{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T19:28:51Z","timestamp":1793820531577,"version":"4.6.1"},"reference-count":71,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"45","funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["2019035"],"award-info":[{"award-number":["2019035"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21AG080425"],"award-info":[{"award-number":["R21AG080425"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01MH129694"],"award-info":[{"award-number":["R01MH129694"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG081768"],"award-info":[{"award-number":["R01AG081768"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01MH132784"],"award-info":[{"award-number":["R01MH132784"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000874","name":"Brain and Behavior Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000874","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Alzheimer\u2019s Association","award":["AARG-22-972541"],"award-info":[{"award-number":["AARG-22-972541"]}],"id":[{"id":"https:\/\/ror.org\/0375f4d26","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Stanford Knight Initiative for Brain Resilience and the Rosenkranz Foundation grant","award":["RAR1-03"],"award-info":[{"award-number":["RAR1-03"]}]},{"DOI":"10.13039\/100008234","name":"Lehigh University","doi-asserted-by":"publisher","award":["CORE grant"],"award-info":[{"award-number":["CORE grant"]}],"id":[{"id":"10.13039\/100008234","id-type":"DOI","asserted-by":"publisher"}]},{"name":"One Mind - Baszucki Brain Research Fund","id":[{"id":"https:\/\/ror.org\/02prz6q96","id-type":"ROR","asserted-by":"crossref"}]},{"name":"SEAL Future Fund"}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,11,6]]},"abstract":"<jats:p>\n                    Identifying the neurobiological basis of cognitive vulnerability is essential for preventing Alzheimer\u2019s disease (AD). We derived the Alzheimer\u2019s Resilience-Vulnerability Connectome (ARC) by contrasting SuperAgers (SA), an extreme phenotype of preserved late-life memory, with AD using resting-state fMRI. ARC distinguished SA from AD in a discovery cohort (\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    \u00a0=\u00a0290; AUC\u00a0=\u00a00.85) and replicated independently (\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    \u00a0=\u00a0143), involving prefrontal, temporal, and insular networks and associating with brain age. Applied to cognitively unimpaired adults (discovery:\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    \u00a0=\u00a0818; replication:\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    \u00a0=\u00a0497), ARC-based subtyping revealed SA-like and AD-like subgroups with comparable baseline cognition but divergent longitudinal trajectories. AD-like individuals exhibited faster cognitive decline, greater amyloid-\u03b2 accumulation, and higher AD conversion risk. Exploratory GWAS nominated\n                    <jats:italic toggle=\"yes\">CLYBL<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">FRMD6<\/jats:italic>\n                    as candidate novel loci associated with the subtype difference. These findings suggest that ARC captures a continuous connectomic dimension of cognitive aging spanning SA, cognitively typical aging, and AD, highlighting the potential of functional connectomic variation for early risk stratification in AD.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aed9351","type":"journal-article","created":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T18:59:38Z","timestamp":1793818778000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["A functional connectome identifies vulnerability to cognitive decline and Alzheimer\u2019s disease progression"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2955-0917","authenticated-orcid":true,"given":"Kanhao","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA."},{"name":"Department of Bioengineering, Lehigh University, Bethlehem, PA, USA."},{"name":"Goodman-Luskin Microbiome Center, Vache and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3462-0147","authenticated-orcid":true,"given":"Hua","family":"Xie","sequence":"additional","affiliation":[{"name":"Center for Neuroscience Research, Children\u2019s National Hospital, Washington, DC, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0213-1034","authenticated-orcid":true,"given":"Gregory A.","family":"Fonzo","sequence":"additional","affiliation":[{"name":"Center for Psychedelic Research and Therapy, Department of Psychiatry and Behavioral Sciences, Dell Medical School, The University of Texas at Austin, Austin, TX, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9161-8556","authenticated-orcid":true,"given":"Nancy B.","family":"Carlisle","sequence":"additional","affiliation":[{"name":"Department of Psychology, Lehigh University, Bethlehem, PA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tovia","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Penn State College of Medicine, Hershey, PA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo S.","family":"Osorio","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1669-9624","authenticated-orcid":true,"given":"Arpana","family":"Church","sequence":"additional","affiliation":[{"name":"Goodman-Luskin Microbiome Center, Vache and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1945-0362","authenticated-orcid":true,"given":"Feng Vankee","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA."},{"name":"Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA."},{"name":"Stanford Institute for Human-Centered Artificial Intelligence, Stanford, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4087-6544","authenticated-orcid":true,"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA."},{"name":"Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA."