Blood p-tau association with cognitive status and future memory decline in early Alzheimers disease

Importance: Detecting early Alzheimers disease (AD) biological and clinical changes is crucial for early diagnostic and therapeutic interventions. Objective: To explore the associations between plasma p-tau biomarkers, cognitive- and biological profiles in predementia AD. Design, Setting, and Participants: In this study (n=619), we examined two independent cohorts consisting of preclinical and prodromal AD. Cohort-1 included 431 participants classified as either cognitively normal (CN) or mild cognitive impaired (MCI) with normal or abnormal cerebrospinal fluid (CSF) AB42/40 ratio (A) and p-tau181 (T) [CN A-/T-, n=169; A+/T-, CN=26; MCI=24; A+/T+, CN=40; MCI=105; CN=34; MCI=33]. A total of n=418 of the participants had longitudinal assessments of verbal memory up to 9.67 years from baseline. Cohort-2 included 190 participants in whom amyloid status was determined using AB positron emission tomography (PET) [AB- CN= 118; AB+ CN= 49; AB+ MCI= 21]. Exposure: CSF and plasma p-tau181, p-tau217 and p-tau231. Main Outcomes and Results: In cohort-1, plasma p-tau217 showed a moderate correlation with its corresponding CSF biomarker (rho=0.65, p<.001) and high accuracy identifying AB+ participants (AUC: 0.85). Diagnostic accuracy of plasma p-tau217 was significantly greater for MCI AB+ (AUC: 0.89) versus CN AB+ (AUC: 0.79, p<.05) and for A+/T+ (AUC: 0.88) versus A+/T- (AUC: 0.78, p<.05). P-tau181 and p-tau231 showed significantly weaker CSF-plasma correlations (rho= 0.47, and rho=0.32, p<.001, respectively) and levels were not as tightly associated with cognitive status in the AB+ group. Moreover, p-tau217 was the only plasma marker that associated with future memory decline (B=0.05, p<0.05). Additionally, plasma p-tau217 had the weakest correlation with glomerular filtration rate (rho=-14, p<.05), followed by p-tau181 (rho=-17, p<.01) and p-tau231 (rho=-22, p<.001). In cohort 1 and 2, plasma p-tau217 showed significantly higher concentrations in MCI AB+ as compared to CN AB+. Furthermore, plasma p-tau217 demonstrates similar biomarker elevations when compared to CN AB- controls in both cohorts. Conclusions: Our findings show that, unlike p-tau181 and p-tau231, plasma p-tau217 aligns consistently with cognitive status in AB+ individuals, potentially reducing disagreements between clinical and biochemical findings. Plasma p-tau217 associations with baseline and future cognitive decline make it a valuable complement to clinical evaluation in preclinical and prodromal AD.