Associations between changes in levels of phosphorylated tau and severity of cognitive impairment in early Alzheimer’s disease

Background and objectives: Aligning biomarker evidence with clinical presentation in early Alzheimer's 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 cerebrospinal fluid (CSF) in predementia AD.<br/>Methods: This longitudinal observational study included predementia cases and controls from two independent cohorts: the Norwegian DDI, and Canadian 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), while classification in PREVENT-AD (A) was based on amyloid positron emission tomography (PET) scans. In DDI, we assessed CSF-plasma correlations for p-tau181, p-tau217, and p-tau231. Diagnostic accuracies via 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. <br/>Results: 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% females. 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% females. In DDI, plasma p-tau217 showed high accuracy in identifying A+ participants (AUC: 0.85) and a moderate correlation with CSF p-tau217 (rho=0.65, p&lt;.001). Plasma p-tau217 diagnostic accuracy was greater in MCI A+ (AUC: 0.89) than CN A+ (AUC: 0.79, p&lt;.05) and in A+/T+ (AUC: 0.88) versus A+/T- (AUC: 0.78, p&lt;.05). P-tau181 and p-tau231 had weaker CSF-plasma correlations (rho=0.47 and rho=0.32, p&lt;.001) and were less associated with cognitive status in A+ individuals. Higher plasma p-tau217 in A+ MCI vs. A+ CN (p&lt;.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&lt;0.05). <br/>Discussion: 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.<br/>