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Performance of plasma phosphorylated tau 181 and 217 in the community

Abstract

Plasma phosphorylated tau 181 (P-tau181) and 217 (P-tau217) are indicators of both amyloid and tau pathology in clinical settings, but their performance in heterogeneous community-based populations is unclear. We examined P-tau181 and P-tau217 (n = 1,329, aged 30–98 years), in the population-based Mayo Clinic Study of Aging. Continuous, unadjusted plasma P-tau181 and P-tau217 predicted abnormal amyloid positron-emission tomography (PET) (area under the receiver operating characteristic curve (AUROC) = 0.81–0.86) and tau PET entorhinal cortex (AUROC > 0.80), but was less predictive of a tau PET temporal region of interest (AUROC < 0.70). Multiple comorbidities were associated with higher plasma P-tau181 and P-tau217 levels; the difference between participants with and without chronic kidney disease (CKD) was similar to the difference between participants with and without elevated brain amyloid. The exclusion of participants with CKD and other comorbidities affected the establishment of a normal reference range and cutpoints. Understanding the effect of comorbidities on P-tau181 and P-tau217 levels is important for their future interpretation in the context of clinical screening, diagnosis or prognosis at the population level.

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Fig. 1: Plasma P-tau181 and P-tau217 levels by age.
Fig. 2: Forest plots of associations between multiple factors and plasma P-tau181 and P-tau217 using linear regression among all participants (n = 1,329 unique biological participants).

Data availability

Raw and analyzed de-identified data from the MCSA can be requested at https://ras-rdrs.mayo.edu/Request/IndexRequest. The request will be reviewed by the MCSA investigators and Mayo Clinic to verify whether the request is subject to any intellectual property or confidentiality obligations. A data sharing agreement must be obtained prior to release.

Code availability

No custom code or mathematical algorithm that was central to the conclusions was used in this study.

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Acknowledgements

Funding for this study was provided by grants from the National Institutes of Health (NIH) (U01 AG006786 to M.M.M., C.R.J. and R.C.P.; R37 AG011378 to C.R.J.; R01 NS097495 to P.V.; P30 AG062677 to R.C.P.; RF1 AG069052 to M.M.M., J.G-R. and P.V.; and R01 AG041851 to C.R.J. and D.S.K.) and the GHR Foundation (to R.C.P.). This study was made possible using the resources of the REP, which is supported by the NIH National Institute on Aging under award no. R01 AG034676. Meso Scale Discovery P-tau181 and P-tau217 assays were performed at Eli Lilly and Company. The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all data in the study, and all authors had final responsibility for the decision to submit for publication.

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Authors and Affiliations

Authors

Contributions

M.M.M. and J.L.D. designed and planned this study. M.M.M. and R.D.F. designed the specific analysis. M.M.M. drafted the manuscript. All authors contributed to interpretation of the study results and revised and approved the manuscript for intellectual content. M.M.M. is the guarantor and accepts full responsibility for the work and conduct of the study, had access to the data and controlled the decision to publish. The corresponding author (M.M.M.) attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Corresponding author

Correspondence to Michelle M. Mielke.

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Competing interests

M.M.M. has served as a consultant for Biogen, Brain Protection Company and Labcorp. J.L.D. was previously an employee and is still a minor shareholder of Eli Lilly and Company. J.L.D. is an inventor on patents or patent applications of Eli Lilly and Company relating to the assays, methods, reagents and/or compositions of matter used in this work. J.L.D. has also served as a consultant for Karuna Therapeutics and received research support from ADx Neurosciences, Roche Diagnostics and Eli Lilly and Company. R.D.F. and A.A.-S. report no conflicts. D.S.K. serves on a data safety monitoring board for the Dominantly Inherited Alzheimer Network (DIAN) study. D.S.K. also serves on a data safety monitoring board for Biogen but receives no personal compensation. D.S.K. is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California. D.S.K. serves as a consultant for Roche, Samus Therapeutics, Third Rock and Alzeca Biosciences but receives no personal compensation. V.J.L. received consulting fees from Bayer Schering Pharma, Piramal Life Sciences and Merck Research, and grants from GE Healthcare, Siemens Molecular Imaging, Avid Radiopharmaceuticals and the NIH. G.B. serves as a consultant for AbbVie, E-Scape and SciNeuro. P.V. received speaking fees from Miller Medical Communications. J.G.-R. receives NIH funding and serves as an assistant editor for Neurology. C.R.J. serves on an independent data monitoring board for Roche, has served as a speaker for Eisai and consulted for Biogen but receives no personal compensation from any commercial entity. C.R.J. receives research support from the NIH and the Alexander Family Alzheimer’s Disease Research Professorship of Mayo Clinic. R.C.P. received consulting fees from Hoffman-La Roche, Merck, Genentech, Biogen, GE Healthcare and Eisai.

