Lactate metabolism links reactive microglia, amyloid pathology, and Aβ dynamics

Alzheimer’s disease (AD) is increasingly recognized as a disorder of early immunometabolic dysfunction, yet how amyloid-β (Aβ) pathology reshapes brain metabolism and neuroinflammation remains poorly defined. Here, we demonstrate interstitial fluid (ISF) lactate levels progressively increase with amyloid plaque accumulation in APPswe/PSEN1dE9 (APP/PS1) mice, a model of cerebral amyloidosis. Stable isotope-resolved metabolomics revealed metabolic reprogramming in APP/PS1 mice, characterized by increased glycolysis at the expense of TCA cycle intermediates and neurotransmitter biosynthesis. Spatial interrogation of lactate production demonstrated lactate dehydrogenase A (Ldha), the enzyme required for lactate generation, is highly enriched in the peri-plaque microenvironment. Approximately 98% of cortical amyloid plaques were Ldha + , with Ldha preferentially localized to diffuse Aβ deposits rather than the dense core of amyloid plaques. Although most plaque-associated Ldha appeared extracellular, higher-resolution analyses demonstrated a pronounced enrichment of Ldha within peri-plaque microglia, identifying microglia as a key cellular source of plaque-associated lactate. Consistent with this, single-cell and single-nucleus transcriptomic analyses in both mouse and human brains identified microglia as the highest expressers of LDHA, with expression further increased in AD and enriched within specific microglial populations. Notably, LDHA was concentrated within a subset of glycolytic microglia (MG7) associated with cytokine production and innate immune signaling, which emerge early with amyloid pathology and decline with disease progression. Functionally, in vitro Aβ42 aggregation assays demonstrated that lactate alters Aβ aggregation kinetics and fibril stability. Critically, this immunometabolic signature was reversible; pharmacologic inhibition of lactate dehydrogenase (LDH) with stiripentol, an FDA-approved anti-seizure medication, reduced ISF Aβ levels by approximately 50% and selectively depleted peri-plaque microglia, including Cd68⁺ and Clec7a⁺ populations. Together, these data demonstrate that amyloid pathology drives early metabolic reprogramming in microglia that elevates brain lactate levels, sustains neuroinflammation, and modulates Aβ dynamics, identifying lactate metabolism as a tractable therapeutic target in presymptomatic Alzheimer’s disease.