Evaluation of Copathology and Clinical Trajectories in Individuals With Tau-Clinical Mismatch.

Importance: Even within individuals who are amyloid positive, clinical symptoms can be impacted by Alzheimer pathology, other pathologic proteins, and cognitive reserve or resilience. Understanding how each of these factors contributes to a patient's clinical presentation is crucial for prognosis and treatment decisions in the era of disease-modifying therapies. Objective: To evaluate tau-clinical mismatch as a means to identify those more likely to harbor copathology and/or exhibit resilience to Alzheimer pathology. Design, Setting, and Participants: This was a longitudinal, observational cohort study conducted from 2004 to 2024. The setting included multiple academic medical centers in the US participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI) or Penn Alzheimer's Disease Research Center (Penn-ADRC). Included in the analysis were individuals with clinical assessment and measures of either tau positron emission tomography (tau-PET) or phosphorylated tau 217 (p-tau217) who were selected from individuals positive for amyloid β (Aβ+) in the ADNI cohort (aged 55-95 years) and the Penn-ADRC cohort (aged 54-92 years). Exposures: Clinical assessment (Clinical Dementia Rating Sum of Boxes [CDR-SB]) and tau burden (tau-PET or p-tau217) for mismatch group classification. 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, and longitudinal CDR-SB. Results: A total of 365 participants (mean [SD] age, 75.4 [7.9] years; 192 female [52.6%]) in the ADNI tau-PET group and 524 participants (mean [SD] age, 77.1 [7.9] years; 268 male [51.1%]) in the ADNI p-tau217 group were selected from the 998 individuals who were Aβ+ in the ADNI cohort and used to generate tau-clinical mismatch models with 55.6% to 57.1% classified as canonical (CDR-SB commensurate to tau), 23.7% to 24.7% as resilient (CDR-SB < tau), and 19.3% to 19.7% as vulnerable (CDR-SB > tau). Vulnerable groups had evidence of greater likelihood of copathology, with TDP-43 neurodegeneration patterns and α-synuclein positivity. Mismatch groups showed diverging clinical trajectories with earlier cognitive impairment in vulnerable groups and later impairment in resilient individuals. Similar findings were seen when applied to an independent dataset of 244 individuals (mean [SD] age, 73.7 [6.8] years; 139 female [57.0%]) of the 248 who were Aβ+ in Penn-ADRC cohort. Finally, these models were applied to a cohort receiving antiamyloid therapy to show the utility of this method for predicting individual cognitive trajectories during therapy. Conclusion and Relevance: Results of this cohort study suggest that tau-clinical mismatch identified individuals more likely to have an accelerated disease course due to the presence of copathology and those exhibiting greater cognitive resilience to disease pathology. 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.