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However, molecular and particularly longitudinal fluid biomarker data for this stage are still limited. This study aimed to determine whether blood-based biomarkers in amyloid-positive individuals with SCD (A\u2009+\u2009SCD) support the notion of stage 2 as a distinct stage between stages 1 and 3 of AD and to identify those at high risk for clinical progression. In a prospective multicenter study (DELCODE) involving 457 participants across the AD continuum, we analyzed plasma phospho-tau 181 (p181) and neurofilament light chain (NfL) and assessed their association with longitudinal cognition, hippocampal atrophy, and AD clinical stage transition. The results showed that baseline plasma p181 levels were elevated and increased more rapidly in A\u2009+\u2009SCD individuals compared to amyloid-positive cognitively unimpaired (A\u2009+\u2009CU) individuals (stage 1). NfL levels rose across A\u2009+\u2009CU, A\u2009+\u2009SCD, and amyloid-positive mild cognitive impairment (A\u2009+\u2009MCI, stage 3). In A\u2009+\u2009SCD, but not in A\u2009+\u2009CU, higher p181 levels predicted cognitive decline (PACC5) and transition to MCI. In conclusion, plasma p181 provides molecular biomarker evidence supporting A\u2009+\u2009SCD as a pre-dementia AD stage (stage 2) distinct from A\u2009+\u2009CU (stage 1) and helps identify individuals at risk for cognitive decline early in the AD continuum.<\/jats:p>","DOI":"10.1038\/s41380-025-03021-0","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T18:30:51Z","timestamp":1744914651000},"page":"3150-3159","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Blood biomarkers confirm subjective cognitive decline (SCD) as a distinct molecular and clinical stage within the NIA-AA framework of Alzheimer\u00b4s 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Alzheimers Dement. 2018;14:734\u201342.","journal-title":"Alzheimers Dement"}],"container-title":["Molecular Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41380-025-03021-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-025-03021-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-025-03021-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T02:59:27Z","timestamp":1750647567000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41380-025-03021-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,18]]},"references-count":40,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["3021"],"URL":"https:\/\/doi.org\/10.1038\/s41380-025-03021-0","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.07.10.24310205","asserted-by":"object"}]},"ISSN":["1359-4184","1476-5578"],"issn-type":[{"value":"1359-4184","type":"print"},{"value":"1476-5578","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,18]]},"assertion":[{"value":"26 July 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 March 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 April 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 April 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"David Berron is a scientific co-founder of neotiv GmbH and owns company shares. Frank Jessen reports grant support from Roche and speaker and advisor honorarium from Abbvie, AC immune, Biogen, Eisai, Grifols, Janssen, Lilly, Novo Nordisk, Roche. Matthis Synofzik has received consultancy honoraria from Ionis, UCB, Prevail, Orphazyme, Servier, Reata, GenOrph, AviadoBio, Biohaven, Solaxa, Biogen, Zevra, and Lilly, all unrelated to the present manuscript. All other authors report no disclosures.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were performed in accordance with the relevant guidelines and regulations. The ethical committees of all participating centers approved the protocol. All participants provided informed consent prior to study participation. Data analysis was approved by the Ethics Committee of the Medical Faculty of the Eberhard Karls University and the University Hospital T\u00fcbingen (665\/2021BO2).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"During the preparation of this work the authors used OpenAI (2024) ChatGPT (Version 4.0) in order to improve readability and language. After using this tool\/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declaration of Generative AI and AI-assisted technologies in the writing process"}}]}}