Biomarkers.

Area of Science:

• Neurology
• Biomarker Discovery
• Neuroimaging

Background:

• Accurate staging of Alzheimer's disease neuropathologic changes (ADNC) is crucial for clinical trials and patient management.
• In vivo tau-PET scans are effective for high ADNC, but minimally invasive plasma biomarkers are emerging.
• Plasma tau phosphorylated at threonine 217 (p-tau217) is a promising blood-based biomarker.

Purpose of the Study:

• To evaluate the diagnostic performance of plasma p-tau217 for identifying intermediate and high ADNC.
• To compare plasma p-tau217 accuracy against autopsy-confirmed ADNC and in vivo tau-PET scans.
• To assess the utility of plasma p-tau217 in different cognitive statuses.

Main Methods:

• Analysis of plasma p-tau217, Aβ42/Aβ40 levels, and [¹⁸F]flortaucipir PET scans in ADNI and A4 study participants.
• Neuropathologic evaluation at autopsy for a subset of participants.
• Receiver operating characteristic (ROC) curve analysis to determine discriminative accuracy.

Main Results:

• Plasma p-tau217 showed high accuracy (AUC>0.93) in distinguishing high ADNC from lower stages at autopsy.
• The biomarker accurately identified "no" or "high" ADNC (80-93%) but showed high variability for low/intermediate ADNC.
• Findings were consistent with tau-PET results, with plasma biomarkers reliably identifying high ADNC (A+T+) but less so for A+T- individuals.

Conclusions:

• Plasma p-tau217 effectively identifies extreme ADNC stages but has limited reliability for intermediate levels, impacting its use in biological staging.
• The biomarker's weaker performance in preclinical cases, including A+T- individuals, challenges its role in early Alzheimer's detection.
• Complementary diagnostic tools, potentially including advanced imaging, may be necessary to enhance reliability in early disease stages.