What does it mean if phosphorylated Tau (pTau) 217 is elevated but the Beta amyloid Positron Emission Tomography (PET) scan is normal?

Elevated P-tau217 with Normal Beta-amyloid PET: Clinical Implications

Elevated p-tau217 with a normal beta-amyloid PET scan likely represents an early stage in the Alzheimer's disease continuum where tau pathology is detectable before significant amyloid deposition appears on imaging, or it may indicate a non-Alzheimer's neurodegenerative process. 1

Pathophysiological Interpretation

The discordance between elevated p-tau217 and normal amyloid PET can be understood through the following framework:

1. Sequential Biomarker Changes in AD:

   • Current evidence suggests that markers of amyloid pathology (CSF and PET) typically precede evidence of neuronal injury 2
   • However, p-tau217 is an extremely sensitive marker that may detect subtle changes before amyloid PET becomes positive

2. Biomarker Classification:

   • P-tau217 reflects tau deposition and neuronal injury 2, 1
   • Beta-amyloid PET specifically detects fibrillar amyloid deposition 2
   • These biomarkers provide different types of information about disease progression 2

3. Possible Explanations:

   • Early AD Pathology: P-tau217 may detect very early AD changes before amyloid PET becomes positive
   • Non-AD Tauopathy: Elevated tau can occur in other neurodegenerative disorders 2
   • Technical Factors: Differences in sensitivity between biomarker tests 3

Diagnostic Implications

The Alzheimer's Association and other guidelines suggest several interpretations:

• High Negative Predictive Value: A normal amyloid PET has high negative predictive value (NPV = 0.94-0.98) for ruling out AD pathology 1
• Diagnostic Accuracy: P-tau217 has high diagnostic accuracy for detecting amyloid pathology (AUC range: 0.91-0.96) and tau pathology (AUC range: 0.94-0.97) 4, 3
• Atypical Presentation: This pattern is not uncommon in patients with mild neurocognitive disorders and suspected AD 5

Clinical Management Approach

1. Consider Confirmatory Testing:

   • If clinical suspicion for AD remains high, consider additional biomarkers such as CSF Aβ42/Aβ40 ratio or repeat testing in 6-12 months 1
   • Very high CSF Aβ42 concentration (>843 pg/mL) with elevated p-tau may predict negative amyloid PET in 93% of cases 5

2. Evaluate for Alternative Diagnoses:

   • Consider non-AD neurodegenerative disorders that can elevate tau markers 2
   • Evaluate for other causes of cognitive impairment

3. Monitor for Progression:

   • Track p-tau217 levels over time to assess disease progression 1
   • Monitor cognitive function, as elevated p-tau217 can predict future cognitive decline even in presymptomatic individuals 6

Prognostic Significance

• Elevated p-tau217 predicts future brain pathology and cognitive decline 1, 6
• In autosomal dominant AD, baseline plasma p-tau217 was associated with subsequent amyloid and tau PET pathology levels and cognitive function 6
• However, without amyloid positivity on PET, the risk of cognitive decline is significantly lower than in those with both biomarkers positive 7

Important Considerations

• Assay Quality Matters: Use only high-performing, validated p-tau217 assays, as performance varies significantly between different tests 1, 3
• Context Matters: Consider the clinical context, including patient's age, comorbidities, and functional status 1
• Biomarker Evolution: The field is rapidly evolving, with mass spectrometry-based p-tau217 tests showing superior performance to immunoassays 3
• Disclosure Implications: Discussing biomarker results with patients has complex ethical implications, especially in presymptomatic individuals 1

Remember that biomarker results alone are insufficient for management decisions and should be interpreted within the full clinical context.