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Comment
. 2025 Oct 1;82(10):985-993.
doi: 10.1001/jamaneurol.2025.2974.

Concurrent Changes in Plasma Phosphorylated Tau 217, Tau PET, and Cognition in Preclinical Alzheimer Disease

Philip S Insel  1 , Niklas Mattsson-Carlgren  2   3   4 , Oliver Langford  5 , Vincent M Caruso  6 , Antoine Leuzy  7 , Christina B Young  8 , Adam Boxer  9 , Paul S Aisen  5 , Reisa A Sperling  10   11 , Elizabeth C Mormino  8   12 , Michael C Donohue  5
Affiliations
Comment

Concurrent Changes in Plasma Phosphorylated Tau 217, Tau PET, and Cognition in Preclinical Alzheimer Disease

Philip S Insel et al. JAMA Neurol. .

Abstract

Importance: Developing disease-modifying treatments is a priority for Alzheimer disease research.

Objective: To determine the potential of plasma phosphorylated tau 217 (p-tau217) and tau positron emission tomography (PET) to assess disease modification in treatment trials.

Design, setting, and participants: This diagnostic/prognostic study used longitudinal data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study collected from April 2014 to June 2023. Recruited from 67 sites in the US, Canada, Australia, and Japan, participants included older individuals (age 65-85 years) who were cognitively unimpaired at screening and underwent an amyloid PET scan. Participants without elevated amyloid PET were included from a companion to the A4 study, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study.

Exposure: 18F-florbetapir PET imaging.

Main outcomes and measures: 18F-florbetapir PET imaging was used to classify participants as having elevated amyloid β (Aβ+). Measures of tau included longitudinal plasma p-tau217 and 18F-flortaucipir PET. Cognition was assessed using the Preclinical Alzheimer Cognitive Composite (PACC).

Results: A total of 1169 individuals were included from A4 Study and 538 without elevated amyloid PET were included from the LEARN Study. Among these 1707 participants, the baseline mean (SD) age was 71.5 (4.7) years, 1024 (60%) were female, and 683 (40%) male; 1169 participants were Aβ+, and the mean (SD) Mini-Mental State Examination score was 28.8 (1.2). The tau PET substudy included 443 participants; plasma p-tau217 levels were available for 1643 participants. The largest effect size of longitudinal tau PET accumulation at 36 months in Aβ+ participants was in the inferior temporal gyrus. Baseline associations with longitudinal change in PACC score in Aβ+ participants were strongest in the entorhinal cortex (correlation [ρ] = -0.55; 95% CI, -0.63 to -0.45) and plasma p-tau217 levels (ρ = -0.47; 95% CI, -0.56 to -0.37). Tau PET changes in frontoparietal regions were strongly correlated with concurrent cognitive changes. Levels of plasma p-tau217 increased significantly in Aβ+ participants before showing significant deceleration (χ2 = 21.7; P < .001) and were not associated with concurrent cognitive change in the tau PET substudy (ρ = -0.03; 95% CI, -0.23 to 0.16) but were modestly associated with concurrent cognitive changes in the full plasma sample (n = 1119; ρ = -0.24; 95% CI, -0.34 to -0.14).

Conclusions and relevance: This study found that tau PET is valuable for both prognostic and real-time tracking of disease progression. Plasma p-tau217 predicts cognitive changes prior to overt cognitive impairment and can efficiently guide participant selection. Imaging-based tau measures may enhance detection of disease-modifying effects and refine therapeutic targets in future Alzheimer disease trials.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Leuzy reported serving as a consultant for Enigma Biomedical Group. Dr Boxer reported personal fees from Alector, Alexion, Arrowhead, Arvinas, Eli Lilly, Janssen, Merck, Neurocrine, Oligomerix, Ono, Switch, and Transposon; equity from Neurovanda; and grants from Eisai, Biogen, and Regeneron outside the submitted work. Dr Aisen reported personal fees from Merck, Biogen, Roche, AbbVie, ImmunoBrain Checkpoint, Bristol Myers Squibb, and Neurimmune and grants from Eisai outside the submitted work. Dr Sperling reported consulting fees from AbbVie, AC Immune, Acumen, Alector, Apellis, Biohaven, Bristol Myers Squibb, Genentech, Janssen, Nervgen, Oligomerixg, Prothena, Roche, Vigil Neuroscience, Ionis, and Vaxxinity outside the submitted work. Dr Mormino reported grants from the National Institutes of Health, Alzheimer’s Association, Simon’s Foundation, Webb Family Foundation, and Archer Foundation and personal fees from Eli Lilly, Roche, and NeuroTrack outside the submitted work. Dr Donohue reported personal fees from Roche (consultant) and Janssen Pharmaceuticals (spouse is full-time employee) outside the submitted work. No other disclosures were reported.

Comment on

References

    1. Cummings J, Fox N. Defining disease modifying therapy for Alzheimer’s disease. J Prev Alzheimers Dis. 2017;4(2):109-115. doi: 10.14283/jpad.2017.12 - DOI - PMC - PubMed
    1. Molenberghs G, Burzykowski T, Alonso A, Assam P, Tilahun A, Buyse M. The meta-analytic framework for the evaluation of surrogate endpoints in clinical trials. J Stat Plan Inference. 2008;138(2):432-449. doi: 10.1016/j.jspi.2007.06.005 - DOI
    1. Digma LA, Winer JR, Greicius MD. Substantial doubt remains about the efficacy of anti-amyloid antibodies. J Alzheimers Dis. 2024;97(2):567-572. doi: 10.3233/JAD-231198 - DOI - PubMed
    1. Planche V, Villain N. Advocating for demonstration of disease modification: have we been approaching clinical trials in early Alzheimer disease incorrectly? JAMA Neurol. 2023;80(7):659-660. doi: 10.1001/jamaneurol.2023.0815 - DOI - PubMed
    1. Mauff K, Steyerberg E, Kardys I, Boersma E, Rizopoulos D. Joint models with multiple longitudinal outcomes and a time-to-event outcome: a corrected two-stage approach. Stat Comput. 2020;30(4):999-1014. doi: 10.1007/s11222-020-09927-9 - DOI