ArticleJAMA network open2026
Plasma Biomarkers and Clinical Outcomes in Early-Onset Dementia.
Article in JAMA network open, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Importance: Clinical utility and dynamics of plasma biomarkers in early-onset dementia remain underexplored. Objective: To investigate plasma biomarker trajectories and their associations with clinical outcomes in early-onset Alzheimer disease (EOAD) and frontotemporal dementia (FTD). Design, Setting, and Participants: This multicenter, prospective cohort study analyzed participants in phase 1 of the Longitudinal Study of Early-onset Dementia and Family Members (LEAF), which was conducted from April 2021 through December 2023 in 34 centers across South Korea. Patients with β-amyloid-positive EOAD and FTD were included and underwent annual blood sampling and clinical assessment, within a follow-up period of approximately 2 years. Data were analyzed between June 2025 and March 2026. Exposure: Levels of plasma phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) biomarkers were analyzed using assays. Main Outcomes and Measures: (1) Associations of baseline biomarkers with clinical outcomes (assessed with the Mini-Mental State Examination [MMSE] and the Clinical Dementia Rating-Sum of Boxes [CDR-SB] for the EOAD group, or the frontotemporal lobar degeneration [FTLD]-modified CDR-SB for the FTD group), (2) biomarker trajectories, and (3) association of biomarker level changes and clinical outcomes. Results: A total of 322 participants with p-tau217, GFAP, and NfL analyses were stratified into the EOAD or FTD group based on their diagnosis. The EOAD group (n = 245) had a mean (SD) age of 61.8 (5.4) years and included 163 females (66.5%), while the FTD group (n = 77) had a mean (SD) age of 65.1 (7.3) years and included 45 females (62.3%). In the EOAD group, higher log2-transformed baseline p-tau217, GFAP, and NfL were each associated with faster decline in the MMSE score (association estimate [SE], -0.390 [0.127], P = .002; -0.775 [0.164], P < .001; and -0.679 [0.182], P < .001, respectively) and the CDR-SB score (estimate [SE], 0.401 [0.099], P < .001; 0.535 [0.126], P < .001; and 0.693 [0.122], P < .001, respectively). In the FTD group, GFAP and NfL were associated with MMSE decline (estimate [SE], -2.118 [0.566], P < .001 and -2.360 [0.428], P < .001, respectively), whereas p-tau217 was not (estimate [SE], 0.071 [0.418], P = .87). No biomarker was associated with FTLD-modified CDR-SB score change. Longitudinally, all mean (SD) biomarker levels increased in the EOAD group (p-tau217: 0.253 [0.077] pg/mL, P = .001; GFAP: 0.173 [0.040] pg/mL, P < .001; NfL: 0.149 [0.045] pg/mL, P = .001), whereas in the FTD group, only NfL level showed an upward pattern (0.251 [0.127] pg/mL, P = .05). Annualized biomarker changes were associated with worsening clinical outcomes in the EOAD group, but not in the FTD group. GFAP and NfL level increases were associated with MMSE score decline (estimate [SE], -0.005 [0.002], P = .007 and -0.010 [0.003], P = .001, respectively), while p-tau217 level increases were associated with CDR-SB score worsening (estimate [SE], 0.072 [0.024], P = .003) in the EOAD group. Conclusions and Relevance: In this cohort study of patients with EOAD and FTD, baseline p-tau217, GFAP, and NfL were consistently associated with clinical outcomes in the EOAD group, whereas GFAP and NfL were associated with cognition only in the FTD group. These findings demonstrate distinct characteristics of plasma biomarkers in EOAD and FTD, supporting their potential utility for risk stratification.
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