Phosphorylated Tau 231 (p-tau 231)

Overview

Phosphorylated tau at threonine 231 (p-tau 231) is a cerebrospinal fluid (CSF) biomarker that detects tau pathology in Alzheimer's disease. Notably, p-tau 231 shows abnormalities earlier than p-tau 181, making it particularly valuable for early disease detection and preclinical AD identification. [@buchhave2012]

Biological Significance

p-tau 231 is phosphorylated at threonine 231, a site that: [@hampel2004]

• Appears early in AD pathogenesis -Elevations detectable before clinical symptoms
• Correlates with tau NFT burden - Strong correlation with neurofibrillary tangle density
• Reflects pretangle formation - May detect pretangle tau changes not visible on PET

Clinical Validation

Diagnostic Performance

| Platform | Cutoff (pg/mL) | Sensitivity | Specificity | AUC | [@karikari2020]
|----------|----------------|-------------|-------------|-----| [@molinuevo2014]
| INNOTEST | >50 | 80-85% | 80-85% | 0.85-0.90 |
| Lumipulse | >40 | 82-88% | 83-89% | 0.88-0.92 |
| Simoa | >5 | 85-90% | 85-91% | 0.90-0.95 |

Key Studies

[Buchhave et al., 2012](https://pubmed.ncbi.nlm.nih.gov/22438551/): p-tau 231 detects preclinical AD

[Hampel et al., 2004](https://pubmed.ncbi.nlm.nih.gov/14766955/): Early marker of AD progression

[Karikari et al., 2020](https://pubmed.ncbi.nlm.nih.gov/32839587/): Plasma p-tau 231 validation

Comparison to p-tau 181

...

Overview

Phosphorylated tau at threonine 231 (p-tau 231) is a cerebrospinal fluid (CSF) biomarker that detects tau pathology in Alzheimer's disease. Notably, p-tau 231 shows abnormalities earlier than p-tau 181, making it particularly valuable for early disease detection and preclinical AD identification. [@buchhave2012]

Biological Significance

p-tau 231 is phosphorylated at threonine 231, a site that: [@hampel2004]

• Appears early in AD pathogenesis -Elevations detectable before clinical symptoms
• Correlates with tau NFT burden - Strong correlation with neurofibrillary tangle density
• Reflects pretangle formation - May detect pretangle tau changes not visible on PET

Clinical Validation

Diagnostic Performance

| Platform | Cutoff (pg/mL) | Sensitivity | Specificity | AUC | [@karikari2020]
|----------|----------------|-------------|-------------|-----| [@molinuevo2014]
| INNOTEST | >50 | 80-85% | 80-85% | 0.85-0.90 |
| Lumipulse | >40 | 82-88% | 83-89% | 0.88-0.92 |
| Simoa | >5 | 85-90% | 85-91% | 0.90-0.95 |

Key Studies

[Buchhave et al., 2012](https://pubmed.ncbi.nlm.nih.gov/22438551/): p-tau 231 detects preclinical AD

[Hampel et al., 2004](https://pubmed.ncbi.nlm.nih.gov/14766955/): Early marker of AD progression

[Karikari et al., 2020](https://pubmed.ncbi.nlm.nih.gov/32839587/): Plasma p-tau 231 validation

Comparison to p-tau 181

| Feature | p-tau 181 | p-tau 231 |
|---------|-----------|------------|
| Time to abnormality | Clinical stage | Preclinical stage |
| Specificity for AD | High | Very high |
| Correlation with PET | Moderate-Strong | Strong |
| Change rate/year | ~15-20% | ~25-35% |

Clinical Applications

Primary Uses

• Preclinical AD detection: Abnormal in cognitively normal individuals with amyloid pathology
• Early MCI detection: More sensitive than p-tau 181 in early disease
• Disease progression: Higher rate of change predicts faster decline

Interpretation

• Elevated p-tau 231 with normal p-tau 181: Early AD or prodromal AD
• Elevated both: Established AD pathology
• Normal both: Unlikely AD (consider other dementias)

Regulatory Status

• Research Use Only: Most p-tau 231 assays remain RUO
• Clinical trials: Widely used as enrollment biomarker
• Plasma version: Under development with several platforms in validation

Detailed Pathophysiological Mechanisms

Tau Phosphorylation at Threonine 231

The phosphorylation of tau protein at threonine 231 occurs through the action of several kinases and represents an early pathological modification in Alzheimer's disease. [@blennow2019]

Key Kinases Involved:

GSK-3β (Glycogen Synthase Kinase-3β): The primary kinase responsible for phosphorylating tau at threonine 231. GSK-3β is hyperactive in Alzheimer's disease brains and its activation correlates with neurofibrillary tangle formation. The enzyme demonstrates increased activity in response to cellular stress, including oxidative stress and inflammation.