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Nature Medicine thanks Julien Dumurgier, Suzanne Schindler and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Jerome Staal, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Plasma P-tau181 and P-tau217 levels by clinical diagnosis and amyloid PET status.

Abnormal amyloid PET (A + ) was defined as standard uptake value ratio (SUVR) > 1.48 using PiB-PET. P-values are from two-sided Wilcoxon rank-sum tests without adjustment for multiple comparisons. Box plots display the median, 25th percentile, 75th percentile (middle, bottom, and top bars of the box), and the whiskers go out to 1.5 times the interquartile range (75th percentile – 25th percentile) from the 25th and 75th percentile. CU, cognitively unimpaired; MCI, mild cognitive impairment; DEM, dementia.

Extended Data Fig. 2 Plasma P-tau181 and P-tau217 levels by clinical diagnosis and amyloid and tau PET status.

Abnormal amyloid PET (A + ) was defined as standard uptake value ratio (SUVR) ≥ 1.48 using PiB-PET. Abnormal tau PET (T + ) meta region of interest (ROI) was defined as standard uptake value ratio (SUVR) ≥ 1.29 using AV1451, and included the amygdala, entorhinal cortex, fusiform, parahippocampal, and inferior temporal and middle temporal gyri. P-values are from two-sided Kruskal-Wallis tests. Box plots display the median, 25th percentile, 75th percentile (middle, bottom, and top bars of the box), and the whiskers go out to 1.5 times the interquartile range (75th percentile – 25th percentile) from the 25th and 75th percentile. CU, cognitively unimpaired; MCI, mild cognitive impairment.

Extended Data Fig. 3 Plasma P-tau181 and P-tau217 levels by presence of an APOE ɛ4 allele.

P-values are from two-sided Wilcoxon rank-sum tests without adjustment for multiple comparisons. Box plots display the median, 25th percentile, 75th percentile (middle, bottom, and top bars of the box), and the whiskers go out to 1.5 times the interquartile range (75th percentile – 25th percentile) from the 25th and 75th percentile. CU, cognitively unimpaired; MCI, mild cognitive impairment; DEM, dementia.

Extended Data Fig. 4 Plasma P-tau181 and P-tau217 levels by sex.

P-values are from two-sided Wilcoxon rank-sum tests without adjustment for multiple comparisons. Box plots display the median, 25th percentile, 75th percentile (middle, bottom, and top bars of the box), and the whiskers go out to 1.5 times the interquartile range (75th percentile – 25th percentile) from the 25th and 75th percentile. CU, cognitively unimpaired; MCI, mild cognitive impairment; DEM, dementia.

Extended Data Fig. 5 Forest plots of associations between multiple factors and plasma P-tau181 and P-tau217 levels using linear regression after excluding all participants with chronic kidney disease (n = 1231).

Black lines indicate univariable associations and red lines indicate associations after adjustment for age and sex. Means and 95% confidence intervals are provided. A + , Elevated amyloid PET; AFib, atrial fibrillation; BAI total, Beck Anxiety Inventory; BDI dep, Beck Depression Inventory; BMI, body mass index; Chemo, chemotherapy for those with a cancer diagnosis; DM, diabetes mellitus; HTN, hypertension; MI, myocardial infarction.

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Mielke, M.M., Dage, J.L., Frank, R.D. et al. Performance of plasma phosphorylated tau 181 and 217 in the community. Nat Med 28, 1398–1405 (2022). https://doi.org/10.1038/s41591-022-01822-2

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