<p>SERPINA3, a serine protease inhibitor, is strongly associated with neuroinflammation, a typical condition of AD. Its expression is linked to microglial and astrocytic markers, suggesting it plays a significant role in modulating neuroinflammatory responses. In this study, we examined the SERPINA3 expression levels, along with CHI3L1, in various brain regions of AD patients and non-demented healthy controls (NDHC). Nineteen microarray datasets were analyzed, with brain samples stratified by sex and age from areas including the prefrontal cortex, occipital lobe, and cerebellum. Results showed that SERPINA3 was significantly highly expressed in AD patients compared to NDHCs only in males. Sex-specific differences were observed only in NDHCs, where females had higher SERPINA3 levels than males. ROC analysis suggested that SERPINA3 could be a strong marker for distinguishing AD in males but not females. In NDHCs, SERPINA3 expression correlated more strongly with age than in AD patients. In brain regions, SERPINA3 expression in NDHC females was higher across multiple areas, while in AD patients, this difference was limited to the prefrontal cortex. The most significant differences between NDHC and AD patients were found in the occipital and prefrontal regions. Furthermore, we identified a potential nuclear localization for SERPINA3, supported by immunohistochemistry analysis from The Human Protein Atlas. Correlation with neuropathological traits, including Clinical Dementia Rating (CDR) and Braak Neurofibrillary Tangle Score, showed positive significant associations between SERPINA3 and CDR in AD patients. Performing a docking analysis, we revealed an interaction region between SERPINA3 and CHI3L1 proteins, suggesting a potential role in AD. Tissue transcriptomic deconvolution analysis indicated a significant overlap between SERPINA3 expression and microglial/astrocytic signatures, suggesting that SERPINA3 plays a key role in modulating neuroinflammation in AD.</p> Graphical Abstract <p><i>SERPINA3</i> was significantly overexpressed in male AD patients compared to NDHCs, while no such difference was observed in females. In NDHCs, sex-specific differences were evident, with females showing higher SERPINA3 levels than males. Regionally, NDHC females exhibited higher <i>SERPINA3</i> expression across multiple brain areas, whereas in AD patients, this elevation was restricted to the prefrontal cortex. <i>SERPINA3</i> expression in NDHCs was also found to correlate with astrocyte and microglia profiles. Structural analysis suggested a potential nuclear localization for <i>SERPINA3</i>, while docking analysis identified key interaction regions between SERPINA3 and CHI3L1 proteins, hinting at a functional relationship in AD. Furthermore, TTDA revealed a strong overlap between <i>SERPINA3</i> expression and microglial/astrocytic genes signatures, underscoring its pivotal role in modulating neuroinflammation in AD.</p> <p></p>