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. 2025 Feb;21(2):e14537.
doi: 10.1002/alz.14537.

Plasma p-tau217 identifies cognitively normal older adults who will develop cognitive impairment in a 10-year window

Yara Yakoub  1 , Fernando Gonzalez-Ortiz  2 , Nicholas J Ashton  2   3   4   5 , Christine Déry  1 , Cherie Strikwerda-Brown  1   6 , Frédéric St-Onge  1 , Valentin Ourry  1 , Michael Schöll  2   3   7 , Maiya R Geddes  8   9   10 , Simon Ducharme  1   8 , Maxime Montembeault  1   11 , Pedro Rosa-Neto  8   10 , Jean-Paul Soucy  8 , John C S Breitner  1   11 , Henrik Zetterberg  2   7   12   13   14   15 , Kaj Blennow  2   12 , Judes Poirier  1   11 , Sylvia Villeneuve  1   8   11 ; PREVENT−AD Research Group
Affiliations

Plasma p-tau217 identifies cognitively normal older adults who will develop cognitive impairment in a 10-year window

Yara Yakoub et al. Alzheimers Dement. 2025 Feb.

Abstract

Introduction: We assessed the prognostic accuracy of plasma p-tau217 in predicting the progression to mild cognitive impairment (MCI) in cognitively unimpaired (CU) individuals over a mean follow-up of 5.65 years after plasma collection (range 1.01-10.47).

Methods: We included 215 participants from the PREVENT-AD cohort with plasma Aβ42/40 and p-tau217, 159 with cerebrospinal fluid (CSF) Aβ42/40 and p-tau217, and 155 with 18F-NAV4694 and 18F-flortaucipir PET scans. MCI progression was determined by multidisciplinary consensus among memory experts blind to biomarker and genetic information.

Results: Cox proportional hazard models indicated a greater progression rate in A+T+plasma and A-T+plasma compared to A-T-plasma individuals (HR = 7.81 [95% CI = 3.92 to 15.59] and HR = 4.25 [1.60-11.31] respectively). Similar results were found with CSF (HR = 3.63 [1.72-7.70]) and PET (HR = 9.30 [3.67-23.55]).

Discussion: Plasma p-tau217 is a prognostic marker for identifying individuals who will develop cognitive impairment within ten years.

Highlights: Elevated plasma p-tau217 levels in CU individuals indicate future clinical progression. Adding plasma Aβ42/40 status to p-tau markers did not improve the prediction to MCI. All individuals with abnormal tau PET measured in a temporal meta-ROI progressed to MCI.

Keywords: CSF; MCI; PET; amyloid; plasma; tau.

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Conflict of interest statement

