Measurement of Phosphorylated Tau Epitopes in the Differential Diagnosisof Alzheimer Disease: A Comparative Cerebrospinal Fluid Study
Abstract
BACKGROUND: Abnormal hyperphosphorylation of the microtubule-associated protein tau and its incorporation into neurofibrillary tangles are major hallmarks of the pathogenesis of Alzheimer disease (AD). Different tau phosphoepitopes can be sensitively detected in cerebrospinal fluid (CSF). OBJECTIVE: To compare the diagnostic accuracy of CSF concentrations of tau proteins phosphorylated at 3 pathophysiologically important epitopes (p-tau) to discriminate among patients with AD, nondemented control subjects, and patients with other dementias. DESIGN AND SETTING: Cross-sectional, bicenter, memory clinic-based studies. PARTICIPANTS: One hundred sixty-one patients with a clinical diagnosis of AD, frontotemporal dementia, dementia with Lewy bodies, or vascular dementia and 45 nondemented controls (N = 206). MAIN OUTCOME MEASURES: Levels of tau protein phosphorylated at threonine 231 (p-tau231), threonine 181 (p-tau181), and serine 199 (p-tau199). The CSF p-tau protein levels were measured using 3 different enzyme-linked immunosorbent assays. RESULTS: The mean CSF levels of the studied p-tau proteins were significantly elevated in patients with AD compared with the other groups. Applied as single markers, p-tau231and p-tau181 reached specificity levels greater than 75% between AD and the combined non-AD group when sensitivity was set at 85% or greater. Statistical differences between the assay performances are presented. Particularly, discrimination between AD and dementia with Lewy bodies was maximized using p-tau181at a sensitivity of 94% and a specificity of 64%, and p-tau231 maximized group separation between AD and frontotemporal dementia with a sensitivity of 88% and a specificity of 92%. Combinations of the 3 markers did not add discriminative power compared with the application as single markers. CONCLUSIONS: The p-tau proteins in CSF come closest to fulfilling the criteria of a biological marker of AD. There is a tendency for p-tau proteins to perform differently in the discrimination of primary dementia disorders from AD.
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Assays for P-tau231 and P-tau199 correlate tightly with P-tau181 and show very similar diagnostic accuracy.
“The most thoroughly examined P-tau epitope as a CSF biomarker for AD is threonine 181 (P-tau181) [143], but assays for the concentration of P-tau231 and P-tau199 correlate tightly with P-tau181 and show very similar diagnostic accuracy [144].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [144]
These biomarkers (t-tau and p-tau) remain at normal concentrations in other neurodegenerative disorders with substantial neurodegeneration, and also those with tau pathology.
“However, these biomarkers remain at normal concentrations in other neurodegenerative disorders with substantial neurodegeneration,8, 9, 10 and also those with tau pathology.11, 12, 13”
From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [11]
CSF p-tau231 has been widely reported as a biomarker to detect AD at both the MCI and dementia stages, but often it has been concluded that these changes are not different from CSF p-tau181 when directly compared.
“CSF p-tau231 has been widely reported as a biomarker to detect AD at both the MCI and dementia stages of disease11,49, 50, 51, 52, 53 but often it has been concluded these changes are not different from CSF p-tau181 when directly compared.54”
From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [11]
The results connect Aβ pathology to a distinct change in soluble tau levels and phosphorylation patterns, explaining why p-tau is significantly elevated in AD but not in other neurodegenerative tauopathies.
“Our results link Aβ pathology to a distinct change in soluble tau levels and phosphorylation patterns, shedding light on the phenomenon in which significant elevation of p-tau occurs in AD but not in other neurodegenerative tauopathies17,18.”
From A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease (2020) · cites this paper as [18]
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- Authors
- Hampel, H., Buerger, K., Zinkowski, R., Teipel, S. J., Goernitz, A., Andreasen, N., Sjoegren, M., DeBernardis, J., Kerkman, D., Ishiguro, K., Ohno, H., Vanmechelen, E., Vanderstichele, H., McCulloch, C., Möller, H.-J., Davies, P., & Blennow, K.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2004-01-01
- Volume
- 61
- Issue
- 1
- Pages
- 95
- ISSN
- 0003-990X (ISSN-L)
- OpenAlex
- W2150246483
- Cited by
- 434
- References
- 32
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 22 · 2023: 12 · 2022: 21 · 2021: 20 · 2020: 21 · 2019: 14 · 2018: 16 · 2017: 11 · 2016: 17 · 2015: 13 · 2014: 16 · 2013: 21 · 2012: 27
- FWCI
- 14.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- 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
- Alzheimer's disease, tau phosphorylation, cerebrospinal fluid biomarkers, p-tau231, p-tau181, differential diagnosis of dementia, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, diagnostic accuracy
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Epitopes, Cross-Sectional Studies, Dementia, Diagnosis, Differential, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Middle Aged, Organophosphates, Phosphorylation, Predictive Value of Tests, Reference Values, Dementia, Vascular, tau Proteins, Lewy Body Disease
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