Molecular signatures of brain glycolysis dysfunction in Alzheimer's disease

Aim

Impaired glucose metabolism, especially glycolytic arrest, is strongly associated with Alzheimer's disease (AD), but its systemic changes in the AD brain are not well defined.

Materials and Methods

Here, we performed an integrated analysis of AD brain transcriptomics, combined with cognitive scoring, tau pathology grading data, to reveal systemic alterations of 28 glycolysis-related genes.

Results

Most genes, including glucose-6-phosphate isomerase (GPI), phosphofructokinase, muscle type (PFKM) and lactate dehydrogenase A (LDHA), were downregulated and correlated with cognitive decline (Mini-Mental State Examination, Clinical Dementia Rating) and tau pathology severity (correlation analysis, p < 0.05). These genes exhibited robust diagnostic potential (receiver operating characteristic area under the curve = 0.679–0.803), highlighting their utility as early AD biomarkers. Notably, OVO-like zinc finger 2 (OVOL2), a transcriptional repressor of glycolysis, was upregulated in AD and positively associated with tau burden and the suppression of GPI, PFKM and LDHA. Functional studies demonstrated that OVOL2 knockdown restored glycolytic gene expression and attenuated tau pathology, suggesting that OVOL2 is a candidate upstream regulatory factor for AD metabolic disorders.

Conclusions

Taken together, glycolysis enzymes were systemically altered in AD progression, and OVOL2 may be a candidate upstream regulator, while GPI, PFKM and LDHA may be potential diagnostic and therapeutic targets.