Fig. 1

Major metabolic alterations and regulatory factors in AD microglia revealed by immuno-metabolomics approaches. Microglia function and phenotype change dynamically as AD pathogenesis progresses, accompanied by significant metabolic alterations. Initially, these cells demonstrate metabolic flexibility, but as the disease becomes chronic, microglia gradually lose their adaptive capacity. This reliance on biased and fragmented metabolic pathways eventually leads to insufficient energy and material supply, resulting in functional impairment and accelerated disease progression. The first notable metabolic shift in AD microglia involves glucose metabolism, characterized by excessive glucose uptake and increased dependence on non-aerobic glycolysis via HIF-1α pathway. This change subsequently leads to the inhibition and breakdown of mitochondrial energy metabolism. Furthermore, prolonged exposure to Aβ plaques, neurofibrillary tangles (NFTs), and excessive cell debris dramatically alters overall lipid metabolism, resulting in the accumulation of lipid droplets (LDs). Microglia with excessive LD accumulation, known as lipid-droplet-accumulating microglia (LDAMs), exhibit significantly reduced phagocytic ability and enhanced inflammatory properties. Recent studies have highlighted the crucial roles of APOE and TREM2, both high-risk genes for AD, in mediating these metabolic transitions in microglia. These genes are increasingly recognized as key players in modulating microglial function and metabolism in the context of AD. The advent of multi-omics approaches has accelerated the identification of candidate substances involved in microglial function and metabolic regulation pathways. This comprehensive analysis provides a deeper understanding of the complex interplay between immune response and metabolism in AD microglia