Vascular dementia increases levels of methylenetetrahydrofolate reductase and cystathionine β-synthase in female patients and changes gene expression of acetylcholine and glutamate clathrin-sculpted transport vesicles.

Deficiencies in one-carbon (1C) metabolism are linked to the onset of vascular dementia (VaD). Our previous work using mouse models has demonstrated that reduced dietary intake of folic acid or genetic deficiencies in 1C metabolism result in worse outcomes using a model of VaD. This study aims to provide a detailed molecular portrait of 1C metabolism within the context of VaD, shedding light on potential molecular mechanisms. In cortical post-mortem tissue from female and male VaD patients and controls we measured the folate receptor (FR) and 1C enzymes including methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), choline acetyltransferase (ChAT), acetylcholinesterase (AChE), cystathionine β-synthase (CBS), with NeuN and DAPI as markers. Additionally, spatial transcriptomics was performed on 4 samples. VaD and gender impacted levels of FR. Both male and female VaD had increased levels of ChAT. Female VaD patients had higher levels of MTHFR and CBS when compared to males. Spatial transcriptomics revealed reduced expression of the glutamate and acetylcholine clathrin-sculpted transport vesicles and increase in glutamatergic neurons. VaD is a complex disease; the results of this study demonstrate that VaD impacts levels of 1C, as well as gene expression. Dietary supplementation with 1C may be beneficial for affected patients.