Elevated Plasma P-tau217 Associated with Cognitive Impairment Onset Up to Four Years Before in Preclinical Alzheimer's

ABSTRACT Background: APOE-{varepsilon}4 is the strongest genetic risk factor for Alzheimer's disease (AD), and plasma phosphorylated tau217 (P-tau217) is a highly sensitive and specific biomarker for AD pathology. Their combined utility to predict cognitive decline before onset of AD has not been systematically evaluated. Methods: Using longitudinal data from multiple cohorts, we evaluated plasma P-tau217 as a predictor of when cognitive impairment occurs in AD. P-tau217 concentrations were analyzed as continuous and binary variables using cohort-specific biomarker positivity thresholds. Association of plasma P-tau217 with prevalent and incident cognitive impairment were assessed using logistic regression and Cox models, stratified by APOE genotype. Adjusted survival curves and restricted mean survival time characterized when the onset of cognitive impairment occurred. Cohort-specific estimates were pooled using random-effects meta-analyses, and analyzed by discrimination performance with AUC, incremental R2, and Harrell's C-index. Results: Elevated P-tau217 levels were significantly associated with the onset of cognitive impairment. Among APOE-{varepsilon}4 allele carriers, increased P-tau217 levels anticipated subsequent cognitive impairment. While P-tau217 levels reached clinically significant levels up to four years before onset of cognitive impairment independent of APOE, the symptom-free interval was briefest for APOE-{varepsilon}4 carriers with elevated P-tau217. Conclusions: Plasma P-tau217 levels and the presence APOE genotype can be used to estimate the interval before the onset of overt cognitive impairment and the diagnosis of AD. The findings here support the use of commercially available APOE genotyping and plasma P-tau217 to determine optimal timing for therapeutic intervention, particularly during the preclinical phase of the disease.