H.Z. has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). M.S. has served on advisory boards for Roche, Novo Nordisk, and Servier; received speaker honoraria from Bioarctic, Eisai, Genentech, Novo Nordisk, and Roche; and receives research support (to the institution) from Alzpath, Bioarctic, Novo Nordisk, and Roche (outside scope of submitted work). He is a co‐founder of Centile Bioscience Ltd. No other disclosures were reported. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Clinical progression to MCI across plasma, CSF, and PET AT biomarker groups. Bar graphs represent the proportion of participants who developed MCI across (A) plasma Aβ42/40 and p‐tau217, (B) CSF Aβ42/40 and p‐tau217, and (C) PET biomarker profiles measured with 18F‐NAV4694 and 18F‐flortaucipir. Survival curves reflecting the progression to MCI across (D) plasma, (E) CSF, and (F) PET biomarker groups. The vertical ticks on the curves refer to censored participants, that is, the lack of follow‐up of the individuals. G–I, Forest plots showing HR and 95% confidence intervals from the survival analyses. Linear mixed effects models show the total RBANS cognitive score over time across (J) plasma, (K) CSF, and (L) PET biomarker profiles. The linear mixed effects models analyses included annual cognitive data before and after plasma, CSF, and PET measures. Models included age at biomarker measurement, sex, and years of education as covariates. Tau PET positivity was determined using temporal meta‐ROI. The A−T− group was used as reference. The A−T+ in the PET (n = 1) biomarker group is displayed for visualization purposes but was not included in the statistical analyses. The exact number of participants per group can be found in the first column of the lower part of panel (D), (E), and (F; number at risk at time 0). * P < 0.05, **P < 0.01, ***p < 0.001. Aβ, amyloid beta; AT, amyloid, tau; CSF, cerebrospinal fluid; CU_CU, cognitively unimpaired older adults at the time of the biomarker measurement and remained cognitively unimpaired during follow‐up; CU_MCI, cognitively unimpaired older adults at the time of the biomarker measurement, who progressed to mild cognitive impairment during follow‐up; HR, hazard ratio; MCI, mild cognitive impairment; PET, positron emission tomography; p‐tau, phosphorylated tau; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; SE, standard error.
FIGURE 2
FIGURE 2
Scatterplots reflecting concordance status among plasma, CSF, and PET Aβ and tau biomarkers. Correlation plots of (A) plasma Aβ42/40 versus Aβ PET biomarkers; (B) plasma p‐tau217 versus tau PET biomarkers; (C) plasma Aβ42/40 versus CSF Aβ42/40 biomarkers; (D) plasma p‐tau217 versus CSF p‐tau217 biomarkers; (E) CSF Aβ42/40 versus Aβ PET biomarkers; (F) CSF p‐tau217 versus tau PET biomarkers. Colors indicate participants’ cognitive status and symbols indicate Aβ/tau positive or negative status. Vertical and horizontal dashed lines correspond to plasma, PET, and CSF biomarker cutoff values, respectively. Cutoff values were 0.09 for plasma Aβ42/40; 0.072 for CSF Aβ42/40; 1.26 SUVR for Aβ PET; 3.98 pg/mL for plasma p‐tau217; 400.19 pg/mL for CSF p‐tau217; and 1.29 SUVR for temporal meta‐ROI tau PET. n = 143 participants had both plasma and PET measurements, n = 158 had both plasma and CSF measurements, and n = 93 had both CSF and PET measurements. Aβ, amyloid beta; CSF, cerebrospinal fluid; CU_CU, cognitively unimpaired older adults at the time of the biomarker measurement and remained cognitively unimpaired during follow‐up; CU_MCI, cognitively unimpaired older adults at the time of the biomarker measurement, who progressed to mild cognitive impairment during follow‐up; PET, positron emission tomography; p‐tau, phosphorylated tau; SUVR, standardized uptake value ratio
FIGURE 3
FIGURE 3
Discriminative accuracy of plasma, CSF, and PET biomarkers for identifying individuals who will progress to MCI. ROC curves and corresponding AUC showing the discriminative ability of (A) individual plasma, CSF, and PET Aβ models; (B) individual plasma, CSF, and PET tau models; and (C) models combining plasma Aβ42/40, CSF Aβ42/40, and Aβ PET biomarkers with plasma p‐tau217, CSF p‐tau217, and tau PET in distinguishing between individuals who remained cognitively normal versus those who developed MCI. Aβ, amyloid beta; AUC, area under the curve; CSF, cerebrospinal fluid; MCI, mild cognitive impairment; PET, positron emission tomography; ROC, receiver operating characteristic
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References

    1. Jack CR Jr, Holtzman DM. Biomarker modeling of Alzheimer's disease. Neuron. 2013;80(6):1347‐1358. doi:10.1016/j.neuron.2013.12.003 - DOI - PMC - PubMed
    1. Jack CR, Andrews JS, Beach TG, et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2024; doi:10.1002/alz.13859 - DOI - PMC - PubMed
    1. Jack CR, Bennett DA, Blennow K, et al. NIA−AA Research Framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535‐562. doi:10.1016/j.jalz.2018.02.018 - DOI - PMC - PubMed
    1. Strikwerda−Brown C, Hobbs DA, Gonneaud J, et al. Association of elevated amyloid and tau positron emission tomography signal with near‐term development of Alzheimer disease symptoms in older adults without cognitive impairment. JAMA Neurol. 2022;79(10):975‐985. doi:10.1001/jamaneurol.2022.2379 - DOI - PMC - PubMed
    1. Ossenkoppele R, Pichet Binette A, Groot C, et al. Amyloid and tau PET−positive cognitively unimpaired individuals are at high risk for future cognitive decline. Nat Med. 2022;28(11):2381‐2387. doi:10.1038/s41591-022-02049-x - DOI - PMC - PubMed

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