Alzheimer's disease (AD) is increasingly recognized as a disorder of dysregulated immunometabolism at the neurovascular-glia-neuron interface. Systemic metabolic stressors such as insulin resistance, dyslipidaemia, and obesity converge on brain innate immune cells to reprogram energy pathways and sustain maladaptive inflammation. In microglia, metabolic rewiring across glycolysis-oxidative phosphorylation balance, glutaminolysis, and lipid handling governs trained-immunity programs that dictate amyloid and tau clearance, synaptic maintenance, and neurotoxicity. These processes converge on druggable nodes including AMPK-mTOR signaling, HIF-1α, and tricarboxylic-acid intermediates. Neurovascular fuel delivery is likewise impaired: endothelial GLUT1 loss and mitochondrial stress at the blood-brain barrier accelerate amyloid accumulation and neuronal injury. Lipid metabolism bridges metabolism and inflammation, as APOE4-driven microglial lipid droplets link genetic risk to inflammatory phenotypes. NLRP3 integrates metabolic danger signals into chronic neuroinflammation. Translational momentum now builds around metabolic interventions particularly GLP-1 receptor agonists and SGLT2 inhibitors that modulate glial metabolism, systemic inflammation, and barrier integrity. Converging metabolomic, lipidomic, and extracellular-vesicle biomarkers enable tracking of these pathways in humans, defining an immunometabolic axis of AD and supporting precision-medicine strategies to reprogram metabolism for disease modification.
Bach et al. (2026) studied this question.