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

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.