Comparison of Plasma Phosphorylated Tau Species With Amyloid and Tau Positron Emission Tomography, Neurodegeneration, Vascular Pathology, and Cognitive Outcomes
Open accessAbstract
Importance: Cerebrospinal fluid phosphorylated tau (p-tau) 181, p-tau217, and p-tau231 are associated with neuropathological outcomes, but a comparison of these p-tau isoforms in blood samples is needed. Objective: To conduct a head-to-head comparison of plasma p-tau181 and p-tau231 measured on the single-molecule array (Simoa) platform and p-tau181 and p-tau217 measured on the Meso Scale Discovery (MSD) platform on amyloid and tau positron emission tomography (PET) measures, neurodegeneration, vascular pathology, and cognitive outcomes. Design, Setting, and Participants: This study included data from the Mayo Clinic Study on Aging collected from March 1, 2015, to September 30, 2017, and analyzed between December 15, 2020, and May 17, 2021. Associations between the 4 plasma p-tau measures and dichotomous amyloid PET, metaregion of interest tau PET, and entorhinal cortex tau PET were analyzed using logistic regression models; the predictive accuracy was summarized using area under the receiver operating characteristic curve (AUROC) statistic. Of 1329 participants without dementia and with p-tau181 and p-tau217 on MSD, 200 participants with plasma p-tau181 and p-tau231 on Simoa and magnetic resonance imaging and amyloid and tau PET data at the same study visit were eligible. Main Outcomes And Measures: Primary outcomes included amyloid (greater than 1.48 standardized uptake value ratio) and tau PET, white matter hyperintensities, white matter microstructural integrity (fractional anisotropy genu of corpus callosum and hippocampal cingulum bundle), and cognition. Results: Of 200 included participants, 101 (50.5%) were male, and the median (interquartile range [IQR]) age was 79.5 (71.1-84.1) years. A total of 177 were cognitively unimpaired (CU) and 23 had mild cognitive impairment. Compared with amyloid-negative CU participants, among amyloid-positive CU participants, the median (IQR) Simoa p-tau181 measure was 49% higher (2.58 [2.00-3.72] vs 1.73 [1.45-2.13] pg/mL), MSD p-tau181 measure was 53% higher (1.22 [0.91-1.56] vs 0.80 [0.66-0.97] pg/mL), MSD p-tau217 measure was 77% higher (0.23 [0.17-0.34] vs 0.13 [0.09-0.18] pg/mL), and Simoa p-tau231 measure was 49% higher (20.21 [15.60-25.41] vs 14.27 [11.27-18.10] pg/mL). There were no differences between the p-tau species for amyloid PET and tau PET metaregions of interest. However, among CU participants, both MSD p-tau181 and MSD p-tau217 more accurately predicted abnormal entorhinal cortex tau PET than Simoa p-tau181 (MSD p-tau181: AUROC, 0.80 vs 0.70; P = .046; MSD p-tau217: AUROC, 0.81 vs 0.70; P = .04). MSD p-tau181 and p-tau217 and Simoa p-tau181, but not p-tau231, were associated with greater white matter hyperintensity volume and lower white matter microstructural integrity. Conclusions and Relevance: In this largely presymptomatic population, these results suggest subtle differences across plasma p-tau species and platforms for the prediction of amyloid and tau PET and magnetic resonance imaging measures of cerebrovascular and Alzheimer-related pathology.
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Detection of Aβ positivity using mass spectrometry %p-tau217 in cognitively normal cohorts appears better than what has been reported when using plasma p-tau217 immunoassays.
“Detection of Aβ positivity using mass spectrometry %p-tau217 in cognitively normal cohorts appears better than what has been reported when using plasma p-tau217 immunoassays, although this must be confirmed in head-to-head studies22,23,48–50.”
From Highly accurate blood test for Alzheimer's disease is similar or superior to clinical cerebrospinal fluid tests (2024) · cites this paper as [48]
Plasma ptau-217 has repeatedly demonstrated strong prognostic performance and generally outperforms other plasma biomarkers in predicting conversion from MCI to dementia.
“Plasma ptau-217 has repeatedly demonstrated strong prognostic performance and generally outperforms other plasma biomarkers in predicting conversion from MCI to dementia (20,24).”
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Self-citation
- Authors
- Mielke, M. M., Frank, R. D., Dage, J. L., Jeromin, A., Ashton, N. J., Blennow, K., Karikari, T. K., Vanmechelen, E., Zetterberg, H., Algeciras-Schimnich, A., Knopman, D. S., Lowe, V., Bu, G., Vemuri, P., Graff-Radford, J., Jack, C. R., & Petersen, R. C.
- Affiliations
- Mayo Clinic (US)
- Eli Lilly (United States) (US)
- Cohen Veterans Bioscience (US)
- King's College London (GB)
- Sahlgrenska University Hospital (SE)
- University of Gothenburg (SE)
- ADx Neurosciences, Ghent, Belgium
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
- Mayo Clinic in Florida (US)
- Department of Neurology, Mayo Clinic, Rochester, Minnesota
- Corresponding author
- Mielke, Michelle M.
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2021-09-01
- Volume
- 78
- Issue
- 9
- Pages
- 1108
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC8314178
- OpenAlex
- W3183927686
- Cited by
- 244
- References
- 44
- Citations by year
- 2026: 33 · 2025: 58 · 2024: 50 · 2023: 48 · 2022: 48 · 2021: 6
- FWCI
- 27.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- European Commission (860197)
- Vetenskapsrådet (2017-00915)
- National Institutes of Health
- National Institute on Aging (U01AG006786, R01AG011378, R01AG041851, R37AG011378, P30AG062677)
- National Institute of Neurological Disorders and Stroke (R01NS097495)
- H2020 European Research Council (681712)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Keywords
- phosphorylated tau, plasma biomarkers, p-tau181, p-tau217, p-tau231, amyloid PET, tau PET, amyloid-beta, neurodegeneration, white matter hyperintensities, fractional anisotropy, cognitive impairment, Simoa, MSD, Alzheimer's disease, vascular pathology
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Cross-Sectional Studies, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Nerve Degeneration, Phosphorylation, Biomarkers, Neurofibrillary Tangles, tau Proteins, Positron-Emission Tomography, Plaque, Amyloid, Cognitive Dysfunction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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