On whom should pTau-217, beta amyloid 42, and their ratio be ordered?

Who Should Receive pTau-217, Beta Amyloid 42/40 Ratio, and Their Combined Testing

Order plasma pTau-217 and Aβ42/40 ratio (preferably combined as pTau-217/Aβ42) in patients with mild cognitive impairment (MCI) or mild dementia to detect Alzheimer's disease pathology and determine eligibility for anti-amyloid therapies like lecanemab or donanemab. 1, 2

Primary Clinical Indications

Patients with Symptomatic Cognitive Impairment

• Order in patients with MCI or mild dementia when you need to confirm amyloid pathology for diagnostic purposes or to determine eligibility for disease-modifying therapies 1, 2
• Plasma pTau-217 alone performs exceptionally well in the dementia stage, with accuracy similar to CSF biomarkers and tau-PET imaging for differentiating AD from other dementias 1
• The pTau-217/Aβ42 ratio shows slightly superior performance (AUC 0.920-0.928) compared to pTau-217 alone (AUC 0.904-0.914) for predicting amyloid positivity 3, 4, 5

Specific Testing Scenarios by Clinical Stage

For MCI patients:

• Plasma Aβ42/Aβ40 ratio is the most studied biomarker for detecting cerebral amyloid pathology in MCI 1
• Adding pTau-217 to Aβ42/Aβ40 has particular value in MCI because pTau levels increase with disease progression and Aβ42/Aβ40 performance may be slightly lower in MCI than in cognitively unimpaired individuals 1
• Both pTau-181 and pTau-217 accurately predict future development of AD dementia in MCI patients over 2-6 years 1

For mild dementia:

• High-performing plasma pTau assays may be sufficient on their own to differentiate AD dementia from other dementias 1
• pTau-217 performs slightly better than other pTau variants for AD diagnosis due to relatively larger increases in the dementia stage 1

For subjective cognitive decline (SCD):

• pTau-217 shows high accuracy (AUC = 0.91) identifying individuals with SCD who have positive CSF Aβ42/40 ratio 6
• However, testing is generally not recommended in SCD patients who are not at elevated risk based on age, APOE genotype, or family history 2

Contraindications and Inappropriate Use

Do NOT Order in These Populations

• Cognitively unimpaired individuals without symptoms - anti-amyloid therapies and their prerequisite biomarker testing are explicitly inappropriate for people who are cognitively unimpaired 2
• Patients with positive biomarkers but normal cognition - donanemab and lecanemab are indicated for symptomatic disease (MCI or mild dementia), not for biomarker-positive individuals with normal cognition 2, 7
• Patients with subjective cognitive decline alone without elevated risk factors should not receive biomarker testing 2

Practical Implementation Algorithm

Step 1: Establish Objective Cognitive Impairment

• Require MoCA score ≤25 OR comprehensive neuropsychological battery showing impairment in ≥1 cognitive domain 2
• Document CDR score of 0.5 (MCI) or 1.0 (mild dementia) 2
• Confirm functional impairment on ADCS-iADL or similar scale 2

Step 2: Select Optimal Biomarker Combination

• First choice: pTau-217/Aβ42 ratio - highest diagnostic accuracy (AUC 0.920-0.928) and most robust to preanalytical delays 3, 4, 5
• Alternative: pTau-217 alone - excellent performance (AUC 0.904-0.914) and simpler interpretation 3, 4
• Consider adding Aβ42/Aβ40 ratio if using pTau-217 alone, particularly in MCI where combined testing improves detection of amyloid pathology 1

Step 3: Interpret Results for Clinical Decision-Making

Using dual-threshold strategy:

• A 90% sensitivity/90% specificity approach with pTau-217/Aβ42 ratio can avoid approximately 93.5% of lumbar punctures with 10.9% misclassification rate 4
• Stricter thresholds (95%-95% or 97.5%-97.5%) reduce misclassification but require more confirmatory testing 4

For treatment eligibility:

• Positive pTau-217 test provides sufficient biomarker evidence of amyloid pathology to initiate lecanemab therapy without requiring additional amyloid PET scan 7
• Both lecanemab and donanemab require confirmed amyloid pathology through either positive amyloid PET, CSF biomarkers, or blood-based biomarkers like pTau-217 2, 7

Critical Caveats and Pitfalls

Assay Selection Matters

• Not all pTau assays perform equally - head-to-head comparisons show commonly used assays with lower performance 1
• High-performing platforms include Quanterix Simoa, Lumipulse G, IP-MS methods, and emerging NULISA technology 1
• The FDA granted Breakthrough Device designation to one pTau-181 assay, and the Lumipulse pTau-217/Aβ42 ratio recently received FDA approval 1, 5

Preanalytical Considerations

• pTau-217 and pTau-217/Aβ42 ratio are robust to preanalytical delays between blood collection and laboratory processing 5
• Aβ42 and Aβ40 individually show significant impact from preanalytical delays, but the ratio maintains performance 5
• This robustness supports the use of pTau-217/Aβ42 ratio as a reliable marker for routine clinical practice 5

Biological Confounders

• Age, creatinine levels, depressive symptoms, comorbidities, and sex are associated with various blood biomarkers 8
• Mild traumatic brain injury and cerebrovascular insults are important potential confounders for GFAP 1
• Peripheral neuropathies, BMI, and kidney disease may affect biomarker performance 1

Interpretation Limitations

• Positive biomarkers in older adults do not automatically mean AD is causing cognitive impairment - 20-40% of cognitively normal older adults harbor AD pathological markers, with percentage increasing with age over 60 1
• Amyloid plaques may coexist with other pathologies including hippocampal sclerosis, argyrophilic grain disease, primary age-related tauopathy, or TDP-43 proteinopathy 1

Differential Diagnosis Support

When pTau is normal but other markers are abnormal:

• High plasma NfL with normal pTau might indicate non-AD dementia with substantial axonal degeneration like frontotemporal dementia or corticobasal degeneration 1

Combining with other accessible tests:

• When pTau is combined with APOE genotype and brief cognitive tests, predictive algorithms perform as accurately as CSF-based algorithms and outperform predictions made by dementia experts 1