Higher Educational Attainment and Accelerated Tau Accumulation in Alzheimer Disease

Yue Cai; Lili Fang; Jie Yang; Xin Zhou; Lin Liu; Anqi Li; Pan Sun; Guoyu Lan; Zhengbo He; Yalin Zhu; Laihong Zhang; Mingxing Jiang; Xianfeng Yu; Zhen Liu; Tengfei Guo; Alzheimer’s Disease Neuroimaging Initiative Group

doi:10.1001/jamaneurol.2025.1801

Higher Educational Attainment and Accelerated Tau Accumulation in Alzheimer Disease

JAMA Neurol. 2025 Jul 7. doi: 10.1001/jamaneurol.2025.1801. Online ahead of print.

Authors

Yue Cai¹, Lili Fang¹, Jie Yang^{1

2}, Xin Zhou^{1

3}, Lin Liu¹, Anqi Li^{1

4}, Pan Sun¹, Guoyu Lan¹, Zhengbo He^{1

5}, Yalin Zhu^{1

4}, Laihong Zhang^{1

6}, Mingxing Jiang^{1

7}, Xianfeng Yu⁸, Zhen Liu¹, Tengfei Guo^{1

9

10}; Alzheimer’s Disease Neuroimaging Initiative Group

Collaborators

Alzheimer’s Disease Neuroimaging Initiative Group:
Michael W Weiner, Paul Aisen, Ronald Petersen, Clifford R Jack Jr, William Jagust, John Q Trojanowki, Arthur W Toga, Laurel Beckett, Robert C Green, Andrew J Saykin, John C Morris, Richard J Perrin, Leslie M Shaw, Zaven Khachaturian, Maria Carrillo, William Potter, Lisa Barnes, Marie Bernard, Hector González, Carole Ho, John K Hsiao, Jonathan Jackson, Eliezer Masliah, Donna Masterman, Ozioma Okonkwo, Laurie Ryan, Nina Silverberg, Adam Fleisher, Diana Truran Sacrey, Juliet Fockler, Cat Conti, Dallas Veitch, John Neuhaus, Chengshi Jin, Rachel Nosheny, Miriam Ashford, Derek Flenniken, Adrienne Kormos, Tom Montine, Michael Rafii, Rema Raman, Gustavo Jimenez, Michael Donohue, Devon Gessert, Jennifer Salazar, Caileigh Zimmerman, Yuliana Cabrera, Sarah Walter, Garrett Miller, Godfrey Coker, Taylor Clanton, Lindsey Hergesheimer, Stephanie Smith, Olusegun Adegoke, Payam Mahboubi, Shelley Moore, Jeremy Pizzola, Elizabeth Shaffer, Brittany Sloan, Danielle Harvey, Arvin Forghanian-Arani, Bret Borowski, Chad Ward, Christopher Schwarz, David Jones, Jeff Gunter, Kejal Kantarci, Matthew Senjem, Prashanthi Vemuri, Robert Reid, Nick C Fox, Ian Malone, Paul Thompson, Sophia I Thomopoulos, Talia M Nir, Neda Jahanshad, Charles DeCarli, Alexander Knaack, Evan Fletcher, Duygu Tosun-Turgut, Stephanie Rossi Chen, Mark Choe, Karen Crawford, Paul A Yushkevich, Sandhitsu Das, Robert A Koeppe, Eric M Reiman, Kewei Chen, Chet Mathis, Susan Landau, Nigel J Cairns, Erin Householder, Erin Franklin, Haley Bernhardt, Lisa Taylor-Reinwald, Magdalena Korecka, Michael Figurski, Scott Neu, Kwangsik Nho, Shannon L Risacher, Liana G Apostolova, Li Shen, Tatiana M Foroud, Kelly Nudelman, Kelley Faber, Kristi Wilmes, Leon Thal, Lisa C Silbert, Betty Lind, Rachel Crissey, Jeffrey A Kaye, Raina Carter, Sara Dolen, Joseph Quinn, Lon S Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Karen Dagerman, Bryan M Spann, James Brewer, Helen Vanderswag, Jaimie Ziolkowski, Judith L Heidebrink, Lisa Zbizek-Nulph, Joanne L Lord, Sara S Mason, Colleen S Albers, David Knopman, Kris Johnson, Javier Villaneuva-Meyer, Valory Pavlik, Nathaniel Pacini, Ashley Lamb, Joseph S Kass, Rachelle S Doody, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S Honig, Akiva Mintz, Beau Ances, David Winkfield, Maria Carroll, Georgia Stobbs-Cucchi, Angela Oliver, Mary L Creech, Mark A Mintun, Stacy Schneider, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Daniel Marson, Hillel Grossman, Martin A Goldstein, Jonathan Greenberg, Effie Mitsis, Raj C Shah, Melissa Lamar, Patricia Samuels, Ranjan Duara, Maria T Greig-Custo, Rosemarie Rodriguez, Marilyn Albert, Chiadi Onyike, Leonie