BackgroundIt is not fully established whether plasma beta-amyloid(A beta)42/A beta 40 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, A beta plaque deposition, tau tangle aggregation, and neurodegeneration.MethodsWe recruited 470 older adults and analyzed plasma A beta 42/A beta 40, 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, A beta and tau positron emission tomography imaging. The plasma A beta 42/A beta 40 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 A beta-PET negative cognitively unimpaired individuals and A beta-PET positive cognitively impaired patients. To evaluate the feasibility of using plasma A beta 42/A beta 40 (A) and p-Tau181 (T) to detect AD and understand how astrocyte reactivity affects this process, we compared plasma GFAP, A beta 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-epsilon 4, and diagnosis as covariates.ResultsPlasma A+/T + individuals showed the highest levels of astrocyte reactivity, A beta plaque, tau tangle, and axonal degeneration, and the lowest hippocampal volume and temporal-metaROI cortical thickness. Lower plasma A beta 42/A beta 40 and higher plasma p-Tau181 were independently and synergistically correlated with higher plasma GFAP and A beta 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 A beta 42/A beta 40 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 A beta 42/A beta 40 and higher plasma p-Tau181 in predicting more temporal-metaROI cortical thinning. Voxel-wise imaging analysis confirmed these findings.DiscussionThis 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.