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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Authors funding information is provided in the manuscript ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymized aggregated level data will be shared by request from a qualified academic investigator for the sole purpose of replicating procedures and results presented in the article, and as long as data transfer is in agreement with EU legislation on the general data protection regulation and decisions by the Ethical Review Boards in charge of each of the cohorts used for this study.