Farrington, Scott Rudow, Rottislav Brichko, Stephanie Kielb, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Martin Sadowski, Thomas Wisniewski, Melanie Shulman, Arline Faustin, Julia Rao, Karen M Castro, Anaztasia Ulysse, Shannon Chen, Mohammed O Sheikh, Jamika Singleton-Garvin, P Murali Doraiswamy, Jeffrey R Petrella, Olga James, Terence Z Wong, Salvador Borges-Neto, Jason H Karlawish, David A Wolk, Sanjeev Vaishnavi, Christopher M Clark, Steven E Arnold, Charles D Smith, Gregory A Jicha, Riham El Khouli, Flavius D Raslau, Oscar L Lopez, MaryAnn Oakley, Donna M Simpson, Anton P Porsteinsson, Kim Martin, Nancy Kowalski, Melanie Keltz, Bonnie S Goldstein, Kelly M Makino, M Saleem Ismail, Connie Brand, Gaby Thai, Aimee Pierce, Beatriz Yanez, Elizabeth Sosa, Megan Witbracht, Brendan Kelley, Trung Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I Levey, James J Lah, Ihab Hajjar, Janet S Cellar, Jeffrey M Burns, Russell H Swerdlow, William M Brooks, Daniel H S Silverman, Sarah Kremen, Kathleen Tingus, Po H Lu, George Bartzokis, Ellen Woo, Edmond Teng, Neill R Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R Farlow, Ann Marie Hake, Brandy R Matthews, Jared R Brosch, Scott Herring, Christopher H van Dyck, Adam P Mecca, Susan P Good, Martha G MacAvoy, Richard E Carson, Pradeep Varma, Howard Chertkow, Susan Vaitekunis, Chris Hosein, Sandra Black, Bojana Stefanovic, Chris Chinthaka Heyn, Ging-Yuek Robin Hsiung, Ellen Kim, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternak, Irina Rachinsky, Andrew Kertesz, Dick Drost, John Rogers, Ian Grant, Brittanie Muse, Emily Rogalski, Jordan Robson, M-Marsel Mesulam, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Howard J Rosen, Bruce L Miller, David Perry, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Kelly MCCann, Jessica Poe, Reisa A Sperling, Keith A Johnson, Gad A Marshall, Jerome Yesavage, Joy L Taylor, Steven Chao, Jaila Coleman, Jessica D White, Barton Lane, Allyson Rosen, Jared Tinklenberg, Christine M Belden, Alireza Atri, Kelly A Clark, Edward Zamrini, Marwan Sabbagh, Ronald Killiany, Robert Stern, Jesse Mez, Neil Kowall, Andrew E Budson, Thomas O Obisesan, Oyonumo E Ntekim, Saba Wolday, Javed I Khan, Evaristus Nwulia, Sheeba Nadarajah, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Pauline Maillard, John Olichney, Owen Carmichael, Vernice Bates, Horacio Capote, Michelle Rainka, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M Carlsson, Allison Perrin, Anna Burke, Douglas W Scharre, Maria Kataki, Rawan Tarawneh, David Hart, Earl A Zimmerman, Dzintra Celmins, Delwyn D Miller, Laura L Boles Ponto, Karen Ekstam Smith, Hristina Koleva, Hyungsub Shim, Ki Won Nam, Susan K Schtulz, Jeff D Williamson, Suzanne Craft, Jo Cleveland, Mia Yang, Kaycee M Sink, Brian R Ott, Jonathan Drake, Geoffrey Tremont, Lori A Daiello, Aaron Ritter, Charles Bernick, Donna Munic, Abigail O'Connell, Jacobo Mintzer, Arthur Wiliams, Joseph Masdeu, Jiong Shi, Angelica Garcia, Paul Newhouse, Steven Potkin, Steven Salloway, Paul Malloy, Stephen Correia, Smita Kittur, Godfrey D Pearlson, Karen Blank, Karen Anderson, Laura A Flashman, Marc Seltzer, Mary L Hynes, Robert B Santulli, Norman Relkin, Gloria Chiang, Athena Lee, Michael Lin, Lisa Ravdin, Ajay Sood, Kimberly S Blanchard, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T Greig, Bonnie Goldstein, Kimberly S Martin, Christopher Reist, Carl Sadowsky, Walter Martinez, Teresa Villena, Howard Rosen, Gad Marshall, Elaine R Peskind, Eric C Petrie, Gail Li