CDK5 (Cyclin-Dependent Kinase 5): Another important tau kinase that phosphorylates multiple sites including threonine 231. CDK5 is activated by neuronal injury and metabolic stress, linking tau pathology to upstream disease mechanisms.

MAPK (Mitogen-Activated Protein Kinases): Several MAPK family members including ERK1/2 and p38 can phosphorylate tau at threonine 231. These kinases respond to inflammatory cytokines and cellular stress signals.

Phosphatases:

The dephosphorylation of p-tau 231 is primarily mediated by protein phosphatases PP1, PP2A, and PP2B. In Alzheimer's disease, these phosphatases show reduced activity, contributing to the accumulation of phosphorylated tau species. The imbalance between kinase and phosphatase activity creates a permissive environment for tau hyperphosphorylation. [@zetterberg2019]

Relationship to Neurofibrillary Tangle Formation

Phosphorylation at threonine 231 represents an intermediate step in the transition from normal tau to paired helical filament (PHF) tau:

Sequential Process:

Early Phosphorylation: Threonine 231 is among the earliest sites to become phosphorylated in the disease process, preceding clinical symptoms by years or even decades. [@schoonenboom2012]

Conformational Change: Phosphorylation at this site promotes conformational changes in tau that expose additional phosphorylation sites, creating a feed-forward loop of pathology.

Oligomer Formation: Phosphorylated tau at threonine 231 promotes the formation of toxic oligomeric species that are believed to be the most neurotoxic form of tau pathology.

NFT Maturation: As phosphorylation accumulates at multiple sites, tau filaments coalesce into mature neurofibrillary tangles that ultimately lead to neuronal death. [@jourdoi2013]

Temporal Sequence in Alzheimer's Disease Progression

p-tau 231 elevations follow a characteristic temporal pattern that makes it valuable for staging AD:

Preclinical Stage:

• p-tau 231 becomes abnormal before clinical symptoms
• Detectable in cognitively normal individuals with amyloid pathology
• May appear before p-tau 181 changes
• Correlates with early memory complaints

Mild Cognitive Impairment (MCI):

• p-tau 231 is highly sensitive for detecting MCI due to AD
• Higher levels predict more rapid progression to dementia
• Provides information beyond amyloid status alone

Dementia Stage:

• p-tau 231 continues to increase with disease progression
• Levels correlate with cognitive impairment severity
• May plateau in advanced disease stages

Comparison with Other Phosphorylated Tau Species

p-tau 231 vs. p-tau 181

While p-tau 181 remains the most widely used clinical biomarker, p-tau 231 offers distinct advantages in certain contexts:

| Characteristic | p-tau 231 | p-tau 181 |
|---------------|-----------|-----------|
| Earliest Abnormality | Very early (preclinical) | Early (prodromal) |
| Specificity for AD | Very high (>95%) | High (85-90%) |
| Correlation with Amyloid | Strong | Moderate |
| Rate of Change | Faster (~30%/year) | Moderate (~15-20%/year) |
| Detection Method | CSF, plasma (newer) | CSF, plasma (established) |
| Clinical Utility | Early detection | Disease monitoring |

p-tau 231 vs. p-tau 217

Both p-tau 231 and p-tau 217 are considered early biomarkers with high specificity:

| Characteristic | p-tau 231 | p-tau 217 |
|---------------|-----------|-----------|
| Timing of Abnormality | Earliest | Early (slightly later than 231) |
| Specificity | Very high | Very high |
| Correlation with NFT Burden | Strong | Very strong |
| Assay Availability | Widely available | Limited |
| Research Status | Well-validated | Validation ongoing |

Biomarker Panels

Optimal biomarker utilization often involves combining multiple tau species:

Recommended Panel:

• p-tau 231: Early detection and preclinical screening
• p-tau 181: Disease monitoring and progression
• p-tau 217: Confirmatory and prognostic

Analytical Considerations

Assay Platforms

CSF Assays:

| Platform | Sensitivity | Use Case |
|----------|-------------|----------|
| INNOTEST | Manual ELISA, well-established | Clinical routine |
| Lumipulse | Automated, high throughput | Clinical labs |
| Simoa | Ultrasensitive, single molecule | Research |
| ECLIA | electrochemiluminescence | Clinical trials |

Plasma Assays:

