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]
p-tau 231 is phosphorylated at threonine 231, a site that: [@hampel2004]
| 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 |
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]
p-tau 231 is phosphorylated at threonine 231, a site that: [@hampel2004]
| 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 |
| 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% |
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:
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]
Phosphorylation at threonine 231 represents an intermediate step in the transition from normal tau to paired helical filament (PHF) tau:
Sequential Process:
p-tau 231 elevations follow a characteristic temporal pattern that makes it valuable for staging AD:
Preclinical Stage:
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 |
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 |
Optimal biomarker utilization often involves combining multiple tau species:
Recommended Panel:
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]
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 |
In patients presenting with cognitive complaints, p-tau 231 provides valuable diagnostic information:
Typical Presentation with Amnestic Syndrome:
p-tau 231 is increasingly used as an enrollment criterion and outcome measure in secondary prevention trials:
Trial Enrichment:
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) |
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.
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.
AT(N) Classification System:
p-tau 231 fits into the AT(N) biomarker framework as a marker of tau pathology (T):