Astrocyte reactivity potentiates longitudinal tau tangle accumulation in cognitively unimpaired individuals
Authors: Bellaver Bruna , Povala Guilherme , Ferreira Pamela C.L. , Ferrari‐Souza João Pedro , Leffa Douglas Teixeira , Lussier Firoza Z , Zalzale Hussein , Soares Carolina , Aguzzoli Cristiano Schaffer , Rohden Francieli , Abbas Sarah , Ashton Nicholas J. , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Lopez Oscar L. , Tudorascu Dana , Villemagne Victor L , Ikonomovic Milos D , Klunk William E , Cohen Ann D. , Gauthier Serge , Zimmer Eduardo R. , Zetterberg Henrik , Blennow Kaj , Karikari Thomas K , Rosa‐Neto Pedro , Pascoal Tharick A. 
Published: December 2023

Background

Aβ accumulation precedes tau pathology in cognitively unimpaired (CU) individuals, which is an event closely related to the development of cognitive symptoms. However, Aβ leads to tau pathology in some individuals, but not in others, suggesting the presence of other processes triggering the deleterious effects of Aβ in the early Alzheimer’s disease (AD) stages. It was already demonstrated that glial fibrillary acidic protein (GFAP)‐positive astrocytes can internalize tau and might contribute to its propagation. Here we investigated whether astrocyte reactivity is a key element to determining the longitudinal accumulation and spreading of tau pathology in CU individuals.

Method

We assessed 147 CU individuals from the TRIAD cohort with available baseline Aβ‐ and Tau‐PET, plasma p‐tau181 and GFAP. Individuals were classified as positive (Ast+) or negative (Ast‐) for astrocyte reactivity using a cutoff based on plasma GFAP levels of younger Aβ‐ individuals. Longitudinal analysis included 71 CU individuals with Tau‐PET (mean follow‐up:2.3 years).Voxel‐wise associations between biomarkers were tested using linear regressions accounting for age, sex, and adjusting for multiple comparisons. We measured the annual rate of progression in Tau uptake as the difference between follow‐up and baseline uptakes divided by the time between scans. To assess individuals’ percentage of abnormal regions, we used composite brain regions corresponding to Braak histopathological stages.

Result

Tau‐PET deposition occurred as a function of Aβ burden only in CU Ast+ and in regions expected to present the earliest tau deposition (Fig.1a). In the longitudinal analysis, we observed that the annual rate of tau‐PET accumulation was higher in the CU Ast+ group (Fig.2a) and predicted by baseline Aβ burden only in CU Ast+ (Fig.2b). Interestingly, while the baseline association was confined to the mesial temporal cortex, the longitudinal tau‐PET accumulation as a function of Aβ/Ast presented initial tau spread over the neocortex in Braak III‐IV regions (Fig.2c).

Conclusion

We observed that Tau‐PET accumulation was highest in CU Ast+ individuals, with astrocyte reactivity being necessary for the spreading of tau over the neocortex. Our findings suggest that astrocyte reactivity is an important upstream event to unleash tau accumulation and spread in CU individuals, which might have implications for selecting individuals for early preventive clinical trials.