},{"name":"Stanford Institute for Human-Centered Artificial Intelligence, Stanford, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02296-6"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2059-23.2024"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awn320"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.22263"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2666-7568(23)00079-X"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00234-020-02562-1"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1355617712000847"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1162\/jocn_a_00300"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab114"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01263-2"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2026.103102"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1415122111"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/arclin\/acx125"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015918"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182553c48"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2020.1807"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac177"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/gps.6034"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-4679(197701)33:1 <208::AID-JCLP2270330146>3.0.CO;2-E"},{"key":"e_1_3_2_21_2","unstructured":"L. Fike \u201cCross-cultural normative indicators on the Wechsler Memory Scale (WMS) associate learning and visual reproduction subtests \u201d dissertation Rhodes University (2008)."},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1355617720000752"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0887-6177(03)00039-8"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhx179"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2017.10.001"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-022-00219-7"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.065438"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.20479"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70291-0"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2015.15070922"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1177\/0891988719882100"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cortex.2019.04.008"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2022.104736"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(200001)47:1<36::AID-ANA8>3.0.CO;2-L"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1492-16.2016"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhab474"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2018.00107"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.jnen.0000182983.87106.d1"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01150-x"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2019.1424"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-025-07362-0"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2024.1428538"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2023.09.042"},{"key":"e_1_3_2_44_2","doi-asserted-by":"crossref","unstructured":"P. J. LaMontagne T. L. Benzinger J. C. Morris S. Keefe R. Hornbeck C. Xiong E. Grant J. Hassenstab K. Moulder A. G. Vlassenko OASIS-3: longitudinal neuroimaging clinical and cognitive dataset for normal aging and Alzheimer disease. MedRxiv 19014902 [Preprint] (2019); https:\/\/doi.org\/10.1101\/2019.12.13.19014902.","DOI":"10.1101\/2019.12.13.19014902"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2015.03.069"},{"key":"e_1_3_2_46_2","unstructured":"ADNI2 Procedures Manual; https:\/\/adni.loni.usc.edu\/wp-content\/uploads\/2008\/07\/adni2-procedures-manual.pdf. [accessed May 2025]."},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.3922\/j.psns.2012.1.08"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.wad.0000213865.09806.92"},{"key":"e_1_3_2_49_2","unstructured":"E. Kaplan H. Goodglass S. Weintraub Boston naming test. (The Clinical Neuropsychologist 2001)."},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1093\/arclin\/acac002"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1006\/nimg.2002.1280"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-201243"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11682-012-9176-1"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-180360"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-161278"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1080\/13803390490918499"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1355617700677044"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-018-0235-4"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.media.2007.06.004"},{"key":"e_1_3_2_60_2","doi-asserted-by":"crossref","unstructured":"Y. Zhang J. M. Brady S. Smith in Medical Imaging: Image Processing (SPIE 2000) vol. 3979 pp. 1126\u20131137.","DOI":"10.1117\/12.387617"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2009.06.060"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1006\/nimg.2002.1132"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2015.02.064"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.24241"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awn016"},{"key":"e_1_3_2_66_2","unstructured":"S. Landau W. Jagust Florbetapir processing methods (ADNI 2015); https:\/\/adni.bitbucket.io\/reference\/docs\/UCBERKELEYAV45\/ADNI_AV45_Methods_JagustLab_06.25.15.pdf."},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2006.01.021"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa209"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09534"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2010.01.042"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.114.164285"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0059-2"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aed9351","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T19:01:15Z","timestamp":1793818875000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.aed9351"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,11,6]]},"references-count":71,"journal-issue":{"issue":"45","published-print":{"date-parts":[[2026,11,6]]}},"alternative-id":["10.1126\/sciadv.aed9351"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.aed9351","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,11,6]]},"assertion":[{"value":"2025-11-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-11-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaed9351"}}