Plasma phosphorylated tau181 predicts cognitive and functional decline

Abstract

Abstract Objective To determine if plasma tau phosphorylated at threonine 181 (p‐tau181) distinguishes pathology‐confirmed Alzheimer's disease (AD) from normal cognition (NC) adults, to test if p‐tau181 predicts cognitive and functional decline, and to validate findings in an external cohort. Methods Thirty‐one neuropathology‐confirmed AD cases, participants with clinical diagnoses of mild cognitive impairment (MCI, N = 91) or AD dementia (N = 64), and NC (N = 241) had plasma collected at study entry. The clinical diagnosis groups had annual cognitive (Mini‐Mental State Examination, MMSE) and functional (Clinical Dementia Rating Scale, CDR) measures. NC (N = 70), MCI (N = 75), and AD dementia (N = 50) cases from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used as a validation cohort. Plasma p‐tau181 was measured using the Quanterix SiMoA HD‐X platform. Results Plasma p‐tau181 differentiated pathology‐confirmed AD from NC with negative amyloid PET scans with an AUC of 0.93. A cut point of 3.44 pg/mL (maximum Youden Index) had a sensitivity of 0.77, specificity of 0.96. p‐Tau181 values above the cut point were associated with the faster rate of decline in MMSE in AD dementia and MCI and a shorter time to a clinically significant functional decline in all groups. In a subset of MCI cases from ADNI, p‐tau181 values above the cut point associated with faster rate of decline in MMSE, and a shorter time to a clinically significant functional decline and conversion to dementia. Interpretation Plasma p‐tau181 differentiates AD pathology cases from NC with high accuracy. Higher levels of plasma p‐tau181 are associated with faster cognitive and functional decline.