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We sought to extend these findings by evaluating the prognostic value of plasma biomarkers in a clinical trial of mild-to-moderate AD.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Post-hoc analyses investigated whether baseline concentrations of plasma biomarkers (A\u03b242\/A\u03b240, T-tau, P-tau181, NfL, and GFAP) predicted change in ADAS-Cog11, CDR-SB, and volumetric MRI among participants in T2 Protect AD, a negative 48-week, phase-2, placebo-controlled trial of troriluzole in mild-to-moderate AD. All trial participants met diagnostic criteria for probable AD. Baseline concentrations of, and 48-week changes in, plasma biomarkers were assessed for association with 48-week change in outcomes using linear regression. Combinations of baseline biomarkers that best predicted change on the ADAS-Cog11 and CDR-SB were identified using least absolute shrinkage and selection operator (LASSO) regression. Biomarker-informed sample size calculations were modeled.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Of 350 trial participants, 319 had all requisite biomarker and clinical outcome data for inclusion in these analyses (mean age 71.5, SD\u2009=\u20098.03; 58.6% female). Higher plasma NfL at baseline predicted worsening scores on the ADAS-Cog11 (effect size (ES)\u2009=\u20091.42, 95%CI\u2009=\u2009[0.43, 2.41], <jats:italic>p<\/jats:italic>\u2009=\u20090.026) and CDR-SB (ES\u2009=\u20090.42, 95%CI\u2009=\u2009[0.10, 0.73], <jats:italic>p<\/jats:italic>\u2009=\u20090.048). LASSO regression revealed that worsening on the ADAS-Cog11 was best predicted by the combination of baseline plasma NfL, T-tau, and A\u03b242\/40 ratio, whereas baseline NfL alone best predicted worsening on CDR-SB. Higher baseline NfL predicted increasing ventricular volume (ES\u2009=\u20091.30cm<jats:sup>3<\/jats:sup>, 95%CI\u2009=\u2009[0.43, 2.17], <jats:italic>p<\/jats:italic>\u2009=\u20090.018) and decreasing mid-temporal cortical volume (ES\u2009=\u2009-0.47, 95%CI\u2009=\u2009[-0.74, -0.20], <jats:italic>p<\/jats:italic>\u2009=\u20090.003). Increasing NfL over the 48-week trial was associated with worsening on CDR-SB but not ADAS-Cog11. Modeling of biomarker-informed power calculations revealed that including high NfL as a trial entry criterion could substantially reduce requisite trial sample size.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Elevated baseline plasma NfL predicted more rapid clinical decline and MRI volume loss. Furthermore, increasing plasma NfL concentration over time was associated with worsening on the CDR-SB. Plasma NfL is an easily accessible biomarker that may enhance the design of clinical trials in mild-to-moderate AD.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Trial registration<\/jats:title>\n            <jats:p>The T2 Protect AD trial was registered as NCT03605667 on clinicaltrials.gov on 2018-07-27.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13195-025-01745-3","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T03:36:53Z","timestamp":1746157013000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Prognostic value of plasma biomarkers for informing clinical trial design in mild-to-moderate Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"17","author":[{"given":"Yuqi","family":"Qiu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane 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Written informed consent was obtained from study participants, legally authorized representatives, or study partners per IRB regulations in accordance with the Declaration of Helsinki and the Belmont Report.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"YQ\u00a0is funded by National Natural Science Foundation of China (grant number 12401347), Chinese MOE Foundation on Humanities and Social Sciences (grant number 23YJC910006) and Shanghai Baiyulan Pujiang project (24PJD087). DMJ reports support from grants to UC San Diego from the NIH, Biohaven Pharmaceuticals, Vivoryon Therapeutics, and a philanthropic donation for the Epstein Family Alzheimer Research Collaboration. KM reports support from grants to UC San Diego from the NIH and Biohaven Pharmaceuticals. DPS reports support from grants to UC San Diego from the NIH and Biohaven Pharmaceuticals and consulting fees from Biogen and Aptinyx. CLW reports no disclosures. SS reports no disclosures. CR reports support from grants to UC San Diego from the NIH and Biohaven Pharmaceuticals. JBB reports support from grants to UC San Diego from the NIH and Biohaven Pharmaceuticals. GCL reports support from grants to UC San Diego from the NIH and Biohaven Pharmaceuticals. BA, LD, SK, VC, and IA are currently employed by Biohaven Pharmaceuticals, Inc. and own stock and hold stock options in Biohaven Pharmaceuticals, Inc. HHF reports grant funding from Biohaven Pharmaceuticals with no personal funds received and all payments to the Alzheimer's Disease Cooperative Study at UC San Diego. HHF also discloses grant funding from Annovis (QR Pharma), Vivoryon (Probiodrug), AC Immune, and LuMind Foundation; service agreements for consulting activities with LuMind, Axon Neuroscience, Novo Nordisk, Arrowhead Pharmaceuticals, Roche\/Genentech Pharmaceuticals (DMC\/DSMB), Tau Consortium (SAB), Janssen Research & Development (DSMB); support for travel from Novo Nordisk, Royal Society of Canada, and Translating Research in Elder Care (TREC); and a philanthropic donation for the Epstein Family Alzheimer Research Collaboration. For these activities, no personal funds have been received with all payments to UC San Diego. HHF personally receives royalties for patent: Feldman HH (filed November 26, 2008). Detecting and Treating Dementia Serial Number 12\/3-2691 U.S. Patent No. PCT\/US2007\/07008. Washington, DC: U.S. Patent and Trademark Office.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"97"}}