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

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 &lt; 0.001], whereas polygenic risk did not (HR = 1.09; 95% CI: 0.84–1.42; P = 0.53). Conversely, for the transition from A+T− to A+T+, the contribution of APOE-e4 burden was reduced (HR = 1.62; 95% CI: 1.05–2.51; P = 0.031), whereas the polygenic risk showed an increased contribution (HR = 1.73; 95% CI: 1.27–2.36; P &lt; 0.001). The marginal APOE effect was driven by e4 homozygotes (HR = 2.58; 95% CI: 1.05–6.35; P = 0.039) as opposed to e4 heterozygotes (HR = 1.74; 95% CI: 0.87–3.49; P = 0.12).

The genetic risk for late-onset Alzheimer’s disease unfolds in a disease stage-dependent fashion. A better understanding of the interplay between disease stage and genetic risk can lead to a more mechanistic understanding of the transition between ATN stages and a better understanding of the molecular processes leading to Alzheimer’s disease, in addition to opening therapeutic windows for targeted interventions.