The development of plasma p-tau 231 assays represents a major advancement, reducing the need for lumbar punctures. Current platforms include Simoa-based assays showing high correlation with CSF levels, and ECLIA platforms in development for clinical use. [@ashford2020]

Preanalytical Variables

Proper sample handling is critical for accurate p-tau 231 measurement:

| Factor | Consideration | Impact |
|--------|---------------|--------|
| Collection | CSF: morning preferred; Plasma: fasting | Moderate |
| Storage | -80°C preferred; -20°C acceptable short-term | Significant |
| Freeze-Thaw | Minimize to ≤3 cycles | Moderate |
| Tubing | Polypropylene preferred | Minimal |

Clinical Utility in Specific Scenarios

Memory Clinic Evaluation

In patients presenting with cognitive complaints, p-tau 231 provides valuable diagnostic information:

Typical Presentation with Amnestic Syndrome:

• Elevated p-tau 231 + elevated p-tau 181: High likelihood of AD
• Elevated p-tau 231 only: Consider early/prodromal AD
• Normal p-tau 231: Less likely AD, investigate other causes

Atypical Presentations:

• Posterior cortical atrophy: p-tau 231 often elevated
• Logopenic aphasia: p-tau 231 typically elevated
• Behavioral variant FTD: p-tau 231 usually normal (except AD-FTD overlap)

Primary Prevention Trials

p-tau 231 is increasingly used as an enrollment criterion and outcome measure in secondary prevention trials:

Trial Enrichment:

• Selecting amyloid-positive individuals with p-tau 231 elevation
• Identifying those most likely to have concurrent tau pathology

Outcome Measures:

• Change in p-tau 231 as proxy for tau pathology modification
• Monitoring treatment effects on tau biological cascade

Advantages for Trials:

• Earlier detection allows for longer treatment windows
• More sensitive to change than clinical measures
• Less expensive than PET imaging

Differential Diagnosis

p-tau 231 helps differentiate AD from other dementias:

| Condition | p-tau 231 | Interpretation |
|-----------|-----------|----------------|
| AD | Elevated | Core AD pathology |
| DLB | Often normal or mildly elevated | Primary tau pathology absent |
| FTD | Usually normal | Non-AD tauopathy |
| Vascular Dementia | Normal | Vascular, not tau-mediated |
| PSP/CBS | Normal or mildly elevated | Different tau isoform (4R) |

Future Directions

Emerging Technologies

Digital Immunoassays:
Single molecule array technology enables detection of extremely low p-tau 231 concentrations in plasma, potentially enabling population screening approaches. [@cullen2022]

Multiplex Platforms:
Next-generation assays will allow simultaneous measurement of multiple phospho-tau species (p-tau 217, p-tau 181, p-tau 231) from single samples, improving diagnostic precision.

Point-of-Care Testing:
Development of rapid, bedside p-tau 231 testing could enable real-time clinical decision making in memory clinics and primary care settings.

Research Applications

Biomarker Verification:
p-tau 231 is being validated as a biomarker for various research applications including genetic studies examining the relationship between AD risk genes and tau pathology, neuropathology studies correlating biomarker levels with post-mortem findings, and epidemiological studies examining prevalence and risk factors for preclinical AD.

Integration with Other Biomarkers

AT(N) Classification System:
p-tau 231 fits into the AT(N) biomarker framework as a marker of tau pathology (T):

• A: Amyloid pathology (Aβ PET, CSF Aβ42/40)
• (N): Neurodegeneration (FDG PET, cortical thickness)
• T: Tau pathology (p-tau 231, p-tau 181, tau PET)

This systematic approach allows researchers and clinicians to characterize AD biological changes independently of clinical symptoms.

Related Biomarkers

• [p-tau 181](/biomarkers/p-tau-181) - Established clinical biomarker
• [p-tau 217](/biomarkers/ptau217-adaptive-dosing) - Emerging high-specificity marker
• [Abeta 42/40](/biomarkers/amyloid-beta-42-40-ratio) - Amyloid biomarker
• [Tau PET](/biomarkers/tau-pet-imaging) - Imaging biomarker for tau pathology
• [Total Tau](/biomarkers/total-tau) - Non-specific neurodegeneration marker

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Mild Cognitive Impairment](/diseases/mild-cognitive-impairment)
• [Biomarker Development](/topics/biomarker-development)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
• [Alzheimer's Disease Neuroimaging Initiative (ADNI)](https://adni.loni.usc.edu/)
• [Gene BLAZE Study](https://clinicaltrials.gov/)