Year: 2026
Type: preprint
Abstract: ABSTRACT Background Plasma brain-derived pTau217 (BD-pTau217) may provide a Alzheimer’s disease-specific plasma tau measure than total pTau217, but its prognostic value is unclear. We compared BD-pTau217 and total plasma pTau217 for predicting clinical and amyloid PET progression in cognitively unimpaired (CU) ADNI participants. Methods Plasma NULISAseq biomarkers were measured in 1,427 ADNI participants, including 529 CU individuals. Amyloid PET progression was assessed in baseline CU amyloid-negative participants (Centiloid ≥24.1) with longitudinal PET imaging; clinical progression was assessed in all baseline CU participants. Associations were evaluated using Cox models and time-dependent AUC. Results BD-pTau217 did not clearly outperform total pTau217 for predicting progression to mild cognitive impairment or dementia. However, among baseline amyloid-negative participants (N=175), BD-pTau217 better predicted amyloid PET positivity at 2.5 years (tdAUC 0.82 vs 0.69; HR=10.54, p=0.00015) and 4 years (tdAUC 0.77 vs 0.64; HR=7.03, p=0.00055). Conclusion BD-pTau217 improved prediction of near-term amyloid PET progression, with less clear advantage for clinical progression. HIGHLIGHTS BD-pTau217 predicted amyloid PET progression in CU ADNI participants. BD-pTau217 outperformed total pTau217 at the CL ≥24.1 threshold. BD-pTau217 and total pTau217 performed similarly for clinical progression. Prognostic performance varied across amyloid PET thresholds. BD-pTau217 may support risk stratification in prevention trials. RESEARCH IN CONTEXT Systematic review Plasma pTau217 biomarkers show strong cross-sectional associations with amyloid and tau pathology and are increasingly used to support Alzheimer’s disease diagnosis and trial screening. Recent assay designs selectively measuring brain-derived pTau217 may reduce peripheral contributions to total pTau217 measurements, but their longitudinal prognostic value relative to total pTau217 remains less well established. Interpretation In cognitively unimpaired ADNI participants, plasma BD-pTau217 showed stronger prognostic performance than total pTau217 for progression from amyloid PET negative to amyloid PET positive status, particularly at the primary CL ≥24.1 threshold. In contrast, BD-pTau217 and total pTau217 showed more similar performance for predicting clinical progression to MCI or dementia. Future directions These findings support further evaluation of BD-pTau217 for biological risk stratification and prevention trial enrichment. Validation is needed in more diverse cohorts, longer follow-up intervals, and across clinical-grade assay platforms.
Source: medRxiv
Authors: Valentina Ghisays, Marisa N. Denkinger, Alpana Singh, Tainá M. Marques, Michael Malek-Ahmadi, Kendall Van-Keuren Jensen, Hillary D. Protas, Javad Sohankar, Dhruman D. Goradia, Vivek Devadas, Yinghua Chen, Shan Li, Jessica B. Langbaum, Michael W. Weiner, Eric M. Reiman, Yi Su, Nicholas J. Ashton, Alzheimer’s Disease Neuroimaging Initiative
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G2000077523, G2190936067, G2957681590, G29951154, G3146424788, G3204659020, G3906884950, G4079001475, G4429651648, G449976137, G5434566101, G5796370532, G7302036219, G781725486, G8858851231, G9000023933, G9000055340, G9000082286, G9000103713, G9000118070, G9000122335, G9000136986, G9000166328, G9000168607, G9000285695, Arizona Alzheimer's Disease Research Center, APOE in the Predisposition to, Protection from and Prevention of Alzheimer's Disease, Safety/Tolerability/Immunogenicity of first-in-human Aβ DNA vaccine, AV-1959D Phase 1 trials in early-stage AD subjects: based on IND18953 cleared by FDA.
OpenAlex ID: W7166721514
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