Plasma p‐tau231 and p‐tau217 provides information on tau tangle deposition in symptomatic Alzheimer’s disease individuals

Abstract Background It has been suggested that phosphorylated tau(p‐tau) at threonine 231 and 217 are markers of amyloid‐β(Aβ) 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 Aβ than tau pathology in symptomatic individuals. Here, we evaluate the contribution of each plasma biomarker to the demographics in identifying brain Aβ and tau pathologies across the AD spectrum. Method We evaluated 138 cognitively unimpaired(CU) and 87 cognitively impaired(CI) individuals with available Aβ[18F]AZD4694 PET and tau[18F]MK‐6340 PET, plasma Aβ42/40, 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 Aβ‐ 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 Aβ 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 Aβ 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 Aβ pathology(Figure 1C), while p‐tau231 only added to detect tau deposition(Figure 1D). P‐tau181, Aβ42/40, 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 Aβ‐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 Aβ‐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 Aβ deposition in preclinical AD. In CI, plasma p‐tau231 is mainly related to tau pathology, and p‐tau217+ appears to be linked to both Aβ and tau pathology.

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