Astrocyte reactivity is associated with tau tangle load and cortical thinning in Alzheimer's disease.

Background: It is not fully established whether plasma β-amyloid(Aβ)₄₂/Aβ₄₀ and phosphorylated Tau₁₈₁ (p-Tau₁₈₁) can effectively detect Alzheimer's disease (AD) pathophysiology in older Chinese adults and how these biomarkers correlate with astrocyte reactivity, Aβ plaque deposition, tau tangle aggregation, and neurodegeneration.

Methods: We recruited 470 older adults and analyzed plasma Aβ₄₂/Aβ₄₀, p-Tau₁₈₁, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using the Simoa platform. Among them, 301, 195, and 70 underwent magnetic resonance imaging, Aβ and tau positron emission tomography imaging. The plasma Aβ₄₂/Aβ₄₀ and p-Tau₁₈₁ thresholds were defined as ≤0.0609 and ≥2.418 based on the receiver operating characteristic curve analysis using the Youden index by comparing Aβ-PET negative cognitively unimpaired individuals and Aβ-PET positive cognitively impaired patients. To evaluate the feasibility of using plasma Aβ₄₂/Aβ₄₀ (A) and p-Tau₁₈₁ (T) to detect AD and understand how astrocyte reactivity affects this process, we compared plasma GFAP, Aβ plaque, tau tangle, plasma NfL, hippocampal volume, and temporal-metaROI cortical thickness between different plasma A/T profiles and explored their relations with each other using general linear models, including age, sex, APOE-ε4, and diagnosis as covariates.

Results: Plasma A+/T + individuals showed the highest levels of astrocyte reactivity, Aβ plaque, tau tangle, and axonal degeneration, and the lowest hippocampal volume and temporal-metaROI cortical thickness. Lower plasma Aβ₄₂/Aβ₄₀ and higher plasma p-Tau₁₈₁ were independently and synergistically correlated with higher plasma GFAP and Aβ plaque. Elevated plasma p-Tau₁₈₁ and GFAP concentrations were directly and interactively associated with more tau tangle formation. Regarding neurodegeneration, higher plasma p-Tau₁₈₁ and GFAP concentrations strongly correlated with more axonal degeneration, as measured by plasma NfL, and lower plasma Aβ₄₂/Aβ₄₀ and higher plasma p-Tau₁₈₁ were related to greater hippocampal atrophy. Higher plasma GFAP levels were associated with thinner cortical thickness and significantly interacted with lower plasma Aβ₄₂/Aβ₄₀ and higher plasma p-Tau₁₈₁ in predicting more temporal-metaROI cortical thinning. Voxel-wise imaging analysis confirmed these findings.

Discussion: This study provides a valuable reference for using plasma biomarkers to detect AD in the Chinese community population and offers novel insights into how astrocyte reactivity contributes to AD progression, highlighting the importance of targeting reactive astrogliosis to prevent AD.