The role of lactate in Alzheimer’s disease: from controversies to therapeutic opportunities

Alzheimer’s disease (AD) is increasingly recognized as a disorder of disrupted brain metabolism, yet the role of specific metabolic intermediates in disease pathogenesis remains incompletely defined. Lactate, long considered a byproduct of glycolysis, is now understood to function as both an energy substrate and signaling molecule that links neuronal activity, glial biology, and network function. In this review, we synthesize clinical, preclinical, and multi-omic evidence to reframe lactate as a dynamic regulator of AD pathophysiology. Emerging data demonstrate that lactate is differentially regulated across disease stages and cellular compartments, with early increases associated with amyloid pathology, reactive glia, and neuronal hyperexcitability. We highlight evidence that disease reactive microglia undergo glycolytic reprogramming and represent a major and spatially enriched source of lactate in the AD brain, challenging the traditional astrocyte-centric view of lactate metabolism. We further discuss how lactate participates in feed-forward mechanisms linking metabolism to inflammation, neuronal excitability, and protein aggregation, but also through epigenetic modifications such as lactylation. Importantly, we propose a context-dependent framework in which lactate exerts both beneficial and maladaptive effects on disease progression. While transient or well-regulated lactate supports synaptic function and cognitive processes, sustained or dysregulated elevations may contribute to neuroinflammation, network dysfunction, sleep loss, and disease progression. Finally, we evaluate the potential of lactate as both a biomarker and therapeutic target. Together, this perspective integrates metabolism, neuroinflammation, and systems-level dysfunction, positioning lactate as a key therapeutic target in AD.