The Microglial Lactate-Lactylation Axis as a Metabolic-Epigenetic Driver of Alzheimer's Disease.

The idea of amyloid-β (Aβ) plaques and tau neurofibrillary tangles has long been central to framing an understanding of Alzheimer disease (AD), but emerging and growing evidence now points to bioenergetic failure and metabolic-epigenetic crosstalk as central to AD progression. Hai et al. summarize animal and human biofluid and neuroimaging data to carve out the pathophysiology of AD in relation to the role of disrupted glucose metabolism, lactate build-up and protein lactylation in glucose metabolism, in their comprehensive review "Lactate, Lactylation and Alzheimer Disease". Building on Hai et al.'s key contributions, we offer a complementary perspective. The microglial lactate-lactylation axis may be remodeled across disease stages during chronic neuroinflammation, potentially serving compensatory functions early but shifting toward maladaptive, pro-inflammatory amplification at later stages. In light of emerging evidence for tau lactylation in human AD brain tissue, we propose a testable hypothesis of intercellular metabolic crosstalk: lactate exported from highly glycolytic microglia may alter local lactate availability and provide an additional substrate for neuronal tau lactylation. Although the causal contribution of lactate from distinct cellular sources remains to be established, this framework provides a useful lens for interpreting coupled metabolic and epigenetic mechanisms in AD. Our future efforts should focus particularly on glycolytic flux, lactate, epigenetic writers/erasers, therapeutic approaches, and non-pharmacological approaches to stage- and cell-specific lactylation profiling, biomarker development, and the incorporation of metabolic and epigenetic endpoints into interventional studies.