Plasma phosphorylated tau217 strongly associates with memory deficits in the Alzheimer’s disease spectrum
Authors: Fernández Arias Jaime , Brum Wagner S , Salvadó Gemma , Therriault Joseph , Servaes Stijn , Wang Yi-Ting , Aumont Etienne , Rahmouni Nesrine , Macedo Arthur , Quispialaya Kely , Hosseini Seyyed Ali , Kunach Peter , Jia Wan Lu , Chan Tevy , Trudel Lydia , Hall Brandon , Zheng Yanseng , Mohapatra Sejal , Mathotaarachchi Sulantha S , Vitali Paolo , Tissot Cécile , Bezgin Gleb , Iturria-Medina Yasser , Ashton Nicholas J , Benedet Andréa Lessa , Karikari Thomas K , Triana-Baltzer Gallen , Klostranec Jesse , Kolb Hartmuth C , Zimmer Eduardo R , Janelidze Shorena , Mattson-Carlgren Niklas , Stomrud Erik , Palmqvist Sebastian , Zetterberg Henrik , Blennow Kaj , Pascoal Tharick , Montembeault Maxime , Hansson Oskar , Rosa-Neto Pedro 
Published: January 2025

Abstract
Plasma phosphorylated tau biomarkers open unprecedented opportunities for identifying carriers of Alzheimer’s disease pathophysiology in early disease stages using minimally invasive techniques. Plasma p-tau biomarkers are believed to reflect tau phosphorylation and secretion. However, it remains unclear to what extent the magnitude of plasma p-tau abnormalities reflects neuronal network disturbance in the form of cognitive impairment.
To address this question, we included 103 cognitively unimpaired elderly and 40 cognitively impaired, amyloid-β positive individuals from the TRIAD cohort, as well as 336 cognitively unimpaired and 216 cognitively impaired, amyloid-β positive older adults from the BioFINDER-2 cohort. Participants had tau PET scans, amyloid PET scans or amyloid CSF, p-tau217, p-tau181 and p-tau231 blood measures, structural T1-MRI and cognitive assessments. In this cross-sectional study, we used regression models and correlation analyses to assess the relationship between plasma biomarkers and cognitive scores. Furthermore, we applied receiver operating characteristic curves to assess cognitive impairment across plasma biomarkers. Finally, we categorized participants into amyloid (A), p-tau (T1), and tau PET (T2) positive (+) or negative (-) profiles and ran nonparametric comparisons to assess differences across cognitive domains.
We found that plasma p-tau217 was more associated with cognitive performance than p-tau181 and p-tau231, and that this relationship was particularly strong for memory scores (TRIAD: βp-tau217=-0.53; βp-tau181=-0.35; βp-tau231=-0.24; BioFINDER-2: βp-tau217=-0.52; βp-tau181=-0.24; βp-tau231=-0.29). Associations in amyloid-β positive participants resembled these results, but other cognitive scores also showed strong associations in cognitively impaired individuals. Moreover, plasma p-tau217 outperformed plasma p-tau181 and plasma p-tau231 in identifying memory impairment (Area Under the Curve values for TRIAD: p-tau217=0.86, p-tau181=0.77, p-tau231=0.75; Area Under the Curve values for BioFINDER-2: p-tau217=0.86, p-tau181=0.76, p-tau231=0.81), and in identifying executive function impairment only in the BioFINDER-2 cohort (p-tau217=0.82, p-tau181=0.76, p-tau231=0.76). Lastly, we showed that subtle memory deficits were present in A+T1+T2- participants for plasma p-tau217 (p=0.007) and plasma p-tau181 (p=0.01) in the TRIAD cohort, and for all biomarkers across cognitive domains in A+T1-T2- and A+T1+T2- individuals (p&lt;0.001 in all) in the BioFINDER-2 cohort. A+T1+T2+ individuals showed cognitive deficits in both cohorts (p&lt;0.001 in all).
Together, our results suggest that plasma p-tau217 stands out as a biomarker capable of identifying memory deficits due to Alzheimer’s disease and that memory impairment certainly occurs in amyloid and plasma p-tau positive individuals that have no significant amounts of tau in the neocortex.