What is the next step for a patient in their early 60s with early dementia and an intermediate plasma phosphorylated tau 217 (p tau 217) level?

Next Step: Obtain Confirmatory Amyloid Testing

For a patient in their early 60s with early dementia and an intermediate plasma p-tau 217 level, the next step is to obtain confirmatory testing for amyloid pathology using either amyloid PET imaging or CSF amyloid-β42/40 ratio measurement. 1

Understanding the Intermediate Result

An intermediate p-tau 217 level indicates diagnostic uncertainty according to the 2025 Alzheimer's Association guidelines. This occurs when:

• One biomarker (in this case, tau via p-tau 217) is positive while amyloid status remains untested, OR
• One biomarker is positive and the other is negative 1

The intermediate classification means you cannot yet determine with high certainty whether this dementia is due to Alzheimer's disease pathophysiology. 1

Why Amyloid Testing is Critical

The diagnostic algorithm requires assessment of BOTH amyloid-β and tau pathology to establish likelihood of AD dementia. 1

According to the 2025 NIA-AA diagnostic framework:

• High likelihood of AD dementia: Both amyloid (PET or CSF) AND neuronal injury markers (including CSF/plasma tau) are positive 1
• Intermediate likelihood: One biomarker positive, the other untested OR conflicting results 1
• Low likelihood (dementia highly unlikely due to AD): Both biomarkers absent 1

Recommended Testing Options

Order one of the following (in order of preference based on availability and patient factors):

1. Amyloid PET imaging - Provides direct visualization of amyloid plaque burden 1
2. CSF amyloid-β42/40 ratio - Highly accurate alternative if PET unavailable 1
3. Plasma amyloid-β42/40 ratio - Emerging option, though may have slightly lower performance in the dementia stage compared to earlier stages 1

Clinical Decision Algorithm Based on Results

If amyloid testing is POSITIVE:

• Diagnosis: High likelihood AD dementia 1
• Consider anti-amyloid therapies (donanemab, aducanumab) which have shown reduction in plasma p-tau217 levels 2
• Initiate symptomatic treatment with cholinesterase inhibitors (rivastigmine, donepezil) 3

If amyloid testing is NEGATIVE:

• Diagnosis: Dementia highly unlikely due to AD 1
• Actively pursue alternative diagnoses including:
  • Frontotemporal dementia (behavioral variant or primary progressive aphasia) 1, 4, 5
  • Dementia with Lewy bodies 1
  • Vascular dementia 1
  • Other tauopathies (progressive supranuclear palsy, corticobasal degeneration) 4, 5

Critical Pitfalls to Avoid

Do not assume elevated p-tau 217 alone confirms AD dementia. While p-tau 217 is highly specific for AD pathology (250-600% elevation in AD vs non-AD neurodegenerative diseases), the intermediate level suggests either:

• Early/mild AD pathology requiring amyloid confirmation 4, 5
• Potential confounding from cerebrovascular disease, cardiovascular disease, or other factors 4
• Possible non-AD tauopathy with different clinical implications 6, 5

Ensure you are using a validated, high-performing p-tau 217 assay. Not all assays perform equally, and lower-performing platforms can produce misleading results. 1, 4

Additional Concurrent Assessments

While awaiting amyloid results, complete the following:

• Structural brain MRI to assess for neurodegeneration patterns, vascular changes, and alternative pathology 1
• Detailed neuropsychological testing to characterize cognitive domain impairments 1
• Collateral history from informant regarding functional decline, behavioral changes, and temporal progression 1
• Rule out reversible causes: B12 deficiency, thyroid dysfunction, medication effects 1

Prognostic Implications

If amyloid testing confirms AD pathology, the intermediate p-tau 217 level has important prognostic value. Plasma p-tau 217 accurately predicts future cognitive decline and conversion rates in early dementia, with higher levels correlating with faster progression. 1, 7, 8, 9