Plasma ceramide mediates the association of peripheral T cells with Alzheimer's disease

Yunhong Sun; Lili Xia; Xiaofan Xu; Xinyu Wang; Jianhe Guo; Ruijie Cheng; Ning Yang; Lihui Shen; Nian Liu; Xiaoxing Mo; Liegang Liu

doi:10.1016/j.jare.2025.08.027

Plasma ceramide mediates the association of peripheral T cells with Alzheimer's disease

J Adv Res. 2025 Aug 18:S2090-1232(25)00642-3. doi: 10.1016/j.jare.2025.08.027. Online ahead of print.

Authors

Yunhong Sun¹, Lili Xia², Xiaofan Xu³, Xinyu Wang⁴, Jianhe Guo⁵, Ruijie Cheng⁶, Ning Yang⁷, Lihui Shen⁸, Nian Liu⁹, Xiaoxing Mo¹⁰, Liegang Liu¹¹

Affiliations

¹ Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: d202381831@hust.edu.cn.
² Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: d202181612@hust.edu.cn.
³ Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: xu_xiaofan@hust.edu.cn.
⁴ Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: xywang_@hust.edu.cn.
⁵ Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: m202275580@hust.edu.cn.
⁶ Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: d202381824@hust.edu.cn.
⁷ Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: d202482041@hust.edu.cn.
⁸ Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: d202482056@hust.edu.cn.
⁹ Prenatal Diagnostic Center, Genetic Lab, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: liunian118@aliyun.com.
¹⁰ Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: 2024520214@hust.edu.cn.
¹¹ Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: lgliu@mails.tjmu.edu.cn.

PMID: 40835004
DOI: 10.1016/j.jare.2025.08.027

Abstract

Introduction: Neuroinflammation involving peripheral immune cells, particularly T lymphocytes, has been implicated in Alzheimer's disease (AD) progression. Metabolic dysregulation in sphingolipid pathways may influence neuroinflammatory processes in AD pathogenesis. However, the specific roles of T cell subsets and their interactions with metabolic pathways in AD pathogenesis remain unclear.

Objectives: To determine the causal contributions of peripheral T cell subsets to AD risk and investigate whether blood metabolites mediate this association.

Methods: We integrated single-cell RNA sequencing with flow cytometry to identify dynamic alterations in T cell subsets during AD progression. Adoptive transfer experiments in APP/PS1 mice validated the functional roles of specific T cell populations. Two-sample Mendelian randomization (MR) evaluated causal relationships between T cell traits and AD risk, while two-step MR assessed the mediating role of blood metabolites.

Results: CD4 effector memory (EM) and CD8 central memory (CM) T cells expanded in AD patients, particularly during mild cognitive impairment. Adoptive transfer of either CD4 EM or CD8 CM T cells into APP/PS1 mice exacerbated cognitive deficits and amyloid-β pathology. MR revealed causal associations of CM CD8br % T cell (OR = 1.22, 95 % CI: 1.07-1.39, P = 0.002) and EM CD4+ % CD4+ (OR = 1.09, 95 % CI: 1.01-1.18, P = 0.027) with AD risk. Elevated plasma ceramide levels were also causally associated with increased AD risk (OR = 1.34, 95 % CI: 1.10-1.64, P = 0.004), with CD4 EM influencing ceramide levels (OR = 1.03, 95 % CI: 1.01-1.06, P = 0.020). Ceramide mediated 11.20 % of the effect between CD4 EM and AD pathogenesis.

Conclusion: This study identifies CD4 EM and CD8 CM T cells as key drivers of AD-related neuroinflammation and uncovers a possible immunometabolic pathway linking CD4 EM, ceramide metabolism, and AD risk, suggesting potential targets for early diagnosis and therapeutic intervention.

Keywords: Alzheimer’s disease; CD4 effector memory T cells; CD8 central memory T cells; Ceramide; Mendelian randomization; Mild cognitive impairment.