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Abstract Importance Detecting early Alzheimer’s 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) 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. 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 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. Conclusions Our 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 points Question Do levels of plasma p-tau markers reflect cognitive performance in preclinical and prodromal Alzheimer’s disease (AD)? Findings In 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. Meaning Plasma 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.
González‐Ortiz et al. (Wed,) studied this question.