Roles of glycolytic and pyruvate metabolism enzymes in Alzheimer’s disease glycometabolic reprogramming and their therapeutic potential

Abstract

Alzheimer’s disease (AD) is characterized by cerebral glucose hypome-tabolism, an early hallmark through neuroimaging and neuropathological investigations. Previous researches have established the phenomenon of reduced glucose uptake. Building upon this established knowledge, the field is now increasingly focused on elucidating the underlying molecular mecha-nisms that govern these metabolic changes. In this review, we synthesize current evidence regarding the dysregulation of major glycolytic and pyruvate-metabolizing enzymes, including hexokinase (HK), phosphofructokinase-1 (PFK1), pyruvate kinase (PK), lactate dehydrogenase (LDH), and the pyruvate dehydrogenase complex (PDHc), in both neurons and glial cells. As well as compromising cerebral energy homeostasis, these enzymatic disruptions engage in bidirectional feedback mechanisms with neuroinflammatory pathways and amyloid-β/Tau pathology. By consolidating recent mechanism research, this review offers a potential framework for understanding how metabolic enzyme dysregulation contributes to AD pathogenesis at a molecular level. Emerging therapeutic strategies targeting these metabolic enzymes are also discussed, along with an evaluation of both their preclinical promise and the translational challenges that remain.