ArticlemedRxiv : the preprint server for health sciences2025
Tau-Clinical Mismatch Identifies Individuals with Co-Pathology and Predicts Clinical Trajectory.
Article in medRxiv : the preprint server for health sciences, 2025. 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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20 authors.
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Abstract
Importance: The heterogeneous course of Alzheimer's disease makes it difficult to predict individuals' cognitive trajectories, which is particularly important in the era of disease modifying therapy. Identifying individuals more likely to have co-pathology and differing disease courses using clinically practical tools remains a critical gap. Objective: To evaluate tau-clinical mismatch for identifying resilient and vulnerable individuals and compare levels of co-pathology and clinical trajectories between groups. Design Setting and Participants: Participants were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI, inclusion from 2005-2024), Penn Alzheimer's Disease Research Center Cohort (Penn-ADRC, inclusion from 2002-2025), and Penn Anti-amyloid Therapy Monitoring (Penn-ATM) cohort (inclusion from 2024-2025). All participants were amyloid-β positive, had clinical assessment, and measures of Tau-PET or plasma p-tau Exposures: Clinical assessment (CDR-SB) and tau burden (tau-PET or p-tau Main Outcomes and Measures: Cross-sectional measures of neurodegeneration (medial temporal lobe volume and thickness, cortical thickness, TAR DNA-binding protein 43 [TDP-43] imaging signature), α-synuclein cerebrospinal fluid seed-amplification assay, longitudinal CDR-SB. Results: 365 ADNI Tau-PET participants (ages 55-93, 52.6% women) and 524 ADNI p-tau Conclusion and Relevance: Tau-clinical mismatch identifies individuals more likely to harbor co-pathology and have diverging clinical trajectories. Plasma-based models produced similar results to Tau-PET models and could be replicated in independent datasets. These models provide an important tool that can be implemented in clinical practice to provide improved individualized prognosis and, potentially, monitoring of response to disease-modifying therapy.
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Registered trials
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