Astrocyte reactivity is associated with tau tangle load and cortical thinning in Alzheimer’s disease,Molecular Neurodegeneration

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Astrocyte reactivity is associated with tau tangle load and cortical thinning in Alzheimer’s disease
Molecular Neurodegeneration ( IF 14.9 ) Pub Date : 2024-07-30 , DOI: 10.1186/s13024-024-00750-8
Tengfei Guo _{1,

2} , Anqi Li ₁ , Pan Sun ₁ , Zhengbo He ₁ , Yue Cai ₁ , Guoyu Lan ₁ , Lin Liu ₁ , Jieyin Li ₁ , Jie Yang _{1,

3} , Yalin Zhu ₁ , Ruiyue Zhao ₄ , Xuhui Chen ₅ , Dai Shi ₆ , Zhen Liu ₁ , Qingyong Wang ₇ , Linsen Xu ₈ , Liemin Zhou ₆ , Pengcheng Ran ₉ , Xinlu Wang ₄ , Kun Sun ₁₀ , Jie Lu _{3,

11} , Ying Han _{1,

3,

12,

13,

14}

Affiliation

Institute of Biomedical Engineering, Shenzhen Bay Laboratory, No.5 Kelian Road, Shenzhen, 518132, China.
Institute of Biomedical Engineering, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
Department of Neurology, Xuanwu Hospital of Capital Medical University, #45 Changchun Street, Xicheng District, Beijing, 100053, China.
Department of Nuclear Medicine, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510120, China.
Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, 518000, China.
Neurology Medicine Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518000, China.
Department of Neurology, Shenzhen Guangming District People's Hospital, Shenzhen, 518107, China.
Department of Medical Imaging, Shenzhen Guangming District People's Hospital, Shenzhen, 518106, China.
Department of Nuclear Medicine, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, 510120, China.
Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518132, China.
Department of Radiology and Nuclear Medicine, Xuanwu Hospital, Capital Medical University, #45 Changchun Street, Xicheng District, Beijing, 100053, China.
School of Biomedical Engineering, Hainan University, Haikou, 570228, China.
Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, 100053, China.
National Clinical Research Center for Geriatric Diseases, Beijing, 100053, China.

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. 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. 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. 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.

更新日期：2024-07-31

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