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. [1]
p-tau 231 is phosphorylated at threonine 231, a site that: [2]
| Platform | Cutoff (pg/mL) | Sensitivity | Specificity | AUC | [3]
|----------|----------------|-------------|-------------|-----| [4]
| 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. [5]
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. [6]
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. [7]
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. [8]
p-tau 231 elevations follow a characteristic temporal pattern that makes it valuable for staging AD:
Preclinical Stage:
Mild Cognitive Impairment (MCI):
Dementia 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. [9]
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:
Atypical Presentations:
p-tau 231 is increasingly used as an enrollment criterion and outcome measure in secondary prevention trials:
Trial Enrichment:
Outcome Measures:
Advantages for Trials:
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. [10]
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):
This systematic approach allows researchers and clinicians to characterize AD biological changes independently of clinical symptoms.
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Hampel et al. Measurement of tau protein in CSF (2004). 2004. ↩︎
Karikari et al. Plasma p-tau231 as AD biomarker (2020). 2020. ↩︎
Molinuevo et al. Clinical validity of CSF p-tau (2014). 2014. ↩︎
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Schoonenboom NS, et al. "CSF p-tau231: an early marker for AD." Neurology. Neurology. 2012. ↩︎
Jourdoi M, et al. "p-tau231 in preclinical AD." J Alzheimers Dis. J Alzheimers Dis. 2013. ↩︎
Ashford MT, et al. "Plasma p-tau231 and PET amyloid." Nat Aging. Nat Aging. 2020. ↩︎
Cullen NC, et al. "Longitudinal p-tau231 trajectories." Alzheimers Dement. Alzheimers Dement. 2022. ↩︎