What is the frequency of p-tau217 (phosphorylated tau 217) positivity in asymptomatic patients?

Frequency of P-tau217 Positivity in Asymptomatic Individuals

Based on the most recent evidence, p-tau217 is positive in approximately 15-30% of cognitively unimpaired individuals over 60 years of age, reflecting underlying Alzheimer's disease pathology before symptoms develop. 1

Prevalence in Asymptomatic Populations

P-tau217 positivity in asymptomatic individuals reflects the presence of early Alzheimer's disease pathophysiology, often referred to as preclinical or asymptomatic Alzheimer's disease. The evidence shows:

• Approximately 15-30% of cognitively unimpaired individuals over age 60 exhibit cerebral accumulation of Aβ pathology changes that can be detected by p-tau217 1
• P-tau217 is an extremely sensitive marker that may detect subtle changes even before amyloid PET becomes positive 2
• In asymptomatic individuals, p-tau217 has demonstrated high diagnostic accuracy (AUC = 0.87-0.89) for predicting amyloid PET positivity 3

Diagnostic Performance in Asymptomatic Individuals

P-tau217 has emerged as one of the most promising blood biomarkers for detecting early Alzheimer's disease pathology:

• In individuals with subjective cognitive decline (SCD), p-tau217 shows high accuracy (AUC = 0.91) in identifying those with positive CSF Aβ42/40 ratio 4
• In cognitively unimpaired individuals, p-tau217 accurately predicts amyloid PET positivity with AUC values of 0.87-0.89 3
• P-tau217 can predict future brain pathology and cognitive decline in presymptomatic individuals 5
• In autosomal dominant Alzheimer's disease carriers who are still non-demented, baseline p-tau217 levels predict subsequent amyloid and tau PET pathology and cognitive function 5

Factors Affecting Positivity Rates

Several factors influence the rate of p-tau217 positivity in asymptomatic individuals:

• Age: Positivity rates increase with age, particularly after age 60
• APOE genotype: Carriers of APOE ε4 allele show higher rates of positivity
• Assay type: Different p-tau217 assays have varying performance characteristics, with some newer ultrasensitive assays showing improved detection in early stages 4
• Cut-off values: The specific threshold used to define "positivity" affects prevalence rates

Clinical Implications

The detection of elevated p-tau217 in asymptomatic individuals has important implications:

• It identifies individuals at risk for developing symptomatic Alzheimer's disease who might benefit from early intervention
• It can serve as a screening tool for clinical trials targeting preclinical Alzheimer's disease 1
• It may reduce costs and time needed for recruitment of study participants to preclinical AD trials 1

Limitations and Considerations

When interpreting p-tau217 positivity in asymptomatic individuals, several caveats should be considered:

• Not all individuals with elevated p-tau217 will progress to symptomatic Alzheimer's disease during their lifetime 1
• The ethical implications of disclosing biomarker results to asymptomatic individuals are complex, given the uncertainty of individual prediction 1
• The sensitivity and specificity of biomarkers may be currently inadequate for broad clinical use in asymptomatic individuals 1
• Only high-performing, validated p-tau217 assays should be used, as performance varies significantly between different assays 2

In conclusion, while p-tau217 is a promising biomarker for detecting preclinical Alzheimer's disease, its use in asymptomatic individuals should be approached with caution, considering both the potential benefits of early detection and the ethical implications of disclosing biomarker results to individuals who may never develop symptoms.