Neurotrophic regulation of lipid metabolism in Alzheimer's disease: Mechanisms and therapeutic implications

Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which lipid metabolic dysregulation is increasingly recognized as an important contributor to pathogenesis. Neurotrophic factors (NTFs), beyond their established roles in neuronal survival and synaptic plasticity, may also regulate lipid metabolism. Objective To summarize current evidence on lipid metabolic dysregulation in AD and evaluate the potential roles of major NTFs in regulating lipid homeostasis. Methods Experimental, clinical, and translational studies addressing lipid metabolism, neurotrophic signaling, and their interactions in AD were reviewed, focusing on cholesterol, sphingolipid, and fatty acid metabolism and on BDNF, NGF, GDNF, CNTF, and Nrn1. Results Disturbances in cholesterol transport, sphingolipid and fatty acid metabolism, and high-density lipoprotein function may promote AD pathology by affecting membrane organization, synaptic plasticity, oxidative stress, insulin signaling, and amyloid-β and tau metabolism. BDNF, NGF, GDNF, CNTF, and Nrn1 may influence lipid-related processes through pathways including PI3K/Akt, AMPK, MAPK, and STAT3. However, evidence strength varies substantially among NTFs, and many proposed interactions are supported mainly by cellular, animal, or non-AD models. Conclusions Neurotrophic signaling and lipid metabolism may form an interconnected regulatory network relevant to AD pathophysiology. This concept may support future biomarker and therapeutic research, but it should currently be regarded as a hypothesis-generating framework requiring direct validation in human AD and well-characterized AD models.