LDH-related Metabolic Alterations in Alzheimer's Disease: Evidence from Clinical and Transcriptomic Analyses

Reduced brain energy metabolism is a key feature of Alzheimer's disease (AD); however, lactate dehydrogenase (LDH)-related metabolic changes in AD are not fully understood. This study aimed to evaluate serum LDH activity in patients with mild cognitive impairment (MCI) and AD. We used public transcriptomic datasets to explore the features of LDHA and LDHB across brain regions, cell types, and co-expression networks.

In a retrospective clinical cohort of 132 healthy controls (HC), 87 patients with MCI, and 103 patients with AD, we compared serum LDH activity after adjusting for major clinical covariates. Next, we used public transcriptomic datasets [AlzData, Agora, CELLxGENE, and genotype-tissue expression (GTEx)] to evaluate regional and cell-type-specific expression patterns of LDHA and LDHB. We also characterized LDH-associated functional networks using GTEx normal brain data for baseline co-expression analysis and AD-related weighted gene co-expression network analysis (WGCNA).

Clinical cohort analysis showed that serum LDH activity was significantly decreased in patients with MCI and AD. Serum LDH activity did not significantly correlate with mini-mental state examination (MMSE) or montreal cognitive assessment (MoCA) scores. Brain transcriptomic analysis revealed that LDHA expression was significantly downregulated in AD-related regions (entorhinal cortex, hippocampus, and temporal cortex), whereas LDHB showed a downward trend in several AD-related regions. Both genes were detectable across multiple brain cell types with relatively prominent expression in neurons. Functional analysis showed that, under normal conditions, LDHA-correlated genes were broadly involved in glycolysis, vesicle trafficking, autophagy, and proteostasis, whereas LDHB-correlated genes were highly concentrated in mitochondrial oxidative phosphorylation and the citric acid (TCA) cycle. AD-related WGCNA showed region-dependent organization of LDHA- and LDHB-containing modules, with repeated enrichment in synaptic vesicle-related processes, mitochondrial respiration, autophagy, and proteostasis-related pathways.

This study provides clinical and transcriptomic evidence of LDH-related metabolic alterations in patients with AD. Reduced serum LDH activity in MCI and AD, together with decreased LDHA/LDHB expression in AD-related brain regions and region-dependent LDH-associated co-expression networks, supports a potential link between LDH-related metabolism and mitochondrial energy metabolism, synaptic function, and proteostasis in AD. These findings should be interpreted as exploratory, and require validation through paired prospective and mechanistic studies.