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While most older adults experience memory decline, a subset known as superagers (SA) maintains youthful memory into late life, offering a unique window into protective mechanisms against neurodegeneration. Here, we identified a functional connectivity (FC) signature, termed Alzheimer\u2019s-resilient connectome (ARC), that robustly differentiates SA from age-matched patients with AD. Using resting-state fMRI in a discovery cohort (N = 290), we identified ARC derived from machine learning classifiers that distinguished SA from AD with high accuracy (AUC = 0.85), and validated the replicability of the ARC in an independent replication cohort (N = 143). ARC involved prefrontal, temporal and insular networks and was strongly associated with brain age. When applied to cognitively unimpaired (CU) adults (discovery cohort: N = 818 and replication cohort: N = 497), ARC-based subtyping revealed SA-like and AD-like subgroups with similar baseline cognitive performance but markedly divergent longitudinal trajectories. SA-like CU individuals showed slower cognitive decline, reduced amyloid-\u03b2 accumulation, and lower risk of conversion to mild cognitive impairment and AD, reinforcing the ARC signature as a potential early indicator of resilience. Genome-wide association analysis identified\n                  <jats:italic>CLYBL<\/jats:italic>\n                  and\n                  <jats:italic>FRMD6<\/jats:italic>\n                  as novel genetic modulators associated with these divergent aging phenotypes. Together, our findings position ARC as a sensitive and generalizable biomarker of resilience, enabling early risk stratification and precision prevention for AD.\n                <\/jats:p>","DOI":"10.1101\/2025.07.20.665707","type":"posted-content","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T11:40:12Z","timestamp":1753357212000},"source":"Crossref","is-referenced-by-count":2,"title":["Functional Connectome of Superagers Reveals Early Markers of Resilience and Vulnerability to Alzheimer\u2019s Disease"],"prefix":"10.64898","author":[{"given":"Kanhao","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory A.","family":"Fonzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy B.","family":"Carlisle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tovia","family":"Jacobs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo S.","family":"Osorio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arpana","family":"Church","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng Vankee","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the ADNI Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025072502353372000_2025.07.20.665707v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02296-6"},{"key":"2025072502353372000_2025.07.20.665707v1.2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2059-23.2024"},{"key":"2025072502353372000_2025.07.20.665707v1.3","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awn320"},{"key":"2025072502353372000_2025.07.20.665707v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.22263"},{"key":"2025072502353372000_2025.07.20.665707v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2012.09.017"},{"key":"2025072502353372000_2025.07.20.665707v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2021.100467"},{"key":"2025072502353372000_2025.07.20.665707v1.7","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab114"},{"key":"2025072502353372000_2025.07.20.665707v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01263-2"},{"key":"2025072502353372000_2025.07.20.665707v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/S2666-7568(23)00079-X"},{"key":"2025072502353372000_2025.07.20.665707v1.10","doi-asserted-by":"publisher","DOI":"10.1007\/s00234-020-02562-1"},{"key":"2025072502353372000_2025.07.20.665707v1.11","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-180360"},{"key":"2025072502353372000_2025.07.20.665707v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2016.02.002"},{"key":"2025072502353372000_2025.07.20.665707v1.13","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0000000000005303"},{"key":"2025072502353372000_2025.07.20.665707v1.14","doi-asserted-by":"crossref","unstructured":"Liem F , Geerligs L , Damoiseaux JS , Margulies DS . 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