooma, Jahmila Al-Amin, James J. Lah, James Webster, Jessica Swiniarski, Latasha Chapman, Laura Donnelly, Lauren Mariotti, Mary Locke, Phyllis Vaughn, Rachael Penn, Sallie Carpentier, Samira Yeboah, Sarah Basadre, Sarah Malakauskas, Stefka Lyron, Tara Villinger, Terra Burney, Jeffrey M. Burns, Ala Abusalim, Alexandra Dahlgren, Alexandria Montero, Anne Arthur, Heather Dooly, Katelynn Kreszyn, Katherine Berner, Lindsey Gillen, Maria Scanlan, Mercedes Madison, Nicole Mathis, Phyllis Switzer, Ryan Townley, Samantha Fikru, Samantha Sullivan, Ella Wright, Maryam Beigi, Anthony Daley, Ashley Ko, Brittney Luong, Glen Nyborg, Jessica Morales, Kelly A. Durbin, Lauren Garcia, Leila Parand, Lorena Macias, Lorena Monserratt, Maya Farchi, Pauline Wu, Robert Hernandez, Thao Rodriguez, Neill R. Graff‐Radford, A’llana Marolt, Anton Thomas, Deborah Aloszka, Ercilia Moncayo, Erin Westerhold, Gregory S. Day, Kandise Chrestensen, Mary Imhansiemhonehi, Sanna McKinzie, Sochenda Stephens, Sylvia Grant, Jared R. Brosch, Amy Perkins, Aubree Saunders, Debra Silberberg Kovac, Heather Polson, Isabell Mwaura, Kassandra Mejia, Katherine Britt, Kathy King, Kayla Nichols, Kayley Lawrence, Lisa Rankin, Martin Farlow, Patricia Wiesenauer, Robert Bryant, Scott Herring, Sheryl Lynch, Skylar Wilson, Traci Day, William Korst, Christopher van Dyck, Adam P. Mecca, Alyssa Miller, Amanda Brennan, Amber Khan, Audrey Ruan, Carol Gunnoud, Chelsea Mendonca, Danielle Raynes-Goldfinger, Elaheh Salardini, Elisa Hidalgo, Emma Cooper, E.A. Singh, Erin R. Murphy, Jeanine May, Jesse Stanhope, Jessica Lam, Julia Waszak, Kimberly Nelsen, Kimberly Sacaza, Mayer Joshua Hasbani, Meghan Donahue, Ming-Kai Chen, Nicole Barcelos, Paul Eigenberger, Robin Bonomi, Ryan S. O’Dell, Sarah Jefferson, Siddharth Khasnavis, Stephen Smilowitz, Susan DeStefano, Susan P. Good, Terry Camarro, Vanessa Clayton, Yanis Cavrel, YuQuan Oliver Lu, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra E. Black, Anish Kapadia, Aparna Bhan, Benjamin Lam, Christopher J.M. Scott, Gillian Gabriel, Jennifer Bray, Ljubica Zotovic, Maria Samira Gutierrez, Mario Masellis, Marjan Farshadi, Maurylette Gui, Meghan Mitchell, Rebecca C. Taylor, Ruby Endre, Zhala Taghi-Zada, Robin Hsiung, Carolyn English, Ellen Kim, Eugene Yau, Haley Tong, Laura Barlow, Lauren Jennings, Michele Assaly, Paula Villela Nunes, Tahlee Marian, Andrew Kertesz, John Rogers, Dick Trost, Dylan Wint, Charles Bernick, Donna Munic, Ian Grant, Aaliyah Korkoyah, A. Raja, Allison Lapins, Caila Ryan, Jelena Pejić, Kailey Basham, Leena Lukose, Loreece Haddad, Lucas Quinlan, Nathaniel Houghtaling, Carl Sadowsky, Walter Martínez, Teresa Villena, Brigid Reynolds, Angelica Forero, Carolyn Ward, Emma Brennan, Esteban Figueroa, Giuseppe Esposito, Jessica Mallory, Kathleen Johnson, Kathryn Turner, Katie Seidenberg, Kelly McCann, Margaret Bassett, Melanie Chadwick, Raymond Scott Turner, Robin Bean, Saurabh Sharma, Gad Marshall, Aferdita Haviari, Alison Pietras, Bradley Wallace, Catherine E. Munro, Gladiliz Rivera-Delpin, Hadley Hustead, Isabella Levesque, Jennifer Ramirez, Karen A. Nolan, Kirsten Glennon, Mariana Palou, Michael Erkkinen, Nicole DaSilva, Pamela Friedman, Regina M Silver, Ricardo Salazar, Roxxanne Polleys, Scott McGinnis, Seth A. Gale, Tia C. Hall, Tuan Luu, Steven Chao, Emmeline Lin, Jaila Coleman, Kevin Epperson, Minal Vasanawala, Alireza Atri, Amy Rangel, Brittani Evans, Candy Monarrez, Carol Cline, Carolyn Liebsack, Daniel Bandy, Danielle Goldfarb, Debbie Intorcia, Jennifer Olgin, Kelly Clark, Kelsey King, Kylee York, Marina Reade, Michael Callan, Michael J. Glass, Michaela Johnson, Michele Gutierrez, Molly Goddard, Nadira Trncic, Parichita Choudhury, P. V. Reyes, Serena Lowery, Shaundra Hall, Sonia Olgin, Stephanie Santiago, Michael L. Alosco, Alyssa Ton, Amanda Jiménez, Andrew Ellison, Anh Tran, Brandon Anderson, Della Carter, Donna Veronelli, Steven Lenio, Eric Steinberg, Jesse Mez, Jason Weller, Jennifer Johns, Jesse Mez, Jessica Harkins, Alexa Puleio, Ina Hoti, Jane Mwicigi, Alexa Puleio, Michael L. Alosco, Olivia Schultz, Mona Lauture, Eric Steinberg, Ridiane Denis, Ronald