Obesity-driven phosphatidylethanolamine dysregulation impairs neuroimmune crosstalk and accelerates Alzheimer's pathogenesis

Background: Midlife obesity is a major modifiable risk factor for Alzheimer’s disease (AD), yet the lipid-mediated mechanisms linking peripheral metabolic dysfunction to brain pathology remain poorly understood. In particular, how adipose-derived lipid perturbations influence immune and neuronal compartments in the brain has not been fully elucidated. Methods: We employed an integrative multi-omics approach combining quantitative lipidomics, single-nucleus RNA sequencing, proteomics, and high-resolution imaging to characterize the metabolic alterations associated with obesity in both peripheral and central tissues. Functional assessments were performed in AD mouse models to evaluate neuroimmune responses and behavioral outcomes. Statistical analyses were performed using appropriate univariate and multivariate methods, with multiple testing correction applied where applicable. Results: We identified elevated phosphatidylethanolamine (PE) abundance as a metabolic hallmark of obesity. Excess PE accumulation led to disrupted lipid homeostasis and ectopic lipid droplet deposition in the brain, resulting in functional exhaustion of T cells, impaired microglial identity and signaling, and enhanced amyloidogenic processing in excitatory neurons. These effects were linked by membrane remodeling as a unifying structural mechanism. Pharmacological targeting of PE homeostasis using the redox-active compound ebselen ameliorated lipid dysregulation, restored neuroimmune function, and improved cognitive performance in AD models. Conclusions: Our study reveals a critical role for PE in coordinating immune-neuronal crosstalk under metabolic stress. These findings suggest that lipid remodeling serves as a structural nexus linking obesity to AD progression, and support the potential of lipid-directed interventions as therapeutic strategies for metabolic-risk-associated neurodegeneration. Supplementary information: The online version contains supplementary material available at 10.1186/s13024-026-00943-3.