Sex-specific modulation of FOLR1 and its cycle enzyme genes in Alzheimer’s disease brain regions

Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive cognitive and functional decline. Its incidence increases significantly with age and is more prevalent in women than men. We investigated the folate receptor alpha (FOLR1) gene expression levels in the central nervous system (CNS) of AD and non-demented healthy control (NDHC) subjects. Our cohort included 3,946 samples: 2,391 NDHC and 1,555 AD patients, stratified by brain region, age, and sex. Interestingly, a significant increase in FOLR1 expression was observed only in females with AD compared to NDHC females. Furthermore, we found that FOLR1 expression was differentially increased in the prefrontal cortex (PFC) and diencephalon (DIE) only in AD females. Moreover, in females, genes involved in the folic acid (FA) cycle that drives DNA synthesis were significantly modulated. In contrast, in males, downregulation of TYMS effectively blocks the completion of the cycle, thereby preventing downstream DNA synthesis. Tissue Transcriptome Deconvolution (TTD) analysis revealed astrocytes and endothelial cells associated with FOLR1 expression in both AD males and females. Gene Ontology analysis supported these findings, showing enrichment in processes aligned with these cell types. Positive correlations between brain FOLR1 expression and markers for astrocytes (glial fibrillary acidic protein) and endothelial cells (CD31) provided further validation. Our findings suggest a potential role for sex-dependent FOLR1 expression and its association with specific brain regions and cellular processes in AD.