Blood p-tau association with cognitive status and future memory decline in early Alzheimer’s disease

Abstract

AbstractImportanceDetecting early Alzheimer’s disease (AD) biological and clinical changes is crucial for early diagnostic and therapeutic interventions.ObjectiveTo explore the associations between plasma p-tau biomarkers, cognitive- and biological profiles in predementia AD.Design, Setting, and ParticipantsIn 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) Aβ42/40 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 Aβ positron emission tomography (PET) [Aβ- CN= 118; Aβ+ CN= 49; Aβ+ MCI= 21].ExposureCSF and plasma p-tau181, p-tau217 and p-tau231.Main Outcomes and ResultsIn cohort-1, plasma p-tau217 showed a moderate correlation with its corresponding CSF biomarker (rho=0.65, p<.001) and high accuracy identifying Aβ+ participants (AUC: 0.85). Diagnostic accuracy of plasma p-tau217 was significantly greater for MCI Aβ+ (AUC: 0.89) versus CN Aβ+ (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 Aβ+ group. Moreover, p-tau217 was the only plasma marker that associated with future memory decline (β=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 Aβ+ as compared to CN Aβ+. Furthermore, plasma p-tau217 demonstrates similar biomarker elevations when compared to CN Aβ-controls in both cohorts.ConclusionsOur findings show that, unlike p-tau181 and p-tau231, plasma p-tau217 aligns consistently with cognitive status in Aβ+ 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.Key pointsQuestionDo levels of plasma p-tau markers reflect cognitive performance in preclinical and prodromal Alzheimer’s disease (AD)?FindingsIn two independent cohorts (n=619) we observed that among AD participants, higher plasma p-tau217, but not p-tau181 or p-tau231, was significantly associated with worse cognitive performance. Furthermore, plasma p-tau217 was the only blood p-tau marker associated with future cognitive decline in predementia AD.MeaningPlasma p-tau217 detects early AD pathology, determined either by CSF Aβ42/40 ratio or Aβ positron emission tomography, and beyond its diagnostic capabilities, p-tau217 levels are linked to clinical severity and future cognitive deterioration in preclinical and prodromal AD.