We investigated phosphorylation-site-specific plasma pTau patterns in cognitively unimpaired older adults with and without cerebral amyloid-β pathology, assessed using amyloid PET. Plasma biomarkers included pTau217, pTau205, pTau231, and pTau181, measured cross-sectionally and longitudinally over 12 months.

 

Plasma pTau217 showed the strongest cross-sectional amyloid discrimination, longitudinal amyloid-related change, and diagnostic performance for amyloid positivity. Plasma pTau231 also showed strong cross-sectional amyloid discrimination, while pTau181 showed more modest discrimination. Plasma pTau205 showed limited amyloid-related utility.

 

Cognitive associations differed by phosphorylation site and amyloid status. Higher plasma pTau231 was associated with poorer cognition in cognitively unimpaired amyloid-positive individuals, whereas higher plasma pTau205 was associated with better cognition in cognitively unimpaired amyloid-negative individuals.

 

These findings support phosphorylation-site-specific plasma pTau signatures in preclinical Alzheimer’s disease and highlight plasma pTau217 as a promising biomarker for early detection and longitudinal monitoring.

 

Keywords: preclinical Alzheimer’s disease; cognitively unimpaired; plasma biomarkers; phosphorylated tau; pTau217; pTau231; pTau205; pTau181; amyloid-beta; amyloid PET; cognition