Sex modulates the role of astrocyte reactivity in preclinical Alzheimer’s disease

Abstract

AbstractBackgroundAstrocyte reactivity is a common finding in individuals across the Alzheimer’s disease (AD) continuum. Recently, we demonstrated that individuals with higher levels of plasma glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity, present a stronger association between amyloid‐ß (Aß) and tau pathologies in preclinical AD. Because cohort studies and clinical trials show sex differences in AD biomarkers, we investigated whether the effects of astrocyte reactivity on the association between Aß and tau differs in men and womenMethodWe assessed 1,016 CU individuals from three cohorts with available Aß (plasma/PET), plasma p‐tau181 and GFAP measures. A subset of individuals also has plasma p‐tau217 available (n = 136).Individuals were classified as positive (Ast+) or negative (Ast‐) for astrocyte reactivity using a cutoff based on plasma GFAP of younger Aß‐ individuals.Linear regressions accounting for age and sex were used to evaluate the association between plasma p‐tau epitopes and Aß burden.An interaction between term between Aß*sex was also added to the models.Voxel‐wise associations between biomarkers were tested using linear regressions accounting for age, sex, and adjusting for multiple comparisons.ResultWe found that Aß burden was associated with plasma p‐tau in Ast+ but not in Ast‐ . Men in the Ast+ group presented a much increased association between Aß with plasma p‐tau181 (ß = 0.71,p<0.0001,Fig.1a) or p‐tau217 (ß = 1.23,p = 0.00086,Fig.1b) compared to women. Similarly, a significant interaction between Aß and sex on plasma p‐tau181 (ß = 0.47,p = 0.005,Fig1a) and p‐tau217 (ß = 1.01,p = 0.002,Fig.1b) was observed only in the Ast+ individuals. Voxel‐wise analysis showed the differences in the topographical association between Aß and plasma p‐tau epitopes between men and women. In men but not women, Aß‐PET associates with plasma p‐tau181 (Fig.2) and plasma p‐tau217 (Fig.3) in important AD regions such as precuneus, posterior cingulate and orbitofrontal cortex.ConclusionA sex effect was observed in the association between Aß burden and plasma p‐tau epitopes in individuals with increased astrocyte reactivity, with the association being stronger in men than women. The greater effect of Aß on tau phosphorylation in the presence of Ast+ in men than in women may have implications for interpretation of biomarkers in clinical trials testing as anti‐Aß therapies already showed different effects between men and women.