Phosphatidylethanolamine-mediated metabolic membrane remodeling in obesity-associated Alzheimer's disease: mechanisms, neuroimmune crosstalk, and therapeutic potential.

Alzheimer's disease is increasingly recognized as a multifactorial neurodegenerative disorder characterized by complex interactions among metabolic dysfunction, chronic inflammation, mitochondrial impairment, and lipid dysregulation. Although the amyloid cascade hypothesis has long dominated Alzheimer's disease research, limited clinical success of amyloid-targeted therapies has highlighted the need for broader mechanistic frameworks integrating systemic metabolic and cellular dysfunction. Emerging evidence suggests that obesity-associated phospholipid remodeling, particularly dysregulation of phosphatidylethanolamine (PE), may critically influence neurodegenerative progression through alterations in membrane dynamics, mitochondrial homeostasis, autophagy, oxidative stress, and neuroimmune signaling. This review critically examines the molecular and cellular mechanisms underlying PE-mediated adipose-brain crosstalk in obesity-associated Alzheimer's disease, with emphasis on mitochondrial dysfunction, blood-brain barrier disruption, ferroptosis, membrane remodeling, and microglial activation. The review further discusses how altered PE metabolism may impair synaptic integrity, promote lipotoxicity, and enhance neuronal vulnerability under chronic metabolic stress. Current evidence, however, remains constrained by methodological heterogeneity, inconsistent lipidomic findings, and substantial reliance on experimental animal models, limiting translational interpretation. In addition, this review proposes the concept of a "metabolic membrane remodeling axis" as an integrative framework linking obesity-driven phospholipid dysregulation with neuroimmune and neurodegenerative progression. A deeper understanding of PE-driven neuroimmunometabolic dysfunction may facilitate biomarker discovery and support the development of lipid-targeted therapeutic strategies for obesity-associated Alzheimer's disease.