Amyloid β‐dependent tau phosphorylation is triggered by reactive astrocytes in preclinical Alzheimer’s disease
Authors: Bellaver Bruna , Povala Guilherme , Ferreira Pamela C.L. , Ferrari‐Souza João Pedro , Leffa Douglas Teixeira , Lussier Firoza Z , Benedet Andrea Lessa , Ashton Nicholas J. , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Lopez Oscar L. , Tudorascu Dana , Villemagne Victor L , Ikonomovic Milos D , Gauthier Serge , Zimmer Eduardo R , Zetterberg Henrik , Blennow Kaj , Aizenstein Howard J , Klunk William E , Snitz Beth E. , Maki Pauline M , Thurston Rebecca C , Cohen Ann D. , Ganguli Mary , Karikari Thomas K , Rosa‐Neto Pedro , Pascoal Tharick Ali 
Published: December 2023

AbstractBackgroundA significant percentage of Aβ‐positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, cognitive decline.Experimental literature suggest that reactive astrocytes are necessary to unleashing Aβ effects in pathological tau phosphorylation.Here we aimed to investigate whether astrocyte reactivity is key to determining the association of Aβ burden with early tau phosphorylation in preclinical Alzheimer’s disease (AD).MethodWe assessed 1,016 CU individuals from two research and one population‐based cohort (TRIAD, Pittsburgh and MYHAT) with Aβ (plasma or PET), plasma p‐tau and GFAP measures. Individuals were classified as positive (Ast+) or negative (Ast‐) for astrocyte reactivity using a cutoff based on plasma GFAP of younger Aβ‐ individuals.Lowess method and linear regressions accounting for age and sex were used to model the trajectories of plasma p‐tau epitopes as a function of Aβ burden. Cohen’s d corrected for age and sex was used to estimate effect sizes between groups.ResultWe observed that plasma p‐tau181 levels increased as a function of Aβ only in CU Ast+ individuals from Pittsburgh (β = ‐0.35,t = 3.10,p = 0.003,Fig.1a,b), MYHAT (β = ‐0.20,t = 2.26,p = 0.026, Fig.1d,e) and TRIAD (β = 0.46,t = 2.92,p = 0.004;Fig.1g,h) cohorts. A significant interaction between Aβ burden and astrocyte reactivity status on plasma p‐tau181 levels was observed in the Pittsburgh (β = ‐0.29,t = 2.30,p = 0.022;Fig.1b), MYHAT (β = ‐0.19,t = 2.07,p = 0.038;Fig.1e) and TRIAD (β = 0.46,t = 2.92,p = 0.004;Fig.1h) cohorts.Cohen’s d analysis revealed that the presence of Aβ+ and Ast+ has a large magnitude of effect on tau phosphorylation (Cohen’s d:Pittsburgh = 0.67; MYHAT = 0.69;TRIAD = 0.98;Fig.1c,f,i), whereas Aβ+ in the absence of Ast+ presented a negligible effect size. Similar results were observed for plasma p‐tau231 and p‐tau217.Voxel‐wise analysis confirmed that Aβ levels in brain regions known to present early Aβ accumulation in AD associated with plasma p‐tau181 only in Ast+ individuals (Fig.2).Tau‐PET deposition occurred as a function of Aβ burden only in CU Ast+ (Fig.3a), affecting 100% and 62% of the extension of the Braak I and II regions, respectively (Fig.3b)ConclusionWe observed biomarker evidence across multiple cohorts that the presence of astrocyte reactivity, measured by plasma GFAP, plays a key role in the association of Aβ with early tau pathology in preclinical AD.Our results might have implications for the biological definition of preclinical AD and selecting individuals for early preventive clinical trials.