Associations Between Changes in Levels of Phosphorylated Tau and Severity of Cognitive Impairment in Early Alzheimer Disease

Aligning biomarker evidence with clinical presentation in early Alzheimer disease (AD) is essential for improving diagnosis, prognosis, and interventions. This study evaluates the relationship between cognitive impairment, future decline, and phosphorylated tau levels in plasma and CSF in predementia AD. This longitudinal observational study included predementia cases and controls from 2 independent cohorts: the Norwegian Dementia Disease Initiation (DDI) and Canadian Pre-Symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD). In DDI, cognitively normal (CN) and mild cognitive impairment (MCI) cases were classified using CSF Aβ42/40 ratio (A) and p-tau181 (T), whereas classification in PREVENT-AD (A) was based on amyloid PET scans. In DDI, we assessed CSF-plasma correlations for p-tau181, p-tau217, and p-tau231. Diagnostic accuracies were evaluated through receiver operating characteristic analyses. Linear mixed models evaluated p-tau associations with future memory decline. Between-group differences in plasma p-tau217 were assessed in both cohorts. In DDI (n = 431), participants were classified as CN A-/T- (n = 169), A+/T- (CN = 26, MCI = 24), A+/T+ (CN = 40, MCI = 105), and A-/T+ (CN = 34, MCI = 33), with a mean age of 64.1 years and 55.9% female. In PREVENT-AD (n = 190), participants were categorized as CN A- (n = 118), CN A+ (n = 49), and MCI A+ (n = 21), with a mean age of 67.8 years and 72.6% female. In DDI, plasma p-tau217 showed high accuracy in identifying A+ participants (areas under the curve [AUC]: 0.85) and a moderate correlation with CSF p-tau217 (rho = 0.65, p < 0.001). Diagnostic accuracy of plasma p-tau217 was greater in MCI A+ (AUC: 0.89) than in CN A+ (AUC: 0.79, p < 0.05) and in A+/T+ (AUC: 0.88) vs A+/T- (AUC: 0.78, p < 0.05). p-Tau181 and p-tau231 had weaker CSF-plasma correlations (rho = 0.47 and rho = 0.32, p < 0.001) and were less associated with cognitive status in A+ individuals. Higher plasma p-tau217 in A+ MCI vs A+ CN individuals (p < 0.001) was confirmed in PREVENT-AD. All CSF p-tau markers, but only plasma p-tau217, were associated with future memory decline (β = 0.05, p < 0.05). Our findings suggest that, unlike p-tau181 and p-tau231, plasma p-tau217 consistently aligns with cognitive status in A+ individuals and better reflects CSF biomarker abnormalities, reducing discrepancies between clinical and biochemical findings. Its association with baseline and future memory decline highlights its diagnostic and prognostic value, particularly when CSF analysis or PET is unavailable.