{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T03:43:17Z","timestamp":1793763797946,"version":"4.6.1"},"reference-count":45,"publisher":"American Medical Association (AMA)","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"published-print":{"date-parts":[[2026,9,15]]},"abstract":"\n Importance<\/jats:title>\n Blood-based biomarkers for Alzheimer disease, particularly plasma phosphorylated tau 217 (p-tau217), accurately reflect early Alzheimer disease brain pathology in cognitively unimpaired individuals, but estimates of absolute risk of progression to cognitive impairment across multiple cohorts are needed.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To estimate absolute risk of progression to cognitive impairment and rates of cognitive decline based on plasma p-tau217 across cognitively unimpaired older adults.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n Longitudinal cohort study using harmonized data from 2684 cognitively unimpaired older adults (defined within cohort) across 6 observational and clinical trial cohorts based in North America, Japan, and Australia. The earliest enrollment was in 2004, with most recent follow-up in 2025.<\/jats:p>\n <\/jats:sec>\n \n Exposure<\/jats:title>\n Baseline plasma p-tau217.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The primary outcome was time to progression to cognitive impairment (mild cognitive impairment, dementia, or 2 consecutive global Clinical Dementia Rating scores \u22650.5). The secondary outcome was longitudinal change on the latent Preclinical Alzheimer Cognitive Composite (PACC; higher values indicate better performance).<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Among the 2684 participants (median [IQR] age, 69.6 [66.2-74.2] years; 1697 [63%] female), there were 478 events of progression to cognitive impairment over a median follow-up of 5.4 years (maximum follow-up of 13.5 years). Each 1-SD increase in baseline p-tau217 level was associated with an increased risk of progression to cognitive impairment (hazard ratio, 1.38 [95% CI, 1.30-1.46]), and the association remained significant after adjustment, including \u03b2-amyloid positron emission tomography scan Centiloids (hazard ratio, 1.32 [95% CI, 1.24-1.41]). Participants with high (1.1-2.4 SD) and very high (&amp;gt;2.5 SD) baseline p-tau217 had 24% (95% CI, 20%-28%) and 38% (95% CI, 33%-43%) absolute risk of progression over 5 years, respectively, and risk was markedly higher over 10 years, although longer-term estimates were constrained by limited data. Elevated p-tau217 was also associated with faster cognitive decline based on change in latent PACC score. Among the overall sample, baseline latent PACC scores ranged from \u22120.8 to 2.7. The 5-year annualized decline for the very high p-tau217 group was \u22120.07 latent PACC units\/y (95% CI, \u22120.10 to \u22120.05), relative to 0.03 units\/y (95% CI, 0.02-0.04) in the low p-tau217 group.<\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In a pooled sample of multiple selected cohorts of cognitively unimpaired older adults, higher plasma p-tau217 levels were consistently associated with increased risk of clinical progression and accelerated cognitive decline. By providing time-specific absolute risk estimates, these findings support the potential of p-tau217 for prognostic model development, with direct implications for future trial design. Further validation in unselected populations is needed to inform individual prognosis and clinical decision-making in cognitively unimpaired individuals.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jama.2026.12556","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T04:30:19Z","timestamp":1784089819000},"page":"950","source":"Crossref","is-referenced-by-count":14,"title":["Prognostic Value of Blood-Based P-Tau217 Levels for Progression to Cognitive Impairment"],"prefix":"10.1001","volume":"336","author":[{"given":"Rachel F.","family":"Buckley","sequence":"first","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Boston, Massachusetts"},{"name":"Melbourne School of Psychological Sciences, The University of Melbourne, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana L.","family":"Townsend","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin J.","family":"Birkenbihl","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison","family":"Cuppels","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillian T.","family":"Coughlan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mabel T.","family":"Seto","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane A.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Properzi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merle C.","family":"H\u00f6nig","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Boston, Massachusetts"},{"name":"Research Center J\u00fclich, Institute of Neurosciences and Medicine II, J\u00fclich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron P.","family":"Schultz","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmeer","family":"Chhatwal","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun-Sik","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Arnold","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"Kivis\u00e4kk","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan D.","family":"James","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University Medical Center, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sid","family":"O\u2019Bryant","sequence":"additional","affiliation":[{"name":"University of North Texas Health Science Center, Denton"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Rissman","sequence":"additional","affiliation":[{"name":"University of Southern California, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Petersen","sequence":"additional","affiliation":[{"name":"University of North Texas Health Science Center, Fort Worth"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica Z. 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