Plasma p‐tau and brain‐derived total tau biomarkers predict longitudinal changes in Aβ, tau, and cognition across the AD continuum
Authors: Ferreira Pamela C.L. , Bellaver Bruna , Povala Guilherme , Rodriguez Juan Lantero , Snellman Anniina , Leffa Douglas Teixeira , Ferrari‐Souza Pedro , Lussier Firoza Z , Zalzale Hussein , Soares Carolina , Aguzzoli Cristiano Schaffer , Tissot Cécile , Benedet Andrea Lessa , Rohden Francieli , Therriault Joseph , Abbas Sarah , Bezgin Gleb , Servaes Stijn , Lopez Oscar L. , Rahmouni Nesrine , Tudorascu Dana , Klunk William E , Villemagne Victor L , Cohen Ann D. , Gauthier Serge , Zimmer Eduardo R. , Karikari Thomas K , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro , Pascoal Tharick A. 
Published: December 2023

Background

Recent studies have suggested that plasma p‐tau biomarkers are associated with cross‐sectional brain amyloid(Aβ) rather than tau tangle pathology. However, it is still unclear if plasma tau biomarkers are closely related to changes in AD pathophysiology over time. In this work, we aimed to determine if cross‐sectional measures of plasma tau biomarkers are associated with longitudinal changes in Aβ‐PET, tau‐PET, and cognition across the AD spectrum.

Method

We evaluated 157 individuals(96 cognitively unimpaired(CU) and 61 cognitively impaired (CI)) with available baseline measures of plasma Aβ42/40, p‐tau(at threonine 181, 217+, and 231), N‐terminal tau fragments(NTA, a new brain derived tau marker), and glial fibrillary acidic protein(GFAP) and with longitudinal [18F]AZD4694 Aβ‐PET, [18F]MK6340 tau‐PET and Clinical Dementia Rating sum of boxes(CDR‐SB) score from the TRIAD cohort. We also included 321(118 CU and 203 CI) individuals from the ADNI cohort with baseline plasma p‐tau181 and [18F]florbetapir Aβ‐PET and longitudinal CDR‐SB. Using linear regressions adjusted for age and sex we tested the associations between plasma biomarkers and longitudinal changes in Aβ‐PET, tau‐PET, and CDR‐SB.

Result

In CU, changes in tau‐PET were significantly associated only with plasma p‐tau217+(β = 0.331, p<0.01,Figure1A). Changes in Aβ‐PET were significantly associated with p‐tau181(β = 0.594, p<0.01,Figure2A), p‐tau217+(β = 0.311, p = 0.02) and NTA(β = 0.435, p<0.01), while no plasma biomarker was associated with changes in cognition in CU(Figure3A). In CI, changes in tau‐PET were significantly associated with plasma p‐tau181(β = ‐0.338, p = 0.03,Figure1B) and NTA(β = ‐0.379, p = 0.03), while no plasma biomarker was significantly associated with changes in Aβ‐PET. Changes in cognition were significantly associated with plasma p‐tau181(β = 0.340, p = 0.01, Figure3B), p‐tau217+(β = 0.54, p<0.01), and NTA(β = 0.530, p<0.01). Similarly, in the ADNI cohort, plasma p‐tau181 was associated with longitudinal changes in cognition in CI (β = 0.247, p<0.01,Figure3D).

Conclusion

We demonstrate that cross‐sectional measures of plasma p‐tau and NTA biomarkers were associated with longitudinal Aβ deposition and tau accumulation in CU, while in CI they were only associated with tau accumulation. Interestingly, plasma tau biomarkers were also associated with changes in cognition in CI individuals. The fact that abnormal levels of plasma tau biomarkers are associated with longitudinal changes in AD pathophysiology has implications for the use of these markers in clinical trials and practice.