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

Background and objectivesDetecting Alzheimers disease (AD) biological and clinical changes is crucial for early diagnostic and therapeutic interventions. Here we investigate the relationship between clinical severity and levels of phosphorylated tau, focusing on plasma biomarkers, in preclinical and prodromal AD. MethodsIn this study (n=621), 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) A{beta}42/40 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 A{beta} positron emission tomography (PET) [A{beta}- CN= 118; A{beta}+ CN= 49; A{beta}+ MCI= 21]. ResultsIn cohort-1, plasma p-tau217 showed a moderate correlation with its corresponding CSF biomarker (rho=0.65, p<.001) and high accuracy identifying A{beta}+ participants (AUC: 0.85). Diagnostic accuracy of plasma p-tau217 was significantly greater for MCI A{beta}+ (AUC: 0.89) versus CN A{beta}+ (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 A{beta}+ group. While all the CSF p-tau markers were associated to future cognitive deterioration, p-tau217 was the only plasma biomarker associated with future memory decline ({beta}=0.05, p<0.05). In cohort 1 and 2, plasma p-tau217 showed significantly higher concentrations in MCI A{beta}+ as compared to CN A{beta}+. Furthermore, plasma p-tau217 demonstrates similar biomarker elevations when compared to CN A{beta}- controls in both cohorts. DiscussionOur findings indicate that, unlike p-tau181 and p-tau231, plasma p-tau217 consistently aligns with cognitive status in A{beta}+ individuals and more closely reflects CSF biomarker abnormalities, potentially reducing discrepancies between clinical and biochemical findings. The associations of plasma p-tau217 with baseline and future cognitive decline make it a valuable complement to clinical evaluations in preclinical and prodromal AD, especially when CSF analysis or PET are not feasible.