Affiliations

¹ Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, China.
² Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China.
³ School of Biomedical Engineering, Hainan University, Haikou, China.
⁴ Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong Special Administrative Region, China.
⁵ School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
⁶ School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China.
⁷ Westlake and Shenzhen Medical Academy of Research and Translation PhD Program, Westlake University, Shenzhen, China.
⁸ Department of Neurology, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
⁹ Institute of Biomedical Engineering, Shenzhen Bay Laboratory, Shenzhen, China.
¹⁰ Institute of Biomedical Engineering, Peking University Shenzhen Graduate School, Shenzhen, China.

PMID: 40622710
DOI: 10.1001/jamaneurol.2025.1801

Abstract

Importance: The impact of educational attainment (EA) on longitudinal tau accumulation remains largely underexplored.

Objective: To investigate the association of EA with tau accumulation in Alzheimer disease (AD).

Design, setting, and participants: This cohort study used 3 independent samples: the Alzheimer's Disease Neuroimaging Initiative (ADNI; October 2015-July 2022, mean follow-up: 3.0 years), Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease study (A4; 2014-2022, mean follow-up: 4.7 years), and Greater-Bay-Area Healthy Aging Brain Study (GHABS; July 2021-August 2024, mean interval from plasma collection to tau positron emission tomography [PET]: 1.0 years). The ADNI and GHABS represent Northern American and Southern Chinese populations, respectively. A4 is a multicenter trial. Participants with amyloid β (Aβ) and subsequent tau PET were included from ADNI, A4, and GHABS, and a subset had plasma phosphorylated tau (p-tau) 217 (p-tau217) and resting-state functional magnetic resonance imaging (RS-fMRI) data. Data were analyzed from July 2022 to January 2025.

Exposures: EA, Aβ-PET, tau-PET, plasma p-tau217, and RS-fMRI.

Main outcomes and measures: Participants were classified as high EA and low EA based on median years of EA. Longitudinal tau changes were compared across Aβ-PET positivity and EA groups. Interactions of EA status with Aβ burden, entorhinal tau, and plasma p-tau217 on tau accumulation were investigated in Aβ-positive (Aβ+) individuals. Connectivity-associated tau spread was compared across different Aβ/EA groups. Whether or not Aβ-targeting treatment attenuated tau accumulation in Aβ+ high-EA individuals was also evaluated.

Results: This study included 887 participants: 377 from ADNI (mean [SD] age, 73.3 [7.2] years; 191 female [50.7%]), 395 from A4 (mean [SD] age, 71.9 [4.8] years; 223 female [56.5%]), and 115 from GHABS (mean [SD] years, 66.0 [7.4] years; 76 female [66.1%]). In the Aβ-negative group, high-EA individuals exhibited slower tau accumulation than low-EA individuals (right middle temporal gyrus: estimate = -0.002; 95% CI, -0.003 to -0.0002; P = .03). Conversely, higher EA in the Aβ+ group was correlated with accelerated tau accumulation (left middle temporal gyrus: estimate = 0.003; 95% CI, 0.0003-0.005; P = .03) and stronger Aβ-associated (left visual region: estimate = 0.38; 95% CI, 0.11-0.65; P = .006), entorhinal tau-associated (left middle temporal gyrus: estimate = 0.35; 95% CI, 0.08-0.63; P = .01), and plasma p-tau217-associated tau accumulation (left inferior temporal gyrus: estimate = 0.46; 95% CI, 0.02-0.90; P = .04), as well as increased connectivity-associated tau spread compared with lower EA (estimate = 0.33; 95% CI, 0.003-0.67; P = .048). Aβ-targeting treatment appeared to mitigate plasma p-tau217-associated tau accumulation in patients with AD and higher EA (estimate = -0.52; 95% CI, -0.80 to -0.24; P < .001).

Conclusions and relevance: Results of this cohort study suggest that higher EA was associated with faster tau accumulation and spread in Aβ+ individuals, highlighting the importance of Aβ clearance in mitigating tau progression in patients with AD and higher EA.