Plasma p‐tau231 and p‐tau217 provides information on tau tangle deposition in symptomatic Alzheimer’s disease individuals
Authors: Ferreira Pamela C.L. , Bellaver Bruna , Povala Guilherme , Therriault Joseph , Ferrari‐Souza João Pedro , Tissot Cécile , Leffa Douglas Teixeira , Brum Wagner S. , Benedet Andrea Lessa , Lussier Firoza Z , Cabrera Arlec , Zalzale Hussein , Soares Carolina , Aguzzoli Cristiano Schaffer , Bezgin Gleb , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Pallen Vanessa , Poltronetti Nina Margherita , Tudorascu Dana , Klunk William E , Villemagne Victor L , Cohen Ann D. , Gauthier Serge , Zimmer Eduardo R. , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Karikari Thomas K , Rosa‐Neto Pedro , Pascoal Tharick A. 
Published: December 2023

Background

It has been suggested that phosphorylated tau(p‐tau) at threonine 231 and 217 are markers of amyloid‐ß(Aß) rather than tau pathology. However, most of the studies were conducted in cohorts composed mainly of preclinical Alzheimer Disease(AD) individuals. It remains to be elucidated if p‐tau is still more associated with Aß than tau pathology in symptomatic individuals. Here, we evaluate the contribution of each plasma biomarker to the demographics in identifying brain Aß and tau pathologies across the AD spectrum.

Method

We evaluated 138 cognitively unimpaired(CU) and 87 cognitively impaired(CI) individuals with available Aß[18F]AZD4694 PET and tau[18F]MK‐6340 PET, plasma Aß42/40, p‐tau (at threonine 181, 217, and 231), neurofilament light chain, and glial fibrillary acidic protein(GFAP), from the McGill TRIAD cohort(Table1). The performance of plasma biomarkers in predicting Aß‐ and tau‐PET abnormalities over that one provided by demographics‐only(age and sex) was evaluated using logistic and linear regression, receiver operating characteristic analysis, and goodness‐of‐fit metrics. Using voxel‐wise linear regression models, we assessed the brain regions where plasma biomarker contribution to the demographic‐only model overlapped to detect Aß and tau‐PET signals.

Result

Our results demonstrated that in the CU only plasma p‐tau231 and p‐tau217+ significantly added to the demographics‐only model to detect Aß pathology(Figure 1A), while no plasma biomarker added information to identify tau pathology(Figure 1B). In the CI, plasma p‐tau217+ and GFAP significantly added to the demographic‐only model to identify tau and Aß pathology(Figure 1C), while p‐tau231 only added to detect tau deposition(Figure 1D). P‐tau181, Aß42/40, and NfL did not significantly add to the demographics‐only in CU or CI group (Figure 1). Voxel‐wise analysis demonstrated that in CU, p‐tau231 and p‐tau217+ were only regionally associated with Aß‐PET(Figure 2A‐C). In CI, p‐tau231 provided additional information on tau tangle accumulation in AD‐related regions(Figure 2D). On the other hand, for p‐tau217+, 3% of brain regions were only associated with Aß‐PET, 35% with only tau‐PET, and 39% overlapped with both(Figure 2E).

Conclusion

Our results support plasma p‐tau231 and p‐tau217+ as state markers of Aß deposition in preclinical AD. In CI, plasma p‐tau231 is mainly related to tau pathology, and p‐tau217+ appears to be linked to both Aß and tau pathology.