Deep learning to quantify the pace of brain aging in relation to neurocognitive changes
Authors: Yin Chenzhong , Imms Phoebe , Chowdhury Nahian F. , Chaudhari Nikhil N. , Ping Heng , Wang Haoqing , Bogdan Paul , Irimia Andrei ,   the Alzheimer’s Disease Neuroimaging Initiative, 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. , Drake Erin , Montine Tom , Conti Cat , Weiner Michael W. , Nosheny Rachel , Truran Sacrey Diana , 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 , Di Benedetto Joseph , 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 , Rossi Chen Stephanie , 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. , Lee Virginia 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 , Booth Robbins Lindsey , Brown Ashley Loren , 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 , 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 , Sadowsky Carl , Martinez Walter , Villena Teresa , 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 , 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 , 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 , Ellis Slaughter Micah , 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. , Gonazalez Rojas Yaneicy , Mintzer Jacobo , Flynn Longmire Crystal , Spicer Kenneth 
Published: February 2025

Brain age (BA), distinct from chronological age (CA), can be estimated from MRIs to evaluate neuroanatomic aging in cognitively normal (CN) individuals. BA, however, is a cross-sectional measure that summarizes cumulative neuroanatomic aging since birth. Thus, it conveys poorly recent or contemporaneous aging trends, which can be better quantified by the (temporal) pace
P
of brain aging. Many approaches to map
P
, however, rely on quantifying DNA methylation in whole-blood cells, which the blood–brain barrier separates from neural brain cells. We introduce a three-dimensional convolutional neural network (3D-CNN) to estimate
P
noninvasively from longitudinal MRI. Our longitudinal model (LM) is trained on MRIs from 2,055 CN adults, validated in 1,304 CN adults, and further applied to an independent cohort of 104 CN adults and 140 patients with Alzheimer’s disease (AD). In its test set, the LM computes
P
with a mean absolute error (MAE) of 0.16 y (7% mean error). This significantly outperforms the most accurate cross-sectional model, whose MAE of 1.85 y has 83% error. By synergizing the LM with an interpretable CNN saliency approach, we map anatomic variations in regional brain aging rates that differ according to sex, decade of life, and neurocognitive status. LM estimates of
P
are significantly associated with changes in cognitive functioning across domains. This underscores the LM’s ability to estimate
P
in a way that captures the relationship between neuroanatomic and neurocognitive aging. This research complements existing strategies for AD risk assessment that estimate individuals’ rates of adverse cognitive change with age.