Reevaluating the Role of Education in Cognitive Decline and Brain Aging: Insights from Large-Scale Longitudinal Cohorts across 33 Countries

Abstract Why education is linked to higher cognitive function in aging is fiercely debated. Leading theories propose that education reduces brain decline in aging, enhances tolerance to brain pathology, or that it does not affect cognitive decline but rather reflects higher early-life cognitive function. To test these theories, we analyzed 407.356 episodic memory scores from 170.795 participants >50 years, alongside 15.157 brain MRIs from 6.472 participants across 33 Western countries. More education was associated with better memory, larger intracranial volume and slightly larger volume of memory-sensitive brain regions. However, education did not protect against age-related decline or weakened effects of brain decline on cognition. The most parsimonious explanation for the results is that the associations reflect factors present early in life, including propensity of individuals with certain traits to pursue more education. While education has numerous benefits, the notion that it provides protection against cognitive or brain decline is not supported. Competing Interest Statement The authors have declared no competing interest. Funding Statement The Lifebrain consortium is funded by the EU Horizon 2020 grant agreement no. 732592 (Lifebrain). The different sub-studies are supported by different sources. LCBC is supported by the European Research Council under grant agreements no. 283634 and no. 725025 (to A.M.F.) and no. 313440 (to K.B.W.), as well as the Norwegian Research Council (325878, 262453 to A.M.F.; 325001, 301395, 239889 to K.B.W.; 249931 to A.M.F & K.B.W.; 324882 to DVP; 325415 to HG), the National Association for Public Health s dementia research program, Norway (to A.M.F.), and the University of Oslo through the UiO:Life Science convergence environment (to A.M.F). Betula is supported by a scholar grant from the Knut and Alice Wallenberg foundation to L.N. Barcelona is partially supported by a Spanish Ministry of Economy and Competitiveness grant to D.B.-F. (grant no. PSI2015-64227-R (AEI/FEDER, UE)); and to and to G.C and J.S.-S (grant no. PID-2022-139298OA-C22 (MCIN /AEI /10.13039/501100011033 / FEDER, UE)); by the Walnuts and Healthy Aging study (http://www.clinicaltrials.gov; grant no. NCT01634841) funded by the California Walnut Commission, Sacramento, California; and by an ICREA Academia 2019 award. BASE-II has been supported by the German Federal Ministry of Education and Research under grant nos 16SV5537, 16SV5837, 16SV5538, 16SV5536K, 01UW0808, 01UW0706, 01GL1716A and 01GL1716B and by the European Research Council under grant agreement no. 677804 (to S.K.). Dr. A. Pascual-Leone is partly supported by grants from the National Institutes of Health (R01AG076708), Jack Satter Foundation, and BrightFocus Foundation. Part of the research was conducted using the UKB resource under application no. 32048. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. LOW is funded by the South-Eastern Norway Regional Health Authorities (# 2017095), the Norwegian Health Association (#19536, #1513) and by Wellcome Leap s Dynamic Resilience Program (jointly funded by Temasek Trust) (#104617). Parts of the data used in preparation of this article were obtained from the Pre-Symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer's Disease (PREVENT-AD) program. Data were provided [in part] by OASIS-3 OASIS-3: Principal Investigators: T. Benzinger, D. Marcus, J. Morris; NIH P50AG00561, P30NS09857781, P01AG026276, P01AG003991, R01AG043434, UL1TR000448, R01EB009352. Parts of the data collection and sharing for this project were provided by the Cambridge Centre for Ageing and Neuroscience (CamCAN). CamCAN funding was provided by the UK Biotechnology and Biological Sciences Research Council (grant number BB/H008217/1), together with support from the UK Medical Research Council and University of Cambridge, UK. Parts of the data are from VETSA, which is funded by the National Institute of Aging grants R01s AG018384, AG018386, AG050595, AG022381, AG076838. The content is the responsibility of the authors and does not necessarily represent official views of the NIA, NIH, or VA. U.S. Department of Veterans Affairs, Department of Defense; National Personnel Records Center, National Archives and Records Administration; Internal Revenue Service; National Opinion Research Center; National Research Council, National Academy of Sciences; and the Institute for Survey Research, Temple University provided invaluable assistance in the conduct of the VET Registry. The Cooperative Studies Program of the U.S. Department of Veterans Affairs provided financial support for development and maintenance of the Vietnam Era Twin Registry. We would also like to acknowledge the continued cooperation and participation of the members of the VET Registry and their families. Part of the data collection and sharing was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer s Association; Alzheimer s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Parts of the data used in the preparation of this article were obtained from the Harvard Aging Brain Study (HABS - P01AG036694; https://habs.mgh.harvard.edu). The HABS study was launched in 2010, funded by the National Institute on Aging, and is led by principal investigators Reisa A. Sperling MD and Keith A. Johnson MD at Massachusetts General Hospital/Harvard Medical School in Boston, MA. The SHARE data collection has been funded by the European Commission, DG RTD through FP5 (QLK6-CT-2001-00360), FP6 (SHARE-I3: RII-CT-2006-062193, COMPARE: CIT5-CT-2005-028857, SHARELIFE: CIT4-CT-2006-028812), FP7 (SHARE-PREP: GA N211909, SHARE-LEAP: GA N227822, SHARE M4: GA N261982, DASISH: GA N283646) and Horizon 2020 (SHARE-DEV3: GA N676536, SHARE-COHESION: GA N870628, SERISS: GA N654221, SSHOC: GA N823782, SHARE-COVID19: GA N101015924) and by DG Employment, Social Affairs & Inclusion through VS 2015/0195, VS 2016/0135, VS 2018/0285, VS 2019/0332, VS 2020/0313, SHARE-EUCOV: GA N101052589 and EUCOVII: GA N101102412. Additional funding from the German Federal Ministry of Education and Research (01UW1301, 01UW1801, 01UW2202), the Max Planck Society for the Advancement of Science, the U.S. National Institute on Aging (U01_AG09740-13S2, P01_AG005842, P01_AG08291, P30_AG12815, R21_AG025169, Y1-AG-4553-01, IAG_BSR06-11, OGHA_04-064, BSR12-04, R01_AG052527-02, R01_AG056329-02, R01_AG063944, HHSN271201300071C, RAG052527A) and from various national funding sources is gratefully acknowledged (see www.share-eric.eu). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Norwegian Regional Committee for Medical and Health Research Ethics South Norway gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Each dataset has different owners. Contact information to be used for requests for data access is specified in a table in the manuscript.