Performance of plasma phosphorylated tau 181 and 217 in the community
Open accessAbstract
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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Hypertension lowers plasma Aβ concentration but increases plasma P-tau181 and P-tau217 levels.
“For example, coexisting αSyn pathology in AD correlates with lower CSF P-tau181 and NG levels,394 while comorbidity like hypertension lowers plasma Aβ concentration but increases plasma P-tau181 and P-tau217 levels.388,395”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [395]
The Results section, “Associations of plasma ptau with other covariates” (page unavailable), associates hypertension with higher plasma P-tau181 and P-tau217, but reports that the association did not persist after participants with chronic kidney disease were excluded. The paper does not report that hypertension lowers plasma Aβ concentration, so that part of the claim is unsupported by this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLower positive percent agreements are expected in settings with lower prevalence, as observed in the preclinical WRAP cohort compared with the higher prevalence seen in TRIAD and SPIN cohorts.
“Lower positive percent agreements are expected in settings with lower prevalence,46 as observed in the preclinical WRAP cohort compared with the higher prevalence seen in TRIAD and SPIN cohorts.”
From Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology (2024) · cites this paper as [46]
The Evaluation of cutpoints section says Table 4 demonstrates how differing prevalences of elevated brain amyloid affect positive predictive value (PPV). That supports a prevalence-related change in PPV, but the cited paper does not establish the claim for positive percent agreement, a different measure. The WRAP, TRIAD and SPIN comparison is presented as the citing authors’ observation, not as a finding attributed to this source. (LLM, conf=0.79)
Experimental — accuracy not yet measuredChronic kidney disease is associated with increased plasma p-tau levels independent of age or AD pathology, likely reflecting reduced peripheral clearance rather than increased central production, as cerebrospinal fluid tau does not show parallel elevations.
“CKD, which is common in TSC, has been associated with increased plasma p-tau levels independent of age or AD pathology, likely reflecting reduced peripheral clearance rather than increased central production, as cerebrospinal fluid tau does not show parallel elevations (26,28).”
From Amyloid-Independent Elevation of Plasma phosphorylated tau-217 Tracks Neurodegenerative Risk in Tuberous Sclerosis Complex: Implications for mTOR-Targeted Intervention (2026) · cites this paper as [28]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThe reported negative and positive predictive accuracy of these reference ranges can vary based on the prevalence of the outcome in the target population.
“Importantly, the reported negative and positive predictive accuracy of these reference ranges can vary based on the prevalence of the outcome in the target population.”
From Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology (2024) · cites this paper as [46]
Certain comorbidities, especially kidney disease, can lead to false elevations in plasma p-tau levels, although this can be mitigated by using the ratio of p-tau217 to non-phosphorylated tau (%p-tau217).
“However, certain comorbidities, especially kidney disease, can lead to false elevations in plasma p-tau levels32,33, although this can be mitigated by using the ratio of p-tau217 to the non-phosphorylated levels of the same tau peptide (%p-tau217)34.”
From Highly accurate blood test for Alzheimer's disease is similar or superior to clinical cerebrospinal fluid tests (2024) · cites this paper as [32]
Mielke et al. showed that comorbidities such as chronic renal disease influenced plasma tau 181 and 217 levels as much as CNS abnormalities.
“Mielke et al. recently showed that, although plasma tau 181 and 217 were elevated in AD samples, comorbidities such as chronic renal disease influenced levels as much as the presence of CNS abnormalities (86).”
From All the Tau We Cannot See (2023) · cites this paper as [86]
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- Authors
- Mielke, M. M., Dage, J. L., Frank, R. D., Algeciras-Schimnich, A., Knopman, D. S., Lowe, V. J., Bu, G., Vemuri, P., Graff-Radford, J., Jack, C. R., & Petersen, R. C.
- Affiliations
- Mayo Clinic (US)
- Indiana University Indianapolis (US)
- Mayo Clinic in Florida (US)
- Corresponding author
- Mielke, Michelle M.
- ORCID
- Venue
- Nature Medicine
- Published
- 2022-05-26
- Volume
- 28
- Issue
- 7
- Pages
- 1398-1405
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC9329262
- OpenAlex
- W4281558685
- Cited by
- 465
- References
- 33
- Citations by year
- 2026: 75 · 2025: 135 · 2024: 149 · 2023: 80 · 2022: 25 · 2021: 1
- FWCI
- 63.55
- Type
- journal article
- Language
- en
- Update notices
- correction (2022-10-10)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (U01 AG006786, R37 AG011378, P30 AG062677, R01 AG041851, R01 AG034676)
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01 NS097495)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
- Keywords
- p-tau181, p-tau217, amyloid PET, tau PET, entorhinal cortex, Alzheimer's disease biomarkers, chronic kidney disease, comorbidities, reference values, Mayo Clinic Study of Aging, community-based population
- MeSH terms
- Alzheimer Disease, Amyloid, Amyloidosis, Humans, Biomarkers, Amyloid beta-Peptides, tau Proteins, Positron-Emission Tomography, Renal Insufficiency, Chronic
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