Abstract
Lactate, long regarded as a mere by-product of glycolysis, is increasingly recognized as a signaling metabolite and epigenetic regulator through protein lactylation. This lysine-specific post-translational modification functionally couples cellular metabolic states to gene regulatory programs and orchestrates cell type-specific functions across neurons, astrocytes, and microglia, thereby shaping synaptic plasticity, neuroinflammatory responses, and protein aggregation. Accumulating evidence implicates dysregulated lactylation in the pathogenesis of Alzheimer's disease (AD), where it modulates amyloid-β deposition, tau aggregation, and glial reactivity. In this Review, we summarize the enzymatic regulation of protein lactylation, delineate its context-dependent roles in distinct central nervous system cell types, and highlight its function as a metabolic-epigenetic-immune nexus in AD progression. We further discuss emerging therapeutic strategies targeting lactate metabolism and lactylation pathways, and outline critical knowledge gaps that must be addressed to translate these insights into innovative diagnostic and therapeutic approaches. By integrating metabolic reprogramming, epigenetic control, and cell-specific mechanisms, this Review positions lactylation as a compelling and emerging frontier in AD research.