Astrocyte reactivity influences the association of amyloid-β and tau biomarkers in preclinical Alzheimer's disease

Abstract

An unresolved question for the understanding of Alzheimer's disease (AD) pathophysiology is why a significant percentage of amyloid β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes are key to unleashing Aβ effects in pathological tau phosphorylation. In a large study ( n =1,016) across three cohorts, we tested whether astrocyte reactivity modulates the association of Aβ with plasma tau phosphorylation in CU people. We found that Aβ pathology was associated with increased plasma phosphorylated tau levels only in individuals positive for astrocyte reactivity (Ast+). Cross-sectional and longitudinal tau-PET analysis revealed that tau tangles accumulated as a function of Aβ burden only in CU Ast+ individuals with a topographic distribution compatible with early AD. Our findings suggest that increased astrocyte reactivity is an important upstream event linking Aβ burden with initial tau pathology which might have implications for the biological definition of preclinical AD and for selecting individuals for early preventive clinical trials.

Figure 1

a,f,h,j Robust local weighted regressions show that plasma p-tau181 increases as a function of Aβ burden only in the of the presence of astrocyte reactivity (Ast+) in (a)all cohorts together (n=1,016) as well as in the (f) Pittsburgh (n=355),(h) MYHAT (n=514) and (j) TRIAD (n=147) cohorts. b,g,I,kLinear regressions revealed an interaction between Aβ burden and astrocyte reactivity status on p-tau181 levels in (b) all cohorts, as well as in (g) Pittsburgh, (i) MYHAT, and (k) TRIAD cohorts. c Continuous association between Aβ pathology, plasma p-tau181, and plasma GFAP d,n,q Cohen’s d analysis accounting for age and sex shows the effect sizes of Aβ and Ast on plasma (d) p-tau181, (n) p-tau231 and (q) p-tau217. e Voxel-wise regressions, corrected for multiple comparison, show that Aβ-PET is associated with plasma p-tau181 only in CU Ast+ in typical AD regions (TRIAD cohort). l,o Robust local weighted regression shows that plasma (l) p-tau231 and (o)p-tau217 increased as a function of Aβ in the presence of astrocyte reactivity. m,p Linear regressions revealed an interaction between Aβ burden and reactive astrocyte status on plasma (m) p-tau231 and (p)p-tau217. r β estimates with respective 95% confidence interval of linear regressions showing the effect of sex on the associations of Aβ with plasma p-tau epitopes in Ast− and Ast+.

Figure 2

a Voxel-wise regression analysis showing the association between Aβ-PET and Tau-PET in individuals classified as negative (Ast−) or positive (Ast+) for astrocyte reactivity (n=147). bPercentage of the extent of the brain region with significant association (after RFT-correction) between Tau-PET and Aβ-PET in each Braak region. cLongitudinal Tau-PET annual rate of change according to astrocyte reactivity status (n=71). d Association between Tau-PET annual rate of change and baseline Aβ-PET according to astrocyte reactivity status. ePercentage of voxels with significant association (after RFT-correction) between Tau-PET annual rate of change and baseline Aβ-PET in each Braak region. Associations were tested using voxel-wise linear regression models corrected for RFT multiple comparison and adjusted by with age and sex.