Killiany, Sarab Singh, Steven Lenio, Wendy Qiu, Ycar Devis, Thomas O. Obisesan, Andrew Stone, Debra Ordor, Ifreke Udodong, Immaculata Okonkwo, Javed Khan, Jillian Turner, Kyliah Hughes, Oshoze Kadiri, Charles J. Duffy, Ariana Moss, Katherine Stapleton, Mária Tóth, Marianne Sanders, Martin Ayres, Melissa Hamski, Parianne Fatica, Paula Ogrocki, Sarah Ash, Stacy Pot, Doris Chen, Andrés Soto, Costin Tanase, David Bissig, Hafsanoor Vanya, Heather Russell, Hitesh Patel, Hongzheng Zhang, Kelly Wallace, Kristi Ayers, Maria Gallegos, Martha R. Forloines, M. Sinn, Queennie Majorie S Kahulugan, Richard Isip, Sandra Calderon, Talia Hamm, Michael Borrie, T-Y Lee, Robert Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Allison Perrin, Pierre N. Tariot, Adam Fleisher, Stephanie Reeder, Horacio Capote, Allison Emborsky, Anna G. Mattle, Bela Ajtai, Ben Wagner, Bennett Myers, Daryn Slazyk, Delaney Fragale, Erin Fransen, Heather Macnamara, J M Falletta, Joseph Hirtreiter, Laszlo Mechtler, Megan C. King, Michael Asbach, Michelle Rainka, R Zawislak, Scott Wisniewski, Stephanie O'Malley, Tatiana Jimenez-Knight, Todd Peehler, Traci Aladeen, Vernice Bates, Violet Wenner, Wisam Elmalik, Douglas W. Scharre, Arun Ramamurthy, Soumya Bouchachi, Maria Kataki, Rawan Tarawneh, Brendan Kelley, Dzintra Celmins, Alicia Leader, Chris Figueroa, Heather Bauerle, Katlynn Patterson, Michael Reposa, Steven Presto, Tuba Ahmed, Wendy Stewart, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Robert B. Santulli, Eben S. Schwartz, Jeff D. Williamson, Alicia Jessup, A. Williams, Crystal Duncan, Abigail O’Connell, Karen Gagnon, Ezequiel Zamora, James Bateman, Freda Crawford, Deb Thompson, E. R. C. Walker, Jennifer Rowell, Mikell White, Phillip Hunter Ledford, Sarah Bohlman, Susan Henkle, Joseph Bottoms, Lena Moretz, Bevan Hoover, Michael Shannon, Samantha Rogers, Wendy Baker, William Harrison, Chuang-Kuo Wu, Alexis DeMarco, Ava Stipanovich, Daniel Arcuri, Jan Clark, Jennifer Davis, Kerstin Doyon, Marie Amoyaw, Mauro Veras Acosta, Ronald Bailey, S. Warren, Terry Fogerty, Victoria Sanborn, Meghan Riddle, Stephen Salloway, Paul Malloy, Stephen Correia, Charles Windon, Morgan Blackburn, Howard J. Rosen, Bruce L. Miller, Amanda Smith, Ijeoma Mba, Jenny Echevarria, Juris Janavs, Emily Roglaski, Meagan Yong, Rebecca Devine, Hamid Okhravi, Edgardo Rivera, Teresa Kalowsky, C. Smith, Christina Rosario, Joseph C. Masdeu, Richard H. Le, Maushami Gurung, Marwan N. Sabbagh, Angélica García, Micah Ellis Slaughter, Nadeen Elayan, Skieff Acothley, Nunzio Pomara, Raymundo Hernando, Vita Pomara, Chelsea Reichert, Olga Brawman‐Mintzer, Allison Acree, Arthur Williams, Campbell Long, Rebecca Long, Paul Newhouse, Sydni Jenee Hill, Amy Boegel, Sudha Seshadri, Amy R. Saklad, Floyd Jones, William T. Hu, Victor Sotelo, Yaneicy Gonazalez Rojas, Jacobo Mintzer, Crystal Flynn Longmire, Kenneth Spicer, Daniel C. Alexander, Frederik Barkhof, Maryam Shoai, John Hardy, Jonathan M. Schott · 发表于：Brain · 年份：2024 · DOI：10.1093/brain/awae176 · 被引用次数：12 · 研究领域：Alzheimer's disease research and treatments、Dementia and Cognitive Impairment Research、Genetic Associations and Epidemiology

Alzheimer's disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, in which each of the biomarkers can be either positive (+) or negative (-). Over the past decades, genome-wide association studies have implicated ∼90 different loci involved with the development of late-onset Alzheimer's disease. Here, we investigate whether genetic risk for Alzheimer's disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect. Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A-T- status, we used Cox proportional hazards models to estimate the contribution of APOE and polygenic risk scores (beyond APOE) to convert to A+T- status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T- status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex and years of education. For progression from A-T- to A+T-, APOE-e4 burden showed a significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70-4.89; P < 0.001], whereas polygenic risk did not (HR = 1.09; 95% CI: 0.84-1.42; P = 0